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Sample records for ca3b interneurons reveals

  1. Synthesis & photoluminescence study of UV emitting borate phosphor Ca3B2O6:Pb2+

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    Gawande, A. B.; Sonekar, R. P.; Omanwar, S. K.

    2013-06-01

    The powder sample of Ca3B2O6:Pb2+ has been prepared by a novel method which is slight variation of solution Combustion Synthesis. The synthesis is based on the exothermic reaction between the fuel (Urea) and Oxidizer (Ammonium nitrate). The structure of Ca3B2O6:Pb2+ has been confirmed by comparing the powder XRD pattern of the samples with the standard ICDD data files. The photoluminescent properties of Ca3B2O6:Pb2+ materials were investigated using F-7000 FL spectrophotometer at room temperature. The emission and excitation bands of Ca3B2O6:Pb2+ were observed at 335 and 270 nm, respectively. The Stoke shifts of phosphors Ca3B2O6:Pb2+ were calculated to be 7186 cm-1. The dependence of the emission intensity on the Pb2+ concentration was studied in detail. It has observed that, the phosphor Ca3B2O6:Pb2+ exhibits optimum emission intensity for 0.5 % concentration of Pb2+.

  2. Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

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    Yan-Feng Zhang

    2017-10-01

    Full Text Available Striatal cholinergic interneurons, the so-called tonically active neurons (TANs, pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.

  3. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

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    Matamales, Miriam; Götz, Jürgen; Bertran-Gonzalez, Jesus

    2016-01-01

    Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs) have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17%) aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the striatum.

  4. Quantitative Imaging of Cholinergic Interneurons Reveals a Distinctive Spatial Organization and a Functional Gradient across the Mouse Striatum.

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    Miriam Matamales

    Full Text Available Information processing in the striatum requires the postsynaptic integration of glutamatergic and dopaminergic signals, which are then relayed to the output nuclei of the basal ganglia to influence behavior. Although cellularly homogeneous in appearance, the striatum contains several rare interneuron populations which tightly modulate striatal function. Of these, cholinergic interneurons (CINs have been recently shown to play a critical role in the control of reward-related learning; however how the striatal cholinergic network is functionally organized at the mesoscopic level and the way this organization influences striatal function remains poorly understood. Here, we systematically mapped and digitally reconstructed the entire ensemble of CINs in the mouse striatum and quantitatively assessed differences in densities, spatial arrangement and neuropil content across striatal functional territories. This approach demonstrated that the rostral portion of the striatum contained a higher concentration of CINs than the caudal striatum and that the cholinergic content in the core of the ventral striatum was significantly lower than in the rest of the regions. Additionally, statistical comparison of spatial point patterns in the striatal cholinergic ensemble revealed that only a minor portion of CINs (17% aggregated into cluster and that they were predominantly organized in a random fashion. Furthermore, we used a fluorescence reporter to estimate the activity of over two thousand CINs in naïve mice and found that there was a decreasing gradient of CIN overall function along the dorsomedial-to-ventrolateral axis, which appeared to be independent of their propensity to aggregate within the striatum. Altogether this work suggests that the regulation of striatal function by acetylcholine across the striatum is highly heterogeneous, and that signals originating in external afferent systems may be principally determining the function of CINs in the

  5. Extended Interneuronal Network of the Dentate Gyrus

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    Gergely G. Szabo

    2017-08-01

    Full Text Available Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

  6. A novel orange-red phosphor Ca3B2O6:Sm3+, A+(A = Li, Na, K) for white light emitting diodes

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    Liu, Qingbo; Liu, Yufeng; Yang, Fu; Han, Bing; Feng, Hao; Yu, Quanmao

    2014-03-01

    A novel orange-red phosphor Ca3B2O6:Sm3+, A+(A = Li, Na, K) has been synthesized by solid-state reaction at 950°C. The phase purity and photoluminescence (PL) behavior of the phosphor are studied in detail using the powder X-ray diffraction (XRD) technique and PL measurements. Ca3B2O6:Sm3+ phosphor can be efficiently excited by near ultraviolet (n-UV) and blue light, and the emission spectrum consists of four emission peaks at 563, 599, 646 and 709 nm, generating bright orange-red light. When a cation A+ is introduced into Ca3B2O6:Sm3+ as charge compensator, the emission intensity of Ca3B2O6:Sm3+ is evidently enhanced, but the PL spectral profile is unchanged. The integral intensity of the emission spectrum of Ca2.96Sm0.02Na0.02B2O6 excited at 401 nm is about 1.2 times than that of Y2O2S:Eu3+ commercial red phosphor. The CIE chromaticity coordinates of Ca2.96Sm0.02Na0.02B2O6 phosphor were (0.608, 0.365), which are close to that of the commercial red phosphors Y2O3:Eu3+ (0.655, 0.345), Y2O2S:Eu3+ (0.622, 0.351) and Sr2Si5N8:Eu2+ (0.620, 0.370).

  7. Postnatal Migration of Cerebellar Interneurons

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    Ludovic Galas

    2017-06-01

    Full Text Available Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer. During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase-activating polypeptide (PACAP, somatostatin or proteins (tissue-type plasminogen activator (tPA, insulin growth factor-1 (IGF-1 have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants, nutrients or drug of abuse (alcohol also alter normal cell migration, leading to cerebellar disorders.

  8. Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons

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    Giorgia Bartolini

    2017-01-01

    Full Text Available Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3 as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

  9. Diversity and overlap of Parvalbumin and Somatostatin expressing interneurons in mouse presubiculum

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    Mérie eNassar

    2015-05-01

    Full Text Available The presubiculum, located between hippocampus and entorhinal cortex, plays a fundamental role in representing spatial information, notably head direction. Little is known about GABAergic interneurons of this region. Here, we used three transgenic mouse lines, Pvalb-Cre, Sst-Cre and X98, to examine distinct interneurons labeled with tdTomato or green fluorescent protein. The distribution of interneurons in presubicular lamina for each animal line was compared to that in the GAD67-GFP knock-in animal line. Labelling was specific in the Pvalb-Cre line with 87% of labeled interneurons immunopositive for (PV. Immunostaining for somatostatin (SOM revealed good specificity in the X98 line with 89% of fluorescent cells, but a lesser specificity in Sst-Cre animals where only 71% of labeled cells were immunopositive. A minority of ~ 6% of interneurons co-expressed PV and SOM in the presubiculum of Sst-Cre animals. The electrophysiological and morphological properties of fluorescent interneurons from Pvalb-Cre, Sst-Cre and X98 mice differed. Distinct physiological groups of presubicular interneurons were resolved by unsupervised cluster analysis of parameters describing passive properties, firing patterns and AP shapes. One group consisted of SOM-positive, Martinotti type neurons with a low firing threshold (cluster 1. Fast spiking basket cells, mainly from the Pvalb-Cre line, formed a distinct group (cluster 3. Another group (cluster 2 contained interneurons of intermediate electrical properties and basket-cell like morphologies. These labeled neurons were recorded from both Sst-Cre and Pvalb-Cre animals. Thus, our results reveal a wide variation in anatomical and physiological properties for these interneurons, a real overlap of interneurons immuno-positive for both PV and SOM as well as an off-target recombination in the Sst-Cre line, possibly linked to maternal cre inheritance.

  10. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice

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    Witts, Emily C.; Nascimento, Filipe

    2015-01-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925–1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output. PMID:26311185

  11. Disrupted Co-activation of Interneurons and Hippocampal Network after Focal Kainate Lesion

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    Lim-Anna Sieu

    2017-11-01

    Full Text Available GABAergic interneurons are known to control activity balance in physiological conditions and to coordinate hippocampal networks during cognitive tasks. In temporal lobe epilepsy interneuron loss and consecutive network imbalance could favor pathological hypersynchronous epileptic discharges. We tested this hypothesis in mice by in vivo unilateral epileptogenic hippocampal kainate lesion followed by in vitro recording of extracellular potentials and patch-clamp from GFP-expressing interneurons in CA3, in an optimized recording chamber. Slices from lesioned mice displayed, in addition to control synchronous events, larger epileptiform discharges. Despite some ipsi/contralateral and layer variation, interneuron density tended to decrease, average soma size to increase. Their membrane resistance decreased, capacitance increased and contralateral interneuron required higher current intensity to fire action potentials. Examination of synchronous discharges of control and larger amplitudes, revealed that interneurons were biased to fire predominantly with the largest population discharges. Altogether, these observations suggest that the overall effect of reactive cell loss, hypertrophy and reduced contralateral excitability corresponds to interneuron activity tuning to fire with larger population discharges. Such cellular and network mechanisms may contribute to a runaway path toward epilepsy.

  12. Interneuron progenitor transplantation to treat CNS dysfunction

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    Muhammad O Chohan

    2016-08-01

    Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

  13. Single dendrite-targeting interneurons generate branch-specific inhibition.

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    Caleb eStokes

    2014-11-01

    Full Text Available Microcircuits composed of dendrite-targeting inhibitory interneurons and pyramidal cells are fundamental elements of cortical networks, however, the impact of individual interneurons on pyramidal dendrites is unclear. Here, we combine paired recordings and calcium imaging to determine the spatial domain over which single dendrite-targeting interneurons influence pyramidal cells in olfactory cortex. We show that a major action of individual interneurons is to inhibit dendrites in a branch-specific fashion.

  14. Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations.

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    Vucurovic, Ksenija; Gallopin, Thierry; Ferezou, Isabelle; Rancillac, Armelle; Chameau, Pascal; van Hooft, Johannes A; Geoffroy, Hélène; Monyer, Hannah; Rossier, Jean; Vitalis, Tania

    2010-10-01

    To identify neocortical neurons expressing the type 3 serotonergic receptor, here we used transgenic mice expressing the enhanced green fluorescent protein (GFP) under the control of the 5-HT(3A) promoter (5-HT(3A):GFP mice). By means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reversed-transcriptase polymerase chain reaction on acute brain slices of 5-HT(3A):GFP mice, we identified 2 populations of 5-HT(3A)-expressing interneurons within the somatosensory cortex. The first population was characterized by the frequent expression of the vasoactive intestinal peptide and a typical bipolar/bitufted morphology, whereas the second population expressed predominantly the neuropeptide Y and exhibited more complex dendritic arborizations. Most interneurons of this second group appeared very similar to neurogliaform cells according to their electrophysiological, molecular, and morphological properties. The combination of 5-bromo-2-deoxyuridine injections with 5-HT(3A) mRNA detection showed that cortical 5-HT(3A) interneurons are generated around embryonic day 14.5. Although at this stage the 5-HT(3A) receptor subunit is expressed in both the caudal ganglionic eminence and the entopeduncular area, homochronic in utero grafts experiments revealed that cortical 5-HT(3A) interneurons are mainly generated in the caudal ganglionic eminence. This protracted expression of the 5-HT(3A) subunit allowed us to study specific cortical interneuron populations from their birth to their final functional phenotype.

  15. Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior

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    O'Hare, Justin K; Li, Haofang; Kim, Namsoo; Gaidis, Erin; Ade, Kristen; Beck, Jeff; Yin, Henry

    2017-01-01

    Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast-spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior. PMID:28871960

  16. Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

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    Ramkumar Kuruba

    Full Text Available Acute seizure (AS activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE. Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY or the calcium binding protein parvalbumin (PV between young adult (5-months old and aged (22-months old F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

  17. Serotonin receptor 3A controls interneuron migration into the neocortex.

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    Murthy, Sahana; Niquille, Mathieu; Hurni, Nicolas; Limoni, Greta; Frazer, Sarah; Chameau, Pascal; van Hooft, Johannes A; Vitalis, Tania; Dayer, Alexandre

    2014-11-20

    Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic serotonin receptor 3A (5-HT(3A)R) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT(3A)R activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT(3A)R is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN.

  18. A NOVEL FUNCTIONALLY DISTINCT SUBTYPE OF STRIATAL NPY INTERNEURON

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    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M.

    2011-01-01

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic green fluorescent protein (GFP)-NPY reporter mice. In vitro whole cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, non-accommodating spiking in response to depolarizing current injections and an absence of plateau depolarizations or low threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense compact and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Further, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPN) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABAA receptor-mediated inhibitory postsynaptic current (IPSC) that has not been previously described in striatum, but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the

  19. Presynaptic miniature GABAergic currents in developing interneurons.

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    Trigo, Federico F; Bouhours, Brice; Rostaing, Philippe; Papageorgiou, George; Corrie, John E T; Triller, Antoine; Ogden, David; Marty, Alain

    2010-04-29

    Miniature synaptic currents have long been known to represent random transmitter release under resting conditions, but much remains to be learned about their nature and function in central synapses. In this work, we describe a new class of miniature currents ("preminis") that arise by the autocrine activation of axonal receptors following random vesicular release. Preminis are prominent in gabaergic synapses made by cerebellar interneurons during the development of the molecular layer. Unlike ordinary miniature postsynaptic currents in the same cells, premini frequencies are strongly enhanced by subthreshold depolarization, suggesting that the membrane depolarization they produce belongs to a feedback loop regulating neurotransmitter release. Thus, preminis could guide the formation of the interneuron network by enhancing neurotransmitter release at recently formed synaptic contacts. Copyright 2010 Elsevier Inc. All rights reserved.

  20. Accumbens nNOS Interneurons Regulate Cocaine Relapse.

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    Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A; Gipson, Cassandra D; Neuhofer, Daniela; Roberts-Wolfe, Doug J; Spencer, Sade; Garcia-Keller, Constanza; Stankeviciute, Neringa M; Smith, Rachel J; Allen, Nicholas P; Lorang, Melissa R; Griffin, William C; Boger, Heather A; Kalivas, Peter W

    2017-01-25

    Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction. Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus

  1. Slow excitatory synaptic potentials evoked by distension in myenteric descending interneurones of guinea-pig ileum

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    Thornton, P D J; Bornstein, J C

    2002-01-01

    The functional significance of the slow excitatory synaptic potentials (EPSPs) in myenteric neurones is unknown. We investigated this using intracellular recording from myenteric neurones in guinea-pig ileum, in vitro. In all, 121 neurones responded with fast EPSPs to distension of the intestine oral to the recording site. In 28 of these neurones, distension also evoked depolarizations similar to the slow EPSPs evoked by electrical stimulation in the same neurones. Intracellular injection of biocytin and immunohistochemistry revealed that neurones responding to distension with slow EPSPs were descending interneurones, which were immunoreactive for nitric oxide synthase (NOS). Other neurones, including inhibitory motor neurones and interneurones lacking NOS, did not respond to distension with slow EPSPs, but many had slow EPSPs evoked electrically. Slow EPSPs evoked electrically or by distension in NOS-immunoreactive descending interneurones were resistant to blockade of NK1 or NK3 tachykinin receptors (SR 140333, 100 nm; SR 142801, 100 nm, respectively) and group I metabotropic glutamate receptors (PHCCC, 10–30 μm), when the antagonists were applied in the recording chamber of a two-chambered organ bath. However, slow EPSPs evoked electrically in inhibitory motor neurones were substantially depressed by SR 140333 (100 nm). Blockade of synaptic transmission in the stimulation chamber of the organ bath abolished slow EPSPs evoked by distension, indicating that they arose from activity in interneurones, and not from anally directed, intrinsic sensory neurones. Thus, distension evokes slow EPSPs in a subset of myenteric neurones, which may be important for intestinal motility. PMID:11882690

  2. Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism

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    Cecilia Tubert

    2016-09-01

    Full Text Available The mechanism underlying a hypercholinergic state in Parkinson’s disease (PD remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.

  3. Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties

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    Casale, Amanda E.; Foust, Amanda J.; Bal, Thierry

    2015-01-01

    The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast-spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin-expressing interneurons also depend on BK Ca2+-activated K+ channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons

  4. Classification of neocortical interneurons using affinity propagation

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    Roberto eSantana

    2013-12-01

    Full Text Available In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. Neuronal classification has been a difficult problem because it is unclear what a neuronal cell class actually is and what are the best characteristics are to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological or molecular characteristics, when applied to selected datasets, have provided quantitative and unbiased identification of distinct neuronal subtypes. However, better and more robust classification methods are needed for increasingly complex and larger datasets. We explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. In fact, using a combined anatomical/physiological dataset, our algorithm differentiated parvalbumin from somatostatin interneurons in 49 out of 50 cases. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits.

  5. Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

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    Jacob, John

    2016-02-01

    Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to

  6. Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.

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    Yaisa Andrews-Zwilling

    Full Text Available Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD, the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear.We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD.

  7. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

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    E. Rossignol

    2011-01-01

    Full Text Available A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.

  8. Do premotor interneurons act in parallel on spinal motoneurons and on dorsal horn spinocerebellar and spinocervical tract neurons in the cat?

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    Krutki, Piotr; Jelen, Sabina

    2011-01-01

    It has previously been established that ventral spinocerebellar tract (VSCT) neurons and dorsal spinocerebellar tract neurons located in Clarke's column (CC DSCT neurons) forward information on actions of premotor interneurons in reflex pathways from muscle afferents on α-motoneurons. Whether DSCT neurons located in the dorsal horn (dh DSCT neurons) and spinocervical tract (SCT) neurons are involved in forwarding similar feedback information has not yet been investigated. The aim of the present study was therefore to examine the input from premotor interneurons to these neurons. Electrical stimuli were applied within major hindlimb motor nuclei to activate axon-collaterals of interneurons projecting to these nuclei, and intracellular records were obtained from dh DSCT and SCT neurons. Direct actions of the stimulated interneurons were differentiated from indirect actions by latencies of postsynaptic potentials evoked by intraspinal stimuli and by the absence or presence of temporal facilitation. Direct actions of premotor interneurons were found in a smaller proportion of dh DSCT than of CC DSCT neurons. However, they were evoked by both excitatory and inhibitory interneurons, whereas only inhibitory premotor interneurons were previously found to affect CC DSCT neurons [as indicated by monosynaptic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) in dh DSCT and only IPSPs in CC DSCT neurons]. No effects of premotor interneurons were found in SCT neurons, since monosynaptic EPSPs or IPSPs were only evoked in them by stimuli applied outside motor nuclei. The study thus reveals a considerable differentiation of feedback information provided by different populations of ascending tract neurons. PMID:21273308

  9. The interesting interplay between interneurons and adult hippocampal neurogenesis

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    Masiulis, Irene; Yun, Sanghee; Eisch, Amelia J.

    2013-01-01

    Adult neurogenesis is a unique form of plasticity found in the hippocampus, a brain region key to learning and memory formation. While many external stimuli are known to modulate the generation of new neurons in the hippocampus, little is known about the local circuitry mechanisms that regulate the process of adult neurogenesis. The neurogenic niche in the hippocampus is highly complex and consists of a heterogeneous population of cells including interneurons. Because interneurons are already highly integrated into the hippocampal circuitry, they are in a prime position to influence the proliferation, survival, and maturation of adult-generated cells in the dentate gyrus. Here we review the current state of our understanding on the interplay between interneurons and adult hippocampal neurogenesis. We focus on activity- and signaling-dependent mechanisms, as well as research on human diseases that could provide better insight into how interneurons in general might add to our comprehension of the regulation and function of adult hippocampal neurogenesis. PMID:21956642

  10. Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate

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    Timothy J. Petros

    2015-11-01

    Full Text Available Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

  11. Cryptic organisation within an apparently irregular rostrocaudal distribution of interneurons in the embryonic zebrafish spinal cord

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    Wells, Simon, E-mail: simon.wells@adelaide.edu.au [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); The Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 (Australia); Conran, John G., E-mail: john.conran@adelaide.edu.au [Ecology and Evolutionary Biology, School of Earth and Environmental Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Tamme, Richard, E-mail: rtamme@ttu.ee [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Gaudin, Arnaud, E-mail: a.gaudin@uq.edu.au [School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072 (Australia); Webb, Jonathan, E-mail: jonathan.webb@worc.ox.ac.uk [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); Lardelli, Michael, E-mail: michael.lardelli@adelaide.edu.au [Discipline of Genetics, School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005 (Australia); The Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005 (Australia)

    2010-11-15

    The molecules and mechanisms involved in patterning the dorsoventral axis of the developing vertebrate spinal cord have been investigated extensively and many are well known. Conversely, knowledge of mechanisms patterning cellular distributions along the rostrocaudal axis is relatively more restricted. Much is known about the rostrocaudal distribution of motoneurons and spinal cord cells derived from neural crest but there is little known about the rostrocaudal patterning of most of the other spinal cord neurons. Here we report data from our analyses of the distribution of dorsal longitudinal ascending (DoLA) interneurons in the developing zebrafish spinal cord. We show that, although apparently distributed irregularly, these cells have cryptic organisation. We present a novel cell-labelling technique that reveals that DoLA interneurons migrate rostrally along the dorsal longitudinal fasciculus of the spinal cord during development. This cell-labelling strategy may be useful for in vivo analysis of factors controlling neuron migration in the central nervous system. Additionally, we show that DoLA interneurons persist in the developing spinal cord for longer than previously reported. These findings illustrate the need to investigate factors and mechanisms that determine 'irregular' patterns of cell distribution, particularly in the central nervous system but also in other tissues of developing embryos.

  12. Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration.

    Science.gov (United States)

    Xiang, Yangfei; Tanaka, Yoshiaki; Patterson, Benjamin; Kang, Young-Jin; Govindaiah, Gubbi; Roselaar, Naomi; Cakir, Bilal; Kim, Kun-Yong; Lombroso, Adam P; Hwang, Sung-Min; Zhong, Mei; Stanley, Edouard G; Elefanty, Andrew G; Naegele, Janice R; Lee, Sang-Hun; Weissman, Sherman M; Park, In-Hyun

    2017-09-07

    Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Striatal cholinergic interneuron regulation and circuit effects

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    Sean Austin Lim

    2014-10-01

    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  14. Classification of neocortical interneurons using affinity propagation

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    Santana, Roberto; McGarry, Laura M.; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

    2013-01-01

    In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID:24348339

  15. Fast-spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward.

    Science.gov (United States)

    Lansink, Carien S; Goltstein, Pieter M; Lankelma, Jan V; Pennartz, Cyriel M A

    2010-08-01

    Although previous in vitro studies revealed inhibitory synaptic connections of fast-spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast-spiking neurons were distinguished from putative medium-sized spiny neurons on the basis of their spike waveforms and rates. Cross-correlograms of fast-spiking and putative medium-sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium-sized spiny neuron spiking around fast-spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast-spiking unit firing. Many of these temporal relationships were dependent on the sleep-wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast-spiking units and putative medium-sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast-spiking neurons in a reward-searching task, they generally showed a pre-reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed-forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast-spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward-related changes in firing rate.

  16. Wnt5a Controls Neurite Development in Olfactory Bulb Interneurons

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    Darya Pino

    2011-05-01

    Full Text Available Neurons born in the postnatal SVZ (subventricular zone must migrate a great distance before becoming mature interneurons of the OB (olfactory bulb. During migration immature OB neurons maintain an immature morphology until they reach their destination. While the morphological development of these cells must be tightly regulated, the cellular pathways responsible are still largely unknown. Our results show that the non-canonical Wnt pathway induced by Wnt5a is important for the morphological development of OB interneurons both in vitro and in vivo. Additionally, we demonstrate that non-canonical Wnt signalling works in opposition to canonical Wnt signalling in neural precursors from the SVZ in vitro. This represents a novel role for Wnt5a in the development of OB interneurons and suggests that canonical and non-canonical Wnt pathways dynamically oppose each other in the regulation of dendrite maturation.

  17. Glycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration

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    Ariel Avila

    2013-08-01

    Full Text Available Glycine receptors (GlyRs are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.

  18. Co-expression of VAL- and TMT-opsins uncovers ancient photosensory interneurons and motorneurons in the vertebrate brain.

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    Ruth M Fischer

    Full Text Available The functional principle of the vertebrate brain is often paralleled to a computer: information collected by dedicated devices is processed and integrated by interneuron circuits and leads to output. However, inter- and motorneurons present in today's vertebrate brains are thought to derive from neurons that combined sensory, integration, and motor function. Consistently, sensory inter-motorneurons have been found in the simple nerve nets of cnidarians, animals at the base of the evolutionary lineage. We show that light-sensory motorneurons and light-sensory interneurons are also present in the brains of vertebrates, challenging the paradigm that information processing and output circuitry in the central brain is shielded from direct environmental influences. We investigated two groups of nonvisual photopigments, VAL- and TMT-Opsins, in zebrafish and medaka fish; two teleost species from distinct habitats separated by over 300 million years of evolution. TMT-Opsin subclasses are specifically expressed not only in hypothalamic and thalamic deep brain photoreceptors, but also in interneurons and motorneurons with no known photoreceptive function, such as the typeXIV interneurons of the fish optic tectum. We further show that TMT-Opsins and Encephalopsin render neuronal cells light-sensitive. TMT-Opsins preferentially respond to blue light relative to rhodopsin, with subclass-specific response kinetics. We discovered that tmt-opsins co-express with val-opsins, known green light receptors, in distinct inter- and motorneurons. Finally, we show by electrophysiological recordings on isolated adult tectal slices that interneurons in the position of typeXIV neurons respond to light. Our work supports "sensory-inter-motorneurons" as ancient units for brain evolution. It also reveals that vertebrate inter- and motorneurons are endowed with an evolutionarily ancient, complex light-sensory ability that could be used to detect changes in ambient light spectra

  19. Local connections of layer 5 GABAergic interneurons to corticospinal neurons

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    Yasuyo H Tanaka

    2011-09-01

    Full Text Available In the local circuit of the cerebral cortex, GABAergic inhibitory interneurons are considered to work in collaboration with excitatory neurons. Although many interneuron subgroups have been described in the cortex, local inhibitory connections of each interneuron subgroup are only partially understood with respect to the functional neuron groups that receive these inhibitory connections. In the present study, we morphologically examined local inhibitory inputs to corticospinal neurons (CSNs in motor areas using transgenic rats in which GABAergic neurons expressed fluorescent protein Venus. By analysis of biocytin-filled axons obtained with whole-cell recording/staining in cortical slices, we classified fast-spiking (FS neurons in layer (L 5 into two types, FS1 and FS2, by their high and low densities of axonal arborization, respectively. We then investigated the connections of FS1, FS2, somatostatin-immunopositive (SOM and other (non-FS/non-SOM interneurons to CSNs that were retrogradely labeled in a Golgi-like manner in motor areas. When close appositions between the axon boutons of the intracellularly labeled interneurons and the somata/dendrites of the retrogradely labeled CSNs were examined electron-microscopically, 74% of these appositions made symmetric synaptic contacts. The axon boutons of single FS1 neurons were 2–4-fold more frequent in appositions to the somata/dendrites of CSNs than those of FS2, SOM and non-FS/non-SOM neurons. Axosomatic appositions were most frequently formed with axon boutons of FS1 and FS2 neurons (approximately 30% and least frequently formed with those of SOM neurons (7%. In contrast, SOM neurons most extensively sent axon boutons to the apical dendrites of CSNs. These results might suggest that motor outputs are controlled differentially by the subgroups of L5 GABAergic interneurons in cortical motor areas. 

  20. Regulation of retinal interneuron subtype identity by the Iroquois homeobox gene Irx6.

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    Star, Erin N; Zhu, Minyan; Shi, Zhiwei; Liu, Haiquan; Pashmforoush, Mohammad; Sauve, Yves; Bruneau, Benoit G; Chow, Robert L

    2012-12-01

    Interneuronal subtype diversity lies at the heart of the distinct molecular properties and synaptic connections that shape the formation of the neuronal circuits that are necessary for the complex spatial and temporal processing of sensory information. Here, we investigate the role of Irx6, a member of the Iroquois homeodomain transcription factor family, in regulating the development of retinal bipolar interneurons. Using a knock-in reporter approach, we show that, in the mouse retina, Irx6 is expressed in type 2 and 3a OFF bipolar interneurons and is required for the expression of cell type-specific markers in these cells, likely through direct transcriptional regulation. In Irx6 mutant mice, presumptive type 3a bipolar cells exhibit an expansion of their axonal projection domain to the entire OFF region of the inner plexiform layer, and adopt molecular features of both type 2 and 3a bipolar cells, highlighted by the ectopic upregulation of neurokinin 3 receptor (Nk3r) and Vsx1. These findings reveal Irx6 as a key regulator of type 3a bipolar cell identity that prevents these cells from adopting characteristic features of type 2 bipolar cells. Analysis of the Irx6;Vsx1 double null retina suggests that the terminal differentiation of type 2 bipolar cells is dependent on the combined expression of the transcription factors Irx6 and Vsx1, but also points to the existence of Irx6;Vsx1-independent mechanisms in regulating OFF bipolar subtype-specific gene expression. This work provides insight into the generation of neuronal subtypes by revealing a mechanism in which opposing, yet interdependent, transcription factors regulate subtype identity.

  1. Serotonin receptor 3A controls interneuron migration into the neocortex

    NARCIS (Netherlands)

    Murthy, S.; Niquille, M.; Hurni, N.; Limoni, G.; Frazer, S.; Chameau, P.; van Hooft, J.A.; Vitalis, T.; Dayer, A.

    2014-01-01

    Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic

  2. Subtype-specific reduction of olfactory bulb interneurons in Pax6 heterozygous mutant mice.

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    Haba, Hasumi; Nomura, Tadashi; Suto, Fumikazu; Osumi, Noriko

    2009-09-01

    Interneurons in the olfactory bulb (OB) play essential roles in the processing of olfactory information. They are classified into several subpopulations by the expression of different neurochemical markers. Here we focused on a transcription factor Pax6, and examined its expression and function in distinct subtypes of OB interneurons. We identified Pax6 expression in specific subtypes of interneurons in the external plexiform layer (EPL). The number of these interneuron subtypes was dramatically decreased in Pax6 heterozygous mutant mice. These results indicate that Pax6 is required for differentiation and/or maintenance of EPL interneurons in the adult mouse OB.

  3. Vibration-processing interneurons in the honeybee brain

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    Hiroyuki Ai

    2010-01-01

    Full Text Available The afferents of the Johnston’s organ (JO in the honeybee brain send their axons to three distinct areas, the dorsal lobe, the dorsal subesophageal ganglion (DL-dSEG, and the posterior protocerebral lobe (PPL, suggesting that vibratory signals detected by the JO are processed differentially in these primary sensory centers. The morphological and physiological characteristics of interneurons arborizing in these areas were studied by intracellular recording and staining. DL-Int-1 and DL-Int-2 have dense arborizations in the DL-dSEG and respond to vibratory stimulation applied to the JO in either tonic excitatory, on-off-phasic excitatory, or tonic inhibitory patterns. PPL-D-1 has dense arborizations in the PPL, sends axons into the ventral nerve cord (VNC, and responds to vibratory stimulation and olfactory stimulation simultaneously applied to the antennae in long-lasting excitatory pattern. These results show that there are at least two parallel pathways for vibration processing through the DL-dSEG and the PPL. In this study, Honeybee Standard Brain was used as the common reference, and the morphology of two types of interneurons (DL-Int-1 and DL-Int-2 and JO afferents was merged into the standard brain based on the boundary of several neuropiles, greatly supporting the understanding of the spatial relationship between these identified neurons and JO afferents. The visualization of the region where the JO afferents are closely appositioned to these DL interneurons demonstrated the difference in putative synaptic regions between the JO afferents and these DL interneurons (DL-Int-1 and DL-Int-2 in the DL. The neural circuits related to the vibration-processing interneurons are discussed.

  4. Anatomically heterogeneous populations of CB1 cannabinoid receptor-expressing interneurons in the CA3 region of the hippocampus show homogeneous input-output characteristics.

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    Szabó, Gergely G; Papp, Orsolya I; Máté, Zoltán; Szabó, Gábor; Hájos, Norbert

    2014-12-01

    A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells. © 2014 Wiley Periodicals

  5. Characterization of a novel subtype of hippocampal interneurons that express corticotropin-releasing hormone.

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    Hooper, Andrew; Maguire, Jamie

    2016-01-01

    A subset of corticotropin-releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV-Flex-ChR2-tdTomato reveal dense back-projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. © 2015 Wiley Periodicals, Inc.

  6. A Subtype of Inhibitory Interneuron with Intrinsic Persistent Activity in Human and Monkey Neocortex

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    Bo Wang

    2015-03-01

    Full Text Available A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na+ current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing.

  7. Atypical PKC and Notch Inhibition Differentially Modulate Cortical Interneuron Subclass Fate from Embryonic Stem Cells

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    David J. Tischfield

    2017-05-01

    Full Text Available Recent studies indicate that the location of neurogenesis within the medial ganglionic eminence (MGE critically influences the fate determination of cortical interneuron subgroups, with parvalbumin (Pv interneurons originating from subventricular zone divisions and somatostatin (Sst interneurons primarily arising from apical divisions. The aPKC-CBP and Notch signaling pathways regulate the transition from apical to basal progenitor and their differentiation into post-mitotic neurons. We find that aPKC inhibition enhances intermediate neurogenesis from stem cell-derived MGE progenitors, resulting in a markedly increased ratio of Pv- to Sst-expressing interneurons. Conversely, inhibition of Notch signaling enriches for Sst subtypes at the expense of Pv fates. These findings confirm that the mode of neurogenesis influences the fate of MGE-derived interneurons and provide a means of further enrichment for the generation of specific interneuron subgroups from pluripotent stem cells.

  8. Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex

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    Rongkang Deng

    2017-05-01

    Full Text Available GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (interneurons showed two spatial patterns of translaminar connection: inputs originating predominantly from supragranular or from supragranular and infragranular layers, including the subplate, which relays early thalamocortical activity. Sensory deprivation altered the development of translaminar inputs. Thus, distinct translaminar circuits to GABAergic interneurons exist throughout development, and the maturation of excitatory synapses is input-specific. Glutamatergic signaling from subplate and intracortical sources likely plays a role in the maturation of GABAergic interneurons.

  9. A pharmacological study of the inhibition of ventral group Ia-excited spinal interneurones.

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    Lodge, D; Curtis, D R; Brand, S J

    1977-08-08

    In cats anaesthetized with pentobarbitone a pharmacological investigation was made of the inhibition by volleys in afferent fibres and ventral roots of physiologically identified Ia interneurones in the ventral horn. The recurrent inhibition of Ia interneurones by Renshaw cells, and the "mutual" inhibition between Ia interneurones, were suppressed by electrophoretic strychnine and are presumably mediated by glycine. Short latency and duration inhibitions by impulses in muscle and cutaneous afferents were also suppressed by strychnine. Electrophoretic GABA inhibited the firing of Ia interneurones and the effects of bicuculline methochloride suggested that this amino acid mediates longer latency and duration inhibition produced by afferent impulses of muscle and cutaneous origin.

  10. Differential distribution and function of GABABRs in somato-dendritic and axonal compartments of principal cells and interneurons in cortical circuits.

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    Kulik, Ákos; Booker, Sam A; Vida, Imre

    2017-10-14

    GABABRs are highly expressed in cortical circuits, controlling neuronal excitability and synaptic transmission in both principal cells and inhibitory interneurons. Light and electron microscopic studies confirmed the wide distribution of receptors and revealed cell type-specific quantitative differences in their cellular and subcellular distributions. At the subcellular level, GABABRs are abundant at the peri- and extrasynaptic membrane of somato-dendritic compartments and to lower levels in the axon terminals of both cortical excitatory principal cells and inhibitory interneurons. Differences in the surface densities are particularly prominent between neurochemically-defined interneuron types. Whole-cell recordings further demonstrated that GABABRs differentially mediate post- and presynaptic inhibition in principal cells and various GABAergic interneurons by preferentially modulating postsynaptic G-protein-coupled inwardly rectifying K+ (Kir3) channels and presynaptic high voltage-activated Ca2+ (Cav) channels. These data convergently indicate that GABABRs not only control the overall level of neuronal excitability and activity, but can also fine tune the activation and interactions of excitatory and inhibitory neurons in cortical circuits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

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    Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

    2014-11-05

    Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

  12. Spatiotemporal alterations of cortical network activity by selective loss of NOS-expressing interneurons .

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    Dan eShlosberg

    2012-02-01

    Full Text Available Deciphering the role of GABAergic neurons in large neuronal networks such as the neocortex forms a particularly complex task as they comprise a highly diverse population. The neuronal isoform of the enzyme nitric oxide synthase (nNOS is expressed in the neocortex by specific subsets of GABAergic neurons. These neurons can be identified in live brain slices by the nitric oxide (NO fluorescent indicator DAF-2DA. However, this indicator was found to be highly toxic to the stained neurons. We used this feature to induce acute phototoxic damage to NO-producing neurons in cortical slices, and measured subsequent alterations in parameters of cellular and network activity.Neocortical slices were briefly incubated in DAF-2DA and then illuminated through the 4X objective. Histochemistry for NADPH diaphorase, a marker for nNOS activity, revealed elimination of staining in the illuminated areas following treatment. Whole cell recordings from several neuronal types before, during and after illumination confirmed the selective damage to non fast-spiking interneurons. Treated slices displayed mild disinhibition. The reversal potential of compound synaptic events on pyramidal neurons became more positive, and their decay time constant was elongated, substantiating the removal of an inhibitory conductance. The horizontal decay of local field potentials (LFPs was significantly reduced at distances of 300-400 m from the stimulation, but not when inhibition was non-selectively weakened with the GABAA blocker picrotoxin. Finally, whereas the depression of LFPs along short trains of 40 Hz stimuli was linearly reduced with distance or initial amplitude in control slices, this ordered relationship was disrupted in DAF-treated slices. These results reveal that NO-producing interneurons in the neocortex convey lateral inhibition to neighboring columns, and shape the spatiotemporal dynamics of the network's activity.

  13. Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty

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    Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2014-01-01

    Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features

  14. Cortical interneurons from human pluripotent stem cells: prospects for neurological and psychiatric disease

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    Charles Edward Arber

    2013-03-01

    Full Text Available Cortical interneurons represent 20% of the cells in the cortex. These cells are local inhibitory neurons whose function is to modulate the firing activities of the excitatory projection neurons. Cortical interneuron dysfunction is believed to lead to runaway excitation underlying (or implicated in seizure-based diseases, such as epilepsy, autism and schizophrenia. The complex development of this cell type and the intricacies involved in defining the relative subtypes are being increasingly well defined. This has led to exciting experimental cell therapy in model organisms, whereby fetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. On the other hand, cortical neurons generated from patient iPSCs serve as a valuable tool to explore genetic influences of interneuron development and function. This is a fundamental step in enhancing our understanding of the molecular basis of neuropsychiatric illnesses and the development of targeted treatments. Protocols are currently being developed for inducing cortical interneuron subtypes from mouse and human pluripotent stem cells. This review sets out to summarize the progress made in cortical interneuron development, fetal tissue transplantation and the recent advance in stem cell differentiation towards interneurons.

  15. Serotonin inhibits low-threshold spike interneurons in the striatum

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    Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

    2012-01-01

    Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μm) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments, XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an M type current. PMID:22495583

  16. Serotonin inhibits low-threshold spike interneurons in the striatum.

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    Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

    2012-05-15

    Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μM) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations.These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT(2C) receptor agonists and reversed by 5-HT(2C) antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments,XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons.We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT(2C) receptors and increasing an M type current.

  17. Molecular layer interneurons of the cerebellum: developmental and morphological aspects.

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    Sotelo, Constantino

    2015-10-01

    During the past 25 years, our knowledge on the development of basket and stellate cells (molecular layer interneurons [MLIs]) has completely changed, not only regarding their origin from the ventricular zone, corresponding to the primitive cerebellar neuroepithelium, instead of the external granular layer, but above all by providing an almost complete account of the genetic regulations (transcription factors and other genes) involved in their differentiation and synaptogenesis. Moreover, it has been shown that MLIs' precursors (dividing neuroblasts) and not young postmitotic neurons, as in other germinal neuroepithelia, leave the germinative zone and migrate all along a complex and lengthy path throughout the presumptive cerebellar white matter, which provides suitable niches exerting epigenetic influences on their ultimate neuronal identities. Recent studies carried out on the anatomical-functional properties of adult MLIs emphasize the importance of these interneurons in regulating PC inhibition, and point out the crucial role played by electrical synaptic transmission between MLIs as well as ephaptic interactions between them and Purkinje cells at the pinceaux level, in the regulation of this inhibition.

  18. Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

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    Radonjić, Nevena V; Jakovcevski, Igor; Bumbaširević, Vladimir; Petronijević, Nataša D

    2013-06-01

    Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.

  19. Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons.

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    Gard, Chris; Gonzalez Curto, Gloria; Frarma, Youcef El-Mokhtar; Chollet, Elodie; Duval, Nathalie; Auzié, Valentine; Auradé, Frédéric; Vigier, Lisa; Relaix, Frédéric; Pierani, Alessandra; Causeret, Frédéric; Ribes, Vanessa

    2017-06-16

    Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates. Copyright © 2017. Published by Elsevier Inc.

  20. Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation

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    Gaelle M Friocourt

    2011-12-01

    Full Text Available Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc12a5, Ets2, Phlda1, Zif268, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, Napb and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b and Slit2 in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.

  1. Parvalbumin fast-spiking interneurons are selectively altered by pediatric traumatic brain injury.

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    Nichols, Joshua; Bjorklund, George Reed; Newbern, Jason; Anderson, Trent

    2018-01-15

    Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Traditionally, ongoing neurodevelopment and neuroplasticity have thought to confer children with an advantage following TBI. However, recent findings indicate that the pediatric brain may be more sensitive to brain injury. Inhibitory interneurons are essential for proper cortical function and implicated in the pathophysiology of TBI, yet few studies have directly examined for TBI induced changes to interneurons themselves. To address this, we examine how inhibitory neurons are altered following controlled cortical impact (CCI) in juvenile mice with targeted Cre-dependent fluorescent labelling of interneurons (Vgat:Cre/Ai9 and PV:Cre/Ai6). While CCI failed to alter the number of excitatory neurons or somatostatin-expressing interneurons in the peri-injury zone it significantly decreased the density of parvalbumin (PV) immunoreactive cells by 71%. However, PV:Cre/Ai6 mice subjected to CCI showed a lesser extent of fluorescently labelled cell loss. PV interneurons are predominantly of a fast-spiking (FS) phenotype and when recorded electrophysiologically from the peri-injury zone exhibited similar intrinsic properties as control neurons. Synaptically, CCI induced a decrease in inhibitory drive onto FS interneurons combined with an increase in the strength of excitatory events. Our results indicate that CCI induced both a loss of PV interneurons and an even greater loss of PV expression. This suggests caution in interpreting changes in PV immunoreactivity alone as direct evidence of interneuronal loss. Further, in contrast with reports in adults TBI in the pediatric brain selectively alter PV-FS interneurons resulting in primarily a loss of interneuronal inhibition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. The vulnerability of calretinin-containing hippocampal interneurons in temporal lobe epilepsy

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    Zsofia eMagloczky

    2014-09-01

    Full Text Available This review focuses on the vulnerability of a special interneuron type – the calretinin (CR-containing interneurons – in temporal lobe epilepsy (TLE.CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons.The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR-containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites.Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation.Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy.

  3. Density and neurochemical profiles of neuronal nitric oxide synthase-expressing interneuron in the mouse basolateral amygdala.

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    Wang, Xiaona; Liu, Chunhua; Wang, Xiaochen; Gao, Fei; Zhan, Ren-Zhi

    2017-05-15

    Neuronal nitric oxide synthase (nNOS)-expressing interneurons reside in the basolateral nucleus of the amygdala (BLA) of rodents. In the present study, we immunohistochemically analyzed nNOS-positive cells in the mouse BLA by focusing on their density, γ-Aminobutyric acid (GABA)ergicity, and co-localization with calcium-binding proteins and neuropeptides. The density of nNOS-containing neurons was analyzed with unbiased stereology. Experiments were conducted in both adult wild-type C57BL/6 and glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice, in which GFP is expressed in GABAergic neurons under the control of the endogenous GAD67 gene promoter. In the BLA, the density of nNOS-positive cells was 3.92×103cells/mm3. Immunofluorescence revealed that nNOS-containing neurons constituted almost 26.93±2.36% of the GAD67-GFP neurons. Almost every nNOS-positive cell expressed glutamic acid decarboxylase 65 (GAD65). Proportions of nNOS-positive interneurons that expressed calbindin, calretinin, parvalbumin, somatostatin and neuropeptide Y were approximately 5.20%, 15.63%, 26.50%, 87.50% and 88.00%, respectively; but exhibited no co-localization with vasoactive intestinal polypeptide. By contrast, percentages of calbindin, calretinin, parvalbumin, somatostatin and neuropeptide Y-positive cells that expressed nNOS were approximately 1.93%, 7.25%, 25.25%, 80.25% and 87.50%, respectively. Together, these findings suggest that nNOS-expressing cells are a discrete interneuronal subpopulation in the mouse BLA and may play a functional role in the inhibitory circuitry of this brain region. Copyright © 2017. Published by Elsevier B.V.

  4. Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex.

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    Peyre, Elise; Silva, Carla G; Nguyen, Laurent

    2015-01-01

    During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: (1) Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; (2) Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; (3) Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex.

  5. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

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    Avital eAdler

    2013-09-01

    Full Text Available The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs, and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs, which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs, presumably parvalbumin (PV expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation. TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

  6. The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity.

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    Scheyltjens, Isabelle; Arckens, Lutgarde

    2016-01-01

    The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning.

  7. Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

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    Megan S. Wyeth

    2017-08-01

    Full Text Available Although Netos are considered auxiliary subunits critical for kainate receptor (KAR function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1-, and parvalbumin (PV-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

  8. The morphology and fine structure of the giant interneurons of the wood cricket Nemobius sylvestris.

    Science.gov (United States)

    Insausti, T C; Lazzari, C R; Casas, J

    2011-02-01

    The structural and ultrastructural characteristics of giant interneurons in the terminal abdominal ganglion of the cricket Nemobius sylvestris were investigated by means of cobalt and fluorescent dye backfilling and transmission electron microscopy. The projections of the 8 eight pairs of the biggest ascending interneurons (giant interneurons) are described in detail. The somata of all interneurons analyzed are located contralateral to their axons, which project to the posterior region of the terminal ganglion and arborise in the cercal glomerulus. Neuron 7-1a is an exception, because its arborisation is restricted to the anterior region of the ganglion. The fine structure of giant interneurons shows typical features of highly active cells. We observed striking indentations in the perineural layer, enabling the somata of the giant interneurons to be very close to the haemolymph. The cercal glomerulus exhibits a high diversity of synaptic contacts (i.e. axo-dendritic, axo-axonic, dendro-axonic, and dendro-dendritic), as well as areas of tight junctions. Electrical synapses seem to be present, as well as mixed synapses. The anatomical organization of the giant interneurons is finally discussed in terms of functional implications and on a comparative basis. Copyright © 2010 Elsevier Ltd. All rights reserved.

  9. Crosstalk between intracellular and extracellular signals regulating interneuron production migration and integration into the cortex

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    Elise ePeyre

    2015-04-01

    Full Text Available During embryogenesis, cortical interneurons are generated by ventral progenitors located in the ganglionic eminences of the telencephalon. They travel along multiple tangential paths to populate the cortical wall. As they reach this structure they undergo intracortical dispersion to settle in their final destination. At the cellular level, migrating interneurons are highly polarized cells that extend and retract processes using dynamic remodeling of microtubule and actin cytoskeleton. Different levels of molecular regulation contribute to interneuron migration. These include: 1/ Extrinsic guidance cues distributed along migratory streams that are sensed and integrated by migrating interneurons; 2/ Intrinsic genetic programs driven by specific transcription factors that grant specification and set the timing of migration for different subtypes of interneurons; 3/ Adhesion molecules and cytoskeletal elements/regulators that transduce molecular signalings into coherent movement. These levels of molecular regulation must be properly integrated by interneurons to allow their migration in the cortex. The aim of this review is to summarize our current knowledge of the interplay between microenvironmental signals and cell autonomous programs that drive cortical interneuron porduction, tangential migration, and intergration in the developing cerebral cortex.

  10. Selective gene expression by postnatal electroporation during olfactory interneuron neurogenesis.

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    Alexander T Chesler

    Full Text Available Neurogenesis persists in the olfactory system throughout life. The mechanisms of how new neurons are generated, how they integrate into circuits, and their role in coding remain mysteries. Here we report a technique that will greatly facilitate research into these questions. We found that electroporation can be used to robustly and selectively label progenitors in the Subventicular Zone. The approach was performed postnatally, without surgery, and with near 100% success rates. Labeling was found in all classes of interneurons in the olfactory bulb, persisted to adulthood and had no adverse effects. The broad utility of electroporation was demonstrated by encoding a calcium sensor and markers of intracellular organelles. The approach was found to be effective in wildtype and transgenic mice as well as rats. Given its versatility, robustness, and both time and cost effectiveness, this method offers a powerful new way to use genetic manipulation to understand adult neurogenesis.

  11. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

    Science.gov (United States)

    Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  12. Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease.

    Science.gov (United States)

    Lax, Nichola Z; Grady, John; Laude, Alex; Chan, Felix; Hepplewhite, Philippa D; Gorman, Grainne; Whittaker, Roger G; Ng, Yi; Cunningham, Mark O; Turnbull, Doug M

    2016-02-01

    Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ-aminobutyric acid (GABA)-ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Histochemical, immunohistochemical and immunofluorescent assays were performed on post-mortem brain tissue from 10 patients and 10 age-matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. © 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of

  13. Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

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    Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

    2017-10-06

    Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

  14. Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice.

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    Nikolas C Vann

    Full Text Available Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBötC interneurons are rhythmogenic in adult mice too. The neural origins of breathing behavior can be attributed to a localized and genetically well-defined interneuron population.

  15. Adult born olfactory bulb dopaminergic interneurons: molecular determinants and experience-dependent plasticity

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    Sara eBonzano

    2016-05-01

    Full Text Available The olfactory bulb (OB is a highly plastic brain region involved in the early processing of olfactory information. A remarkably feature of the OB circuits in rodents is the constitutive integration of new neurons that takes place during adulthood. Newborn cells in the adult OB are mostly inhibitory interneurons belonging to chemically, morphologically and functionally heterogeneous types. Although there is general agreement that adult neurogenesis in the OB plays a key role in sensory information processing and olfaction-related plasticity, the contribution of each interneuron subtype to such functions is far to be elucidated. Here, we focus on the dopaminergic (DA interneurons: we highlight recent findings about their morphological features and then describe the molecular factors required for the specification/differentiation and maintenance of the DA phenotype in adult born neurons. We also discuss dynamic changes of the DA interneuron population related to age, environmental stimuli and lesions, and their possible functional implications.

  16. A comparative perspective on minicolumns and inhibitory GABAergic interneurons in the neocortex

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    Mary Ann Raghanti

    2010-02-01

    Full Text Available Neocortical columns are functional and morphological units whose architecture may have been under selective evolutionary pressure in different mammalian lineages in response to encephalization and specializations of cognitive abilities. Inhibitory interneurons make a substantial contribution to the morphology and distribution of minicolumns within the cortex. In this context, we review differences in minicolumns and GABAergic interneurons among species and discuss possible implications for signaling among and within minicolumns. Furthermore, we discuss how abnormalities of both minicolumn disposition and inhibitory interneurons might be associated with neuropathological processes, such as Alzheimer’s disease, autism, and schizophrenia. Specifically, we will explore the possibility that phylogenetic variability in calcium-binding protein-expressing interneuron subtypes is directly related to differences in minicolumn morphology among species and might contribute to neuropathological susceptibility in humans.

  17. Modeling of inter-neuronal coupling medium and its impact on neuronal synchronization.

    Science.gov (United States)

    Iqbal, Muhammad; Rehan, Muhammad; Hong, Keum-Shik

    2017-01-01

    In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium's intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency.

  18. Modeling of inter-neuronal coupling medium and its impact on neuronal synchronization

    Science.gov (United States)

    Iqbal, Muhammad; Hong, Keum-Shik

    2017-01-01

    In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium’s intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency. PMID:28486505

  19. P1 interneurons promote a persistent internal state that enhances inter-male aggression in Drosophila

    Science.gov (United States)

    Hoopfer, Eric D; Jung, Yonil; Inagaki, Hidehiko K; Rubin, Gerald M; Anderson, David J

    2015-01-01

    How brains are hardwired to produce aggressive behavior, and how aggression circuits are related to those that mediate courtship, is not well understood. A large-scale screen for aggression-promoting neurons in Drosophila identified several independent hits that enhanced both inter-male aggression and courtship. Genetic intersections revealed that 8-10 P1 interneurons, previously thought to exclusively control male courtship, were sufficient to promote fighting. Optogenetic experiments indicated that P1 activation could promote aggression at a threshold below that required for wing extension. P1 activation in the absence of wing extension triggered persistent aggression via an internal state that could endure for minutes. High-frequency P1 activation promoted wing extension and suppressed aggression during photostimulation, whereas aggression resumed and wing extension was inhibited following photostimulation offset. Thus, P1 neuron activation promotes a latent, internal state that facilitates aggression and courtship, and controls the overt expression of these social behaviors in a threshold-dependent, inverse manner. DOI: http://dx.doi.org/10.7554/eLife.11346.001 PMID:26714106

  20. NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

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    Marta Perez-Rando

    2017-06-01

    Full Text Available N-methyl-D-aspartate receptors (NMDARs are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB. We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

  1. A Method to Culture GABAergic Interneurons Derived from the Medial Ganglionic Eminence

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    Franchi, Sira A.; Macco, Romina; Astro, Veronica; Tonoli, Diletta; Savino, Elisa; Valtorta, Flavia; Sala, Kristyna; Botta, Martina; de Curtis, Ivan

    2018-01-01

    Understanding the mechanisms guiding interneuron development is a central aspect of the current research on cortical/hippocampal interneurons, which is highly relevant to brain function and pathology. In this methodological study we have addressed the setup of protocols for the reproducible culture of dissociated cells from murine medial ganglionic eminences (MGEs), to provide a culture system for the analysis of interneurons in vitro. This study includes the detailed protocols for the preparation of the dissociated cells, and for their culture on optimal substrates for cell migration or differentiation. These cultures enriched in interneurons may allow the investigation of the migratory behavior of interneuron precursors and their differentiation in vitro, up to the formation of morphologically identifiable GABAergic synapses. Live imaging of MGE–derived cells plated on proper substrates shows that they are useful to study the migratory behavior of the precursors, as well as the behavior of growth cones during the development of neurites. Most MGE-derived precursors develop into polarized GABAergic interneurons as determined by axonal, dendritic, and GABAergic markers. We present also a comparison of cells from WT and mutant mice as a proof of principle for the use of these cultures for the analysis of the migration and differentiation of GABAergic cells with different genetic backgrounds. The culture enriched in interneurons described here represents a useful experimental system to examine in a relatively easy and fast way the morpho-functional properties of these cells under physiological or pathological conditions, providing a powerful tool to complement the studies in vivo. PMID:29358905

  2. Identification of DVA interneuron regulatory sequences in Caenorhabditis elegans.

    Science.gov (United States)

    Puckett Robinson, Carmie; Schwarz, Erich M; Sternberg, Paul W

    2013-01-01

    The identity of each neuron is determined by the expression of a distinct group of genes comprising its terminal gene battery. The regulatory sequences that control the expression of such terminal gene batteries in individual neurons is largely unknown. The existence of a complete genome sequence for C. elegans and draft genomes of other nematodes let us use comparative genomics to identify regulatory sequences directing expression in the DVA interneuron. Using phylogenetic comparisons of multiple Caenorhabditis species, we identified conserved non-coding sequences in 3 of 10 genes (fax-1, nmr-1, and twk-16) that direct expression of reporter transgenes in DVA and other neurons. The conserved region and flanking sequences in an 85-bp intronic region of the twk-16 gene directs highly restricted expression in DVA. Mutagenesis of this 85 bp region shows that it has at least four regions. The central 53 bp region contains a 29 bp region that represses expression and a 24 bp region that drives broad neuronal expression. Two short flanking regions restrict expression of the twk-16 gene to DVA. A shared GA-rich motif was identified in three of these genes but had opposite effects on expression when mutated in the nmr-1 and twk-16 DVA regulatory elements. We identified by multi-species conservation regulatory regions within three genes that direct expression in the DVA neuron. We identified four contiguous regions of sequence of the twk-16 gene enhancer with positive and negative effects on expression, which combined to restrict expression to the DVA neuron. For this neuron a single binding site may thus not achieve sufficient specificity for cell specific expression. One of the positive elements, an 8-bp sequence required for expression was identified in silico by sequence comparisons of seven nematode species, demonstrating the potential resolution of expanded multi-species phylogenetic comparisons.

  3. Mechanisms of firing patterns in fast-spiking cortical interneurons.

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    David Golomb

    2007-08-01

    Full Text Available Cortical fast-spiking (FS interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering. What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+, delayed-rectifier K(+, and slowly inactivating d-type K(+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.

  4. Kainate receptor-mediated modulation of hippocampal fast spiking interneurons in a rat model of schizophrenia.

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    Barbara Gisabella

    Full Text Available Kainate receptor (KAR subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP in schizophrenia (SZ and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO of sectors CA2/3, where the basolateral amygdala (BLA sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in

  5. Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.

    Science.gov (United States)

    Dabrowska, J; Rainnie, D G

    2010-12-15

    The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Hilar somatostatin interneurons contribute to synchronized GABA activity in an in vitro epilepsy model.

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    Sabine Grosser

    Full Text Available Epilepsy is a disorder characterized by excessive synchronized neural activity. The hippocampus and surrounding temporal lobe structures appear particularly sensitive to epileptiform activity. Somatostatin (SST-positive interneurons within the hilar region have been suggested to gate hippocampal activity, and therefore may play a crucial role in the dysregulation of hippocampal activity. In this study, we examined SST interneuron activity in the in vitro 4-aminopyridine (4-AP model of epilepsy. We employed a multi-disciplinary approach, combining extracellular multi-electrode array (MEA recordings with patch-clamp recordings and optical imaging using a genetically encoded calcium sensor. We observed that hilar SST interneurons are strongly synchronized during 4-AP-induced local field potentials (LFPs, as assayed by Ca(2+ imaging as well as juxtacellular or intracellular recording. SST interneurons were particularly responsive to GABA-mediated LFPs that occurred in the absence of ionotropic glutamatergic transmission. Our results present evidence that the extensive synchronized activity of SST-expressing interneurons contribute to the generation of GABAergic LFPs in an in vitro model of temporal lobe seizures.

  7. A mutation in the pericentrin gene causes abnormal interneuron migration to the olfactory bulb in mice.

    Science.gov (United States)

    Endoh-Yamagami, Setsu; Karkar, Kameel M; May, Scott R; Cobos, Inma; Thwin, Myo T; Long, Jason E; Ashique, Amir M; Zarbalis, Konstantinos; Rubenstein, John L R; Peterson, Andrew S

    2010-04-01

    Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal coiled-coil protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia. Copyright 2009 Elsevier Inc. All rights reserved.

  8. Extended Production of Cortical Interneurons into the Third Trimester of Human Gestation.

    Science.gov (United States)

    Arshad, Arslan; Vose, Linnea R; Vinukonda, Govindaiah; Hu, Furong; Yoshikawa, Kazuaki; Csiszar, Anna; Brumberg, Joshua C; Ballabh, Praveen

    2016-05-01

    In humans, the developmental origins of interneurons in the third trimester of pregnancy and the timing of completion of interneuron neurogenesis have remained unknown. Here, we show that the total and cycling Nkx2.1(+)and Dlx2(+)interneuron progenitors as well as Sox2(+)precursor cells were higher in density in the medial ganglionic eminence (MGE) compared with the lateral ganglionic eminence and cortical ventricular/subventricular zone (VZ/SVZ) of 16-35 gw subjects. The proliferation of these progenitors reduced as a function of gestational age, almost terminating by 35 gw. Proliferating Dlx2(+)cells were higher in density in the caudal ganglionic eminence (CGE) compared with the MGE, and persisted beyond 35 gw. Consistent with these findings, Sox2, Nkx2.1, Dlx2, and Mash1 protein levels were higher in the ganglionic eminences relative to the cortical VZ/SVZ. The density of gamma-aminobutyric acid-positive (GABA(+)) interneurons was higher in the cortical VZ/SVZ relative to MGE, but Nkx2.1 or Dlx2-expressing GABA(+)cells were more dense in the MGE compared with the cortical VZ/SVZ. The data suggest that the MGE and CGE are the primary source of cortical interneurons. Moreover, their generation continues nearly to the end of pregnancy, which may predispose premature infants to neurobehavioral disorders. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Electrophysiological and morphological characterization of propriospinal interneurons in the thoracic spinal cord

    DEFF Research Database (Denmark)

    Saywell, S A; Ford, T W; Meehan, Claire Francesca

    2011-01-01

    Propriospinal interneurons in the thoracic spinal cord have vital roles not only in controlling respiratory and trunk muscles, but also in providing possible substrates for recovery from spinal cord injury. Intracellular recordings were made from such interneurons in anesthetized cats under...... neuromuscular blockade and with the respiratory drive stimulated by inhaled CO(2). The majority of the interneurons were shown by antidromic activation to have axons descending for at least two to four segments, mostly contralateral to the soma. In all, 81% of the neurons showed postsynaptic potentials (PSPs......) to stimulation of intercostal or dorsal ramus nerves of the same segment for low-threshold (= 5T) afferents. A monosynaptic component was present for the majority of the peripherally evoked excitatory PSPs. A central respiratory drive potential was present in most of the recordings, usually of small amplitude...

  10. New insights into the classification and nomenclature of cortical GABAergic interneurons

    Science.gov (United States)

    DeFelipe, Javier; López-Cruz, Pedro L.; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F.; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R.; Huang, Josh; Jones, Edward G.; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A.; Marín, Oscar; Markram, Henry; McBain, Chris J.; Meyer, Hanno S.; Monyer, Hannah; Nelson, Sacha B.; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L. R.; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M.; Sherwood, Chet C.; Staiger, Jochen F.; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A.

    2013-01-01

    A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts’ assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. PMID:23385869

  11. Age-Related Uptake of Heavy Metals in Human Spinal Interneurons.

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    Roger Pamphlett

    Full Text Available Toxic heavy metals have been implicated in the loss of spinal motoneurons in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND. Motoneuron loss in the spinal anterior horn is severe in ALS/MND at the time of death, making this tissue unsuitable for examination. We therefore examined spinal cords of people without muscle weakness to look for any presence of heavy metals that could make these neurons susceptible to damage. Spinal cord samples from 50 individuals aged 1-95 y who had no clinical or histopathological evidence of spinal motoneuron loss were studied. Seven μm formalin-fixed paraffin-embedded sections were stained for heavy metals with silver nitrate autometallography (AMGHM which detects intracellular mercury, silver or bismuth. Neurons in the spinal cord were classified as interneurons or α-motoneurons based on their site and cell body diameter. Spinal interneurons containing heavy metals were present in 8 of 24 people (33% aged 61-95 y, but not at younger ages. These AMGHM interneurons were most numerous in the lumbar spinal cord, with moderate numbers in the caudal cervical cord, few in the rostral cervical cord, and almost none in the thoracic cord. All people with AMGHM interneurons had occasional AMGHM staining in α-motoneurons as well. In one man AMGHM staining was present in addition in dorsomedial nucleus and sensory neurons. In conclusion, heavy metals are present in many spinal interneurons, and in a few α-motoneurons, in a large proportion of older people. Damage to inhibitory interneurons from toxic metals in later life could result in excitotoxic injury to motoneurons and may underlie motoneuron injury or loss in conditions such as ALS/MND, multiple sclerosis, sarcopenia and calf fasciculations.

  12. MGE-derived nNOS+interneurons promote fear acquisition in nNOS-/-mice.

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    Zhang, Lin; Yuan, Hong-Jin; Cao, Bo; Kong, Cheng-Cheng; Yuan, Fang; Li, Jun; Ni, Huan-Yu; Wu, Hai-Yin; Chang, Lei; Liu, Yan; Luo, Chun-Xia

    2017-12-02

    Neuronal nitric oxide synthase (nNOS) 1 , mainly responsible for NO release in central nervous system (CNS) 2 , plays a significant role in multiple physiological functions. However, the function of nNOS + interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3 -derived nNOS + interneurons in fear learning. To determine the origin of nNOS + interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4 , caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6 . The results showed that MGE contained the most abundant precursors of nNOS + interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS + interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS + interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS -/- ) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS -/- but not the wild-type mice, suggesting the importance of nNOS + neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS -/- mice or wild-type mice into DG of the nNOS -/- mice and found that only MGE cells from wild-type mice but not the nNOS -/- mice rescued the deficit in acquisition of the nNOS -/- mice, further confirming the positive role of nNOS + neurons in fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Differential expression of parvalbumin interneurons in neonatal phencyclidine treated rats and socially isolated rats

    DEFF Research Database (Denmark)

    Kaalund, Sanne Simone; Riise, Jesper; Broberg, Brian

    2013-01-01

    of parvalbumin-positive interneurons (PV(+) interneurons). In this study we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia, the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical......Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration...

  14. Closed-loop response properties of a visual interneuron involved in fly optomotor control.

    Science.gov (United States)

    Ejaz, Naveed; Krapp, Holger G; Tanaka, Reiko J

    2013-01-01

    Due to methodological limitations neural function is mostly studied under open-loop conditions. Normally, however, nervous systems operate in closed-loop where sensory input is processed to generate behavioral outputs, which again change the sensory input. Here, we investigate the closed-loop responses of an identified visual interneuron, the blowfly H1-cell, that is part of a neural circuit involved in optomotor flight and gaze control. Those behaviors may be triggered by attitude changes during flight in turbulent air. The fly analyses the resulting retinal image shifts and performs compensatory body and head rotations to regain its default attitude. We developed a fly robot interface to study H1-cell responses in a 1 degree-of-freedom image stabilization task. Image shifts, induced by externally forced rotations, modulate the cell's spike rate that controls counter rotations of a mobile robot to minimize relative motion between the robot and its visual surroundings. A feedback controller closed the loop between neural activity and the rotation of the robot. Under these conditions we found the following H1-cell response properties: (i) the peak spike rate decreases when the mean image velocity is increased, (ii) the relationship between spike rate and image velocity depends on the standard deviation of the image velocities suggesting adaptive scaling of the cell's signaling range, and (iii) the cell's gain decreases linearly with increasing image accelerations. Our results reveal a remarkable qualitative similarity between the response dynamics of the H1-cell under closed-loop conditions with those obtained in previous open-loop experiments. Finally, we show that the adaptive scaling of the H1-cell's responses, while maximizing information on image velocity, decreases the cell's sensitivity to image accelerations. Understanding such trade-offs in biological vision systems may advance the design of smart vision sensors for autonomous robots.

  15. Closed-loop response properties of a visual interneuron involved in fly optomotor control

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    Naveed eEjaz

    2013-03-01

    Full Text Available Due to methodological limitations neural function is mostly studied under open-loop conditions. Normally, however, nervous systems operate in closed-loop where sensory input is processed to generate behavioural outputs, which again change the sensory input. Here, we investigate the closed-loop responses of an identified visual interneuron, the blowfly H1-cell, that is part of a neural circuit involved in optomotor flight and gaze control. Those behaviours may be triggered by attitude changes during flight in turbulent air. The fly analyses the resulting retinal image shifts and performs compensatory body and head rotations to regain its default attitude. We developed a fly-robot interface to study H1-cell responses in a 1 degree-of-freedom image stabilization task. Image shifts, induced by externally forced rotations, modulate the cell’s spike rate that controls counter rotations of a mobile robot to minimize relative motion between the robot and its visual surroundings. A feedback controller closed the loop between neural activity and the rotation of the robot. Under these conditions we found the following H1-cell response properties: (i the peak spike rate decreases when the mean image velocity is increased, (ii the relationship between spike rate and image velocity depends on the standard deviation of the image velocities suggesting adaptive scaling of the cell’s signalling range, and (iii the cell’s gain decreases linearly with increasing image accelerations.Our results reveal a remarkable qualitative similarity between the response dynamics of the H1-cell under closed-loop conditions with those obtained in previous open-loop experiments. Finally, we show that the adaptive scaling of the H1-cell’s responses, while maximizing information on image velocity, decreases the cell’s sensitivity to image accelerations. Understanding such trade-offs in biological vision systems may advance the design of smart vision sensors for autonomous

  16. Effects of active conductance distribution over dendrites on the synaptic integration in an identified nonspiking interneuron.

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    Akira Takashima

    Full Text Available The synaptic integration in individual central neuron is critically affected by how active conductances are distributed over dendrites. It has been well known that the dendrites of central neurons are richly endowed with voltage- and ligand-regulated ion conductances. Nonspiking interneurons (NSIs, almost exclusively characteristic to arthropod central nervous systems, do not generate action potentials and hence lack voltage-regulated sodium channels, yet having a variety of voltage-regulated potassium conductances on their dendritic membrane including the one similar to the delayed-rectifier type potassium conductance. It remains unknown, however, how the active conductances are distributed over dendrites and how the synaptic integration is affected by those conductances in NSIs and other invertebrate neurons where the cell body is not included in the signal pathway from input synapses to output sites. In the present study, we quantitatively investigated the functional significance of active conductance distribution pattern in the spatio-temporal spread of synaptic potentials over dendrites of an identified NSI in the crayfish central nervous system by computer simulation. We systematically changed the distribution pattern of active conductances in the neuron's multicompartment model and examined how the synaptic potential waveform was affected by each distribution pattern. It was revealed that specific patterns of nonuniform distribution of potassium conductances were consistent, while other patterns were not, with the waveform of compound synaptic potentials recorded physiologically in the major input-output pathway of the cell, suggesting that the possibility of nonuniform distribution of potassium conductances over the dendrite cannot be excluded as well as the possibility of uniform distribution. Local synaptic circuits involving input and output synapses on the same branch or on the same side were found to be potentially affected under

  17. Gsg1, Trnp1, and Tmem215 Mark Subpopulations of Bipolar Interneurons in the Mouse Retina

    Science.gov (United States)

    Park, Ko Uoon; Randazzo, Grace; Jones, Kenneth L.; Brzezinski, Joseph A.

    2017-01-01

    Purpose How retinal bipolar cell interneurons are specified and assigned to specialized subtypes is only partially understood. In part, this is due to a lack of early pan- and subtype-specific bipolar cell markers. To discover these factors, we identified genes that were upregulated in Blimp1 (Prdm1) mutant retinas, which exhibit precocious bipolar cell development. Methods Postnatal day (P)2 retinas from Blimp1 conditional knock-out (CKO) mice and controls were processed for RNA sequencing. Genes that increased at least 45% and were statistically different between conditions were considered candidate bipolar-specific factors. Candidates were further evaluated by RT-PCR, in situ hybridization, and immunohistochemistry. Knock-in Tmem215-LacZ mice were used to better trace retinal expression. Results A comparison between Blimp1 CKO and control RNA-seq datasets revealed approximately 40 significantly upregulated genes. We characterized the expression of three genes that have no known function in the retina, Gsg1 (germ cell associated gene), Trnp1 (TMF-regulated nuclear protein), and Tmem215 (a predicted transmembrane protein). Germ cell associated gene appeared restricted to a small subset of cone bipolars while Trnp1 was seen in all ON type bipolar cells. Using Tmem215-LacZ heterozygous knock-in mice, we observed that β-galactosidase expression started early in bipolar cell development. In adults, Tmem215 was expressed by a subset of ON and OFF cone bipolar cells. Conclusions We have identified Gsg1, Tmem215, and Trnp1 as novel bipolar subtype-specific genes. The spatial and temporal pattern of their expression is consistent with a role in controlling bipolar subtype fate choice, differentiation, or physiology. PMID:28199486

  18. Innervation of burst firing spiny interneurons by pyramidal cells in deep layers of rat somatomotor cortex: paired intracellular recordings with biocytin filling.

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    Deuchars, J; Thomson, A M

    1995-12-01

    Intracellular recordings were obtained from a class of neuron defined electrophysiologically as burst firing interneurons in layers V and VI in slices of adult rat somatomotor cortex. Four of these cells were recovered histologically. These four cells had resting membrane potentials between -68 and -80 mV, a mean input resistance of 77 +/- 16.2 M omega (measured from the voltage deflection produced by a 100 ms, 0.5 nA hyperpolarizing pulse delivered from a membrane potential of -80 mV) and responded to injections of depolarizing current from membrane potentials negative of -70 to -75 mV with an initial burst of action potentials followed by a complex afterhyperpolarization. In response to injection of larger (0.5-1.5 nA) hyperpolarizing current pulses from membrane potentials between -60 and -70 mV, 15 of 20 burst firing cells (three of four recovered histologically) that were tested displayed delayed inward rectification, and in all 20 cells of this type, responses to large negative current pulses were followed by a rebound depolarization that could initiate action potentials. Filling of four of these cells with biocytin and subsequent histological processing revealed that they were bitufted with sparsely to medium spiny dendrites and extensive local axon ramifications. These neurons are similar to low threshold spiking cells [Kawaguchi (1993) J. Neurophysiol. 69, 416-431]. Ultrastructural examination of the axons of three cells revealed that of 53 labelled terminals studied, the majority formed synaptic contacts with dendritic shafts. Filling neurons with biocytin during paired intracellular recordings resulted in three well labelled interneurons, each of which was postsynaptic to a simultaneously recorded pyramidal neuron. In these pairs both cells were identified, but the presynaptic axon was poorly labelled in one. In one of the two pairs in which the pre- and postsynaptic neurons were fully recovered, light microscopic assessment indicated that the axon of

  19. Functional organization of locomotor interneurons in the ventral lumbar spinal cord of the newborn rat.

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    Myriam Antri

    Full Text Available Although the mammalian locomotor CPG has been localized to the lumbar spinal cord, the functional-anatomical organization of flexor and extensor interneurons has not been characterized. Here, we tested the hypothesis that flexor and extensor interneuronal networks for walking are physically segregated in the lumbar spinal cord. For this purpose, we performed optical recordings and lesion experiments from a horizontally sectioned lumbar spinal cord isolated from neonate rats. This ventral hemi spinal cord preparation produces well-organized fictive locomotion when superfused with 5-HT/NMDA. The dorsal surface of the preparation was visualized using the Ca(2+ indicator fluo-4 AM, while simultaneously monitoring motor output at ventral roots L2 and L5. Using calcium imaging, we provided a general mapping view of the interneurons that maintained a stable phase relationship with motor output. We showed that the dorsal surface of L1 segment contains a higher density of locomotor rhythmic cells than the other segments. Moreover, L1 segment lesioning induced the most important changes in the locomotor activity in comparison with lesions at the T13 or L2 segments. However, no lesions led to selective disruption of either flexor or extensor output. In addition, this study found no evidence of functional parcellation of locomotor interneurons into flexor and extensor pools at the dorsal-ventral midline of the lumbar spinal cord of the rat.

  20. GABAERGIC MODULATION OF STRIATAL CHOLINERGIC INTERNEURONS - AN IN-VIVO MICRODIALYSIS STUDY

    NARCIS (Netherlands)

    DEBOER, P; WESTERINK, BHC

    Striatal cholinergic interneurons have been shown to receive input from striatal gamma-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA(A) and the GABA(B) receptor. Using in vivo microdialysis, we have studied the effect of

  1. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation

    Science.gov (United States)

    Ognjanovski, Nicolette; Schaeffer, Samantha; Wu, Jiaxing; Mofakham, Sima; Maruyama, Daniel; Zochowski, Michal; Aton, Sara J.

    2017-04-01

    Activity in hippocampal area CA1 is essential for consolidating episodic memories, but it is unclear how CA1 activity patterns drive memory formation. We find that in the hours following single-trial contextual fear conditioning (CFC), fast-spiking interneurons (which typically express parvalbumin (PV)) show greater firing coherence with CA1 network oscillations. Post-CFC inhibition of PV+ interneurons blocks fear memory consolidation. This effect is associated with loss of two network changes associated with normal consolidation: (1) augmented sleep-associated delta (0.5-4 Hz), theta (4-12 Hz) and ripple (150-250 Hz) oscillations; and (2) stabilization of CA1 neurons' functional connectivity patterns. Rhythmic activation of PV+ interneurons increases CA1 network coherence and leads to a sustained increase in the strength and stability of functional connections between neurons. Our results suggest that immediately following learning, PV+ interneurons drive CA1 oscillations and reactivation of CA1 ensembles, which directly promotes network plasticity and long-term memory formation.

  2. Subcellular Targeting of VIP Boutons in Mouse Barrel Cortex is Layer-Dependent and not Restricted to Interneurons.

    Science.gov (United States)

    Zhou, Xiaojuan; Rickmann, Michael; Hafner, Georg; Staiger, Jochen F

    2017-11-01

    Neocortical vasoactive intestinal polypeptide (VIP) expressing cells are a diverse subpopulation of GABAergic interneurons issuing distinct axonal projections. They are known to inhibit other types of interneurons as well as excitatory principal neurons and possess a disinhibitory net effect in cortical circuits. In order to elucidate their targeting specificity, the output connectivity of VIP interneurons was studied at the subcellular level in barrel cortex of interneuron-specific Cre-driver mice, using pre- and postembedding electron microscopy. Systematically sampling VIP boutons across all layers, we found a substantial proportion of the innervated subcellular structures were dendrites (80%), with somata (13%), and spines (7%) being much less targeted. In layer VI, a high proportion of axosomatic synapses was found (39%). GABA-immunopositive ratio was quantified among the targets using statistically validated thresholds: only 37% of the dendrites, 7% of the spines, and 26% of the somata showed above-threshold immunogold labeling. For the main target structure "dendrite", a higher proportion of GABAergic subcellular profiles existed in deep than in superficial layers. In conclusion, VIP interneurons innervate non-GABAergic excitatory neurons and interneurons at their subcellular domains with layer-dependent specificity. This suggests a diverse output of VIP interneurons, which predicts multiple functionality in cortical circuitry beyond disinhibition. © The Author 2017. Published by Oxford University Press.

  3. Evolution of a new sense for wind in flying phasmids? Afferents and interneurons

    Science.gov (United States)

    Hustert, Reinhold; Klug, Rebecca

    2009-12-01

    The evolution of winged stick insects (phasmids) from secondarily wingless ancestors was proposed in recent studies. We explored the cuticle of flying phasmids for wind sensors that could be involved in their flight control, comparable to those known for locusts. Surprisingly, wind-sensitive hairs (wsH) occur on the palps of mouthparts and on the antennae of the winged phasmid Sipyloidea sipylus which can fly in tethered position only when air currents blow over the mouthparts. The present study describes the morphology and major functional properties of these “new” wsH with soft and bulging hair bases which are different from the beaker-like hair bases of the wsH on the cerci of phasmids and the wsH described in other insects. The most sensitive wsH of antennae and palps respond with phasic-tonic afferents to air currents exceeding 0.2 ms-1. The fields of wsH on one side of the animal respond mainly to ventral, lateral, and frontal wind on the ipsilateral side of the head. Afferent inputs from the wsH converge but also diverge to a group of specific interneurons at their branches in the suboesophageal ganglion and can send their integrated input from wsH fields of the palps and antennae to the thoracic central nervous system. Response types of individual wsH-interneurons are either phasic or phasic-tonic to air puffs or constant air currents and also, the receptive fields of individual interneurons differ. We conclude that the “new” wsH system and its interneurons mainly serve to maintain flight activity in airborne phasmids and also, the “new” wsH must have emerged together with the integrating interneurons during the evolution from wingless to the recent winged forms of phasmids.

  4. GABA regulates the multidirectional tangential migration of GABAergic interneurons in living neonatal mice.

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    Hiroyuki Inada

    Full Text Available Cortical GABAergic interneurons originate from ganglionic eminences and tangentially migrate into the cortical plate at early developmental stages. To elucidate the characteristics of this migration of GABAergic interneurons in living animals, we established an experimental design specialized for in vivo time-lapse imaging of the neocortex of neonate mice with two-photon laser-scanning microscopy. In vesicular GABA/glycine transporter (VGAT-Venus transgenic mice from birth (P0 through P3, we observed multidirectional tangential migration of genetically-defined GABAergic interneurons in the neocortical marginal zone. The properties of this migration, such as the motility rate (distance/hr, the direction moved, and the proportion of migrating neurons to stationary neurons, did not change through P0 to P3, although the density of GABAergic neurons at the marginal zone decreased with age. Thus, the characteristics of the tangential motility of individual GABAergic neurons remained constant in development. Pharmacological block of GABA(A receptors and of the Na⁺-K⁺-Cl⁻ cotransporters, and chelating intracellular Ca²⁺, all significantly reduced the motility rate in vivo. The motility rate and GABA content within the cortex of neonatal VGAT-Venus transgenic mice were significantly greater than those of GAD67-GFP knock-in mice, suggesting that extracellular GABA concentration could facilitate the multidirectional tangential migration. Indeed, diazepam applied to GAD67-GFP mice increased the motility rate substantially. In an in vitro neocortical slice preparation, we confirmed that GABA induced a NKCC sensitive depolarization of GABAergic interneurons in VGAT-Venus mice at P0-P3. Thus, activation of GABA(AR by ambient GABA depolarizes GABAergic interneurons, leading to an acceleration of their multidirectional motility in vivo.

  5. Acute phencyclidine administration induces c-Fos-immunoreactivity in interneurons in cortical and subcortical regions.

    Science.gov (United States)

    Hervig, Mona E; Thomsen, Morten S; Kalló, Imre; Mikkelsen, Jens D

    2016-10-15

    Dysfunction of N-Methyl-d-aspartate receptors (NMDARs) is believed to underlie some of the symptoms in schizophrenia, and non-competitive NMDAR antagonists (including phencyclidine (PCP)) are widely used as pharmacological schizophrenia models. Furthermore, mounting evidence suggests that impaired γ-aminobutyric acid (GABA) neurotransmission contributes to the cognitive deficits in schizophrenia. Thus alterations in GABAergic interneurons have been observed in schizophrenia patients and animal models. Acute systemic administration of PCP increases levels of c-Fos in several cortical and subcortical areas, but whether such induction occurs in specific populations of GABAergic interneuron subtypes still remains to be established. We performed an immunohistochemical analysis of the PCP-induced c-Fos-immunoreactivity (IR) in parvalbumin (PV) and calbindin (CB) interneuron subtypes in the cortex and thalamus of rats. A single dose of PCP (10mg/kg, s.c.) significantly increased total number of c-Fos-IR in: (1) the prelimbic, infralimbic, anterior cingulate, ventrolateral orbital, motor, somatosensory and retrosplenial cortices as well as the nucleus accumbens (NAc), field CA1 of the hippocampus (CA1) field of hippocampus and mediodorsal thalamus (MD); (2) PV-IR cells in the ventrolateral orbitofrontal and retrosplenial cortices and CA1 field of hippocampus; and (3) CB-IR cells in the motor cortex. Overall, our data indicate that PCP activates a wide range of cortical and subcortical brain regions and that a substantial part of this activation is present in GABAergic interneurons in certain regions. This suggests that the psychotomimetic effect of PCP may be mediated via GABAergic interneurons. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. The influence of contralateral primary afferents on Ia inhibitory interneurones in humans.

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    Delwaide, P J; Pepin, J L

    1991-01-01

    1. Contralateral influences on short latency reciprocal inhibition between wrist extensor and flexor muscles were investigated in twenty-two healthy volunteers. Reciprocal inhibition, probably mediated through the Ia inhibitory interneurone, was measured by conditioning the flexor carpi radialis (FCR) H reflex by weak stimulation of the ipsilateral radial nerve. Maximum reciprocal inhibition occurring at a precise delay between conditioning and conditioned stimulations was taken as the test level of inhibition. 2. Contralateral median or radial nerves were stimulated at short intervals before the onset of reciprocal inhibition. The latter was increased by 8.6% after median nerve stimulation and decreased by 16.5% after radial nerve stimulation. 3. The contribution of sensory fibres in the two nerves to contralateral effects was investigated by stimulating purely sensory branches of the nerves. No clear modification of the contralateral reciprocal inhibition was observed. The effects produced by mixed nerve stimulation are thus likely to have been mediated by Ia fibres. 4. In three hemiplegic patients where reciprocal inhibition was reduced unilaterally, stimulation on the spastic side produced contralateral effects similar to those observed in normal subjects. This result indicates that contralateral effects are not mediated through the Ia inhibitory interneurone ipsilateral to the conditioning stimulus. 5. Since contralateral effects occur after short delays (2 ms, median nerve; 3 ms, radial nerve), we suggest a functional scheme in which the excitability of Ia inhibitory interneurones is modified by contralateral primary afferents via the interneurones activated by group I fibres, probably Ia fibres. The short delays indicate that the interneurone transmitting primary afferent influences to the contralateral side is probably excitatory. PMID:1895236

  7. Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

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    Ribeiro-da-Silva Alfredo

    2009-05-01

    Full Text Available Abstract Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic transmission in lamina II inhibitory interneurons identified under visual guidance in spinal slices taken from transgenic mice expressing enhanced green fluorescent protein (EGFP under the control of the GAD promoter. The majority of these cells fired tonically to a long depolarizing current pulse. Monosynaptically evoked inhibitory postsynaptic currents (eIPSCs in these cells were mediated by both GABAA and glycine receptors. Consistent with this, both GABAA and glycine receptor-mediated miniature IPSCs were recorded in all of the cells. These inhibitory inputs originated at least in part from local lamina II interneurons as verified by simultaneous recordings from pairs of EGFP+ cells. These synapses appeared to have low release probability and displayed potentiation and asynchronous release upon repeated activation. In summary, we report on a previously unexamined component of the dorsal horn circuitry that likely constitutes an essential element of the fine tuning of nociception.

  8. Meningeal defects alter the tangential migration of cortical interneurons in Foxc1hith/hith mice

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    Zarbalis Konstantinos

    2012-01-01

    Full Text Available Abstract Background Tangential migration presents the primary mode of migration of cortical interneurons translocating into the cerebral cortex from subpallial domains. This migration takes place in multiple streams with the most superficial one located in the cortical marginal zone. While a number of forebrain-expressed molecules regulating this process have emerged, it remains unclear to what extent structures outside the brain, like the forebrain meninges, are involved. Results We studied a unique Foxc1 hypomorph mouse model (Foxc1hith/hith with meningeal defects and impaired tangential migration of cortical interneurons. We identified a territorial correlation between meningeal defects and disruption of interneuron migration along the adjacent marginal zone in these animals, suggesting that impaired meningeal integrity might be the primary cause for the observed migration defects. Moreover, we postulate that the meningeal factor regulating tangential migration that is affected in homozygote mutants is the chemokine Cxcl12. In addition, by using chromatin immunoprecipitation analysis, we provide evidence that the Cxcl12 gene is a direct transcriptional target of Foxc1 in the meninges. Further, we observe migration defects of a lesser degree in Cajal-Retzius cells migrating within the cortical marginal zone, indicating a less important role for Cxcl12 in their migration. Finally, the developmental migration defects observed in Foxc1hith/hith mutants do not lead to obvious differences in interneuron distribution in the adult if compared to control animals. Conclusions Our results suggest a critical role for the forebrain meninges to promote during development the tangential migration of cortical interneurons along the cortical marginal zone and Cxcl12 as the factor responsible for this property.

  9. Zebrafish Mnx proteins specify one motoneuron subtype and suppress acquisition of interneuron characteristics

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    Seredick Steve D

    2012-11-01

    Full Text Available Abstract Background Precise matching between motoneuron subtypes and the muscles they innervate is a prerequisite for normal behavior. Motoneuron subtype identity is specified by the combination of transcription factors expressed by the cell during its differentiation. Here we investigate the roles of Mnx family transcription factors in specifying the subtypes of individually identified zebrafish primary motoneurons. Results Zebrafish has three Mnx family members. We show that each of them has a distinct and temporally dynamic expression pattern in each primary motoneuron subtype. We also show that two Mnx family members are expressed in identified VeLD interneurons derived from the same progenitor domain that generates primary motoneurons. Surprisingly, we found that Mnx proteins appear unnecessary for differentiation of VeLD interneurons or the CaP motoneuron subtype. Mnx proteins are, however, required for differentiation of the MiP motoneuron subtype. We previously showed that MiPs require two temporally-distinct phases of Islet1 expression for normal development. Here we show that in the absence of Mnx proteins, the later phase of Islet1 expression is initiated but not sustained, and MiPs become hybrids that co-express morphological and molecular features of motoneurons and V2a interneurons. Unexpectedly, these hybrid MiPs often extend CaP-like axons, and some MiPs appear to be entirely transformed to a CaP morphology. Conclusions Our results suggest that Mnx proteins promote MiP subtype identity by suppressing both interneuron development and CaP axon pathfinding. This is, to our knowledge, the first report of transcription factors that act to distinguish CaP and MiP subtype identities. Our results also suggest that MiP motoneurons are more similar to V2 interneurons than are CaP motoneurons.

  10. Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via alpha4 beta2* nicotinic receptor activation

    Directory of Open Access Journals (Sweden)

    L. Andrew Bell

    2015-04-01

    Full Text Available Acetylcholine (ACh release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were assessed on both pyramidal neurons and different interneuron subtypes via whole cell patch clamp methods. Vasoactive intestinal peptide (VIP-expressing interneurons that selectively innervate other interneurons (VIP/IS were excited by ACh through the activation of nicotinic receptors containing alpah4 and beta2 subunits (alpha4 beta2*. ACh release onto VIP/IS was presynaptically inhibited by M2 muscarinic autoreceptors. ACh release produced spontaneous inhibitory postsynaptic current (sIPSC barrages blocked by dihydro-beta-erythroidine in interneurons but not pyramidal neurons. Optogenetic suppression of VIP interneurons did not inhibit these sIPSC barrages suggesting other interneuron-selective interneurons were also excited by 42* nicotinic receptor activation. In contrast, interneurons that innervate pyramidal neuron perisomatic regions were not activated by ACh release onto nicotinic receptors. Therefore, we propose ACh release in CA1 facilitates disinhibition through activation of 42* nicotinic receptors on interneuron-selective interneurons whereas interneurons that innervate pyramidal neurons are less affected by nicotinic receptor activation.

  11. Caudal Ganglionic Eminence Precursor Transplants Disperse and Integrate as Lineage-Specific Interneurons but Do Not Induce Cortical Plasticity

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    Phillip Larimer

    2016-08-01

    Full Text Available The maturation of inhibitory GABAergic cortical circuits regulates experience-dependent plasticity. We recently showed that the heterochronic transplantation of parvalbumin (PV or somatostatin (SST interneurons from the medial ganglionic eminence (MGE reactivates ocular dominance plasticity (ODP in the postnatal mouse visual cortex. Might other types of interneurons similarly induce cortical plasticity? Here, we establish that caudal ganglionic eminence (CGE-derived interneurons, when transplanted into the visual cortex of neonatal mice, migrate extensively in the host brain and acquire laminar distribution, marker expression, electrophysiological properties, and visual response properties like those of host CGE interneurons. Although transplants from the anatomical CGE do induce ODP, we found that this plasticity reactivation is mediated by a small fraction of MGE-derived cells contained in the transplant. These findings demonstrate that transplanted CGE cells can successfully engraft into the postnatal mouse brain and confirm the unique role of MGE lineage neurons in the induction of ODP.

  12. Oscillation-Driven Spike-Timing Dependent Plasticity Allows Multiple Overlapping Pattern Recognition in Inhibitory Interneuron Networks

    DEFF Research Database (Denmark)

    Garrido, Jesús A.; Luque, Niceto R.; Tolu, Silvia

    2016-01-01

    The majority of operations carried out by the brain require learning complex signal patterns for future recognition, retrieval and reuse. Although learning is thought to depend on multiple forms of long-term synaptic plasticity, the way this latter contributes to pattern recognition is still poorly...... understood. Here, we have used a simple model of afferent excitatory neurons and interneurons with lateral inhibition, reproducing a network topology found in many brain areas from the cerebellum to cortical columns. When endowed with spike-timing dependent plasticity (STDP) at the excitatory input synapses...... and at the inhibitory interneuron-interneuron synapses, the interneurons rapidly learned complex input patterns. Interestingly, induction of plasticity required that the network be entrained into theta-frequency band oscillations, setting the internal phase-reference required to drive STDP. Inhibitory plasticity...

  13. Calcium-binding protein, secretagogin, characterizes novel groups of interneurons in the rat striatum.

    Science.gov (United States)

    Kosaka, Toshio; Yasuda, Seiko; Kosaka, Katsuko

    2017-06-01

    In the rat striatum numerous secretagogin (SCGN) positive neurons were scattered. They were heterogeneous in their morphological and chemical properties. We examined the colocalization of SCGN with known four interneuron markers, parvalbumin (PV), calretinin (CR), nitric oxide synthase (NOS) and choline acetyl transferase (ChAT). 60-70% of SCGN positive striatal neurons contained either PV or CR or ChAT, but none contained NOS. On the other hand the remaining 30-40% expressed none of these markers, most of which were GAD positive. The present study indicates that there are hitherto unknown groups of striatal interneurons in the rat striatum. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  14. The many tunes of perisomatic targeting interneurons in the hippocampal network

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    Tommas J Ellender

    2010-07-01

    Full Text Available The axonal targets of perisomatic targeting interneurons make them ideally suited to synchronise excitatory neurons. As such they have been implicated in rhythm generation of network activity in many brain regions including the hippocampus. However, several recent publications indicate that their roles extend beyond that of rhythm generation. Firstly, it has been shown that, in addition to rhythm generation, GABAergic perisomatic inhibition also serves as a current generator contributing significantly to hippocampal oscillatory EEG signals. Furthermore, GABAergic interneurons have a hitherto unexpected role in the initiation of hippocampal population bursts, both in the developing and adult hippocampus. In this review, we describe these new observations in detail and discuss the implications they have for our understanding of the mechanisms underlying physiological and pathological hippocampal network activities. This review is part of the Frontiers in Cellular Neuroscience's special topic entitled GABA signalling in health and disease based on the meeting at the CNCR Amsterdam.

  15. skn-1 is required for interneuron sensory integration and foraging behavior in Caenorhabditis elegans.

    Science.gov (United States)

    Wilson, Mark A; Iser, Wendy B; Son, Tae Gen; Logie, Anne; Cabral-Costa, Joao V; Mattson, Mark P; Camandola, Simonetta

    2017-01-01

    Nrf2/skn-1, a transcription factor known to mediate adaptive responses of cells to stress, also regulates energy metabolism in response to changes in nutrient availability. The ability to locate food sources depends upon chemosensation. Here we show that Nrf2/skn-1 is expressed in olfactory interneurons, and is required for proper integration of multiple food-related sensory cues in Caenorhabditis elegans. Compared to wild type worms, skn-1 mutants fail to perceive that food density is limiting, and display altered chemo- and thermotactic responses. These behavioral deficits are associated with aberrant AIY interneuron morphology and migration in skn-1 mutants. Both skn-1-dependent AIY autonomous and non-autonomous mechanisms regulate the neural circuitry underlying multisensory integration of environmental cues related to energy acquisition.

  16. Short-term synaptic plasticity at interneuronal synapses could sculpt rhythmic motor patterns

    Directory of Open Access Journals (Sweden)

    Yan eJia

    2016-02-01

    Full Text Available The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca2+ levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca2+ (and compensatory adjustments in Mg2+ in some cases could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord

  17. In vivo calcium accumulation in presynaptic and postsynaptic dendrites of visual interneurons

    OpenAIRE

    Dürr, Volker; Egelhaaf, Martin

    1999-01-01

    In this comparative in vivo study of dendritic calcium accumulation, we describe the time course and spatial integration properties of two classes of visual interneurons in the lobula plate of the blowfly. Calcium accumulation was measured during visual motion stimulation, ensuring synaptic activation of the neurons within their natural spatial and temporal operating range. The compared cell classes, centrifugal horizontal (CH) and horizontal system (HS) cells, are known to receive retinotopi...

  18. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    OpenAIRE

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform ...

  19. Sox5 controls dorsal progenitor and interneuron specification in the spinal cord.

    Science.gov (United States)

    Quiroga, Alejandra C; Stolt, C Claus; Diez del Corral, Ruth; Dimitrov, Spas; Pérez-Alcalá, Siro; Sock, Elisabeth; Barbas, Julio A; Wegner, Michael; Morales, Aixa V

    2015-05-01

    The basic organization of somatosensory circuits in the spinal cord is already setup during the initial patterning of the dorsal neural tube. Extrinsic signals, such as Wnt and TGF-β pathways, activate combinatorial codes of transcription factors that are responsible for generating a pattern of discrete domains of dorsal progenitors (dp). These progenitors will give rise to distinct dorsal interneurons (dI). The Wnt/ βcatenin signaling pathway controls specification of dp/dI1-3 progenitors and interneurons. According to the current model in the field, Wnt/βcatenin activity seems to act in a graded fashion in the spinal cord, as different relative levels determine the identity of adjacent progenitors. However, it is not clear how this activity gradient is controlled and how the identities of dI1-3 are differentially regulated by Wnt signalling. We have determined that two SoxD transcription factors, Sox5 and Sox6, are expressed in restricted domains of dorsal progenitors in the neural tube. Using gain- and loss-of function approaches in chicken embryos, we have established that Sox5 controls cell fate specification of dp2 and dp3 progenitors and, as a result, controls the correct number of the corresponding dorsal interneurons (dI2 and dI3). Furthermore, Sox5 exerts its function by restricting dorsally Wnt signaling activity via direct transcriptional induction of the negative Wnt pathway regulator Axin2. By that way, Sox5 acts as a Wnt pathway modulator that contributes to sharpen the dorsal gradient of Wnt/βcatenin activity to control the distinction of two functionally distinct types of interneurons, dI2 and dI3 involved in the somatosensory relay. © 2014 Wiley Periodicals, Inc.

  20. Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact

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    Andreas eKlaus

    2011-07-01

    Full Text Available In the striatal microcircuit, fast-spiking (FS interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization, do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

  1. Short-Term Synaptic Plasticity at Interneuronal Synapses Could Sculpt Rhythmic Motor Patterns.

    Science.gov (United States)

    Jia, Yan; Parker, David

    2016-01-01

    The output of a neuronal network depends on the organization and functional properties of its component cells and synapses. While the characterization of synaptic properties has lagged cellular analyses, a potentially important aspect in rhythmically active networks is how network synapses affect, and are in turn affected by, network activity. This could lead to a potential circular interaction where short-term activity-dependent synaptic plasticity is both influenced by and influences the network output. The analysis of synaptic plasticity in the lamprey locomotor network was extended here to characterize the short-term plasticity of connections between network interneurons and to try and address its potential network role. Paired recordings from identified interneurons in quiescent networks showed synapse-specific synaptic properties and plasticity that supported the presence of two hemisegmental groups that could influence bursting: depression in an excitatory interneuron group, and facilitation in an inhibitory feedback circuit. The influence of activity-dependent synaptic plasticity on network activity was investigated experimentally by changing Ringer Ca(2+) levels, and in a simple computer model. A potential caveat of the experimental analyses was that changes in Ringer Ca(2+) (and compensatory adjustments in Mg(2+) in some cases) could alter several other cellular and synaptic properties. Several of these properties were tested, and while there was some variability, these were not usually significantly affected by the Ringer changes. The experimental analyses suggested that depression of excitatory inputs had the strongest influence on the patterning of network activity. The simulation supported a role for this effect, and also suggested that the inhibitory facilitating group could modulate the influence of the excitatory synaptic depression. Short-term activity-dependent synaptic plasticity has not generally been considered in spinal cord models. These

  2. Staining of cerebellar cortex granular layer interneurons with natural dye of Madder.

    Science.gov (United States)

    Gharravi, Anneh Mohammad

    2016-01-01

    The objective of the present study was an investigation of root Rubia Tinctorum (Madder) as a natural dye to identification of granular layer interneurons of the rat cerebellum. Seven to ten micrometre sections were collected from the cerebellum and stained only with Madder for 2, 24 and 48 h. Other sections were stained with Madder then with hematoxyllin, cresyl violet, eosin, light green. Microscopic identification of cells was performed based on cell morphology, reaction and binding of with the dye. All data were expressed as mean ± SD in and significance was set at p ≤0.05. Madder with alum as mordant resulted a deep red staining of interneurons. Unipolar brush cells (UBCs) were observed with a cell body diameter intermediate between granule and Golgi cells in the superficial layer of the granular layer. Golgi cells were identified almost as large as Purkinje cells with irregular rounded or polygonal morphology. Lugaro cells were observed as spindle-shaped cells adjacent to Purkinje layer. Results of the present study showed that mader could stain granular layer interneurons in cerebellum cortex of rat.

  3. Local Integration Accounts for Weak Selectivity of Mouse Neocortical Parvalbumin Interneurons.

    Science.gov (United States)

    Scholl, Benjamin; Pattadkal, Jagruti J; Dilly, Geoffrey A; Priebe, Nicholas J; Zemelman, Boris V

    2015-07-15

    Dissecting the functional roles of excitatory and inhibitory neurons in cortical circuits is a fundamental goal in neuroscience. Of particular interest are their roles in emergent cortical computations such as binocular integration in primary visual cortex (V1). We measured the binocular response selectivity of genetically defined subpopulations of excitatory and inhibitory neurons. Parvalbumin (PV+) interneurons received strong inputs from both eyes but lacked selectivity for binocular disparity. Because broad selectivity could result from heterogeneous synaptic input from neighboring neurons, we examined how individual PV+ interneuron selectivity compared to that of the local neuronal network, which is primarily composed of excitatory neurons. PV+ neurons showed functional similarity to neighboring neuronal populations over spatial distances resembling measurements of synaptic connectivity. On the other hand, excitatory neurons expressing CaMKIIα displayed no such functional similarity with the neighboring population. Our findings suggest that broad selectivity of PV+ interneurons results from nonspecific integration within local networks. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Graphene Oxide Dysregulates Neuroligin/NLG-1-Mediated Molecular Signaling in Interneurons in Caenorhabditis elegans

    Science.gov (United States)

    Chen, He; Li, Huirong; Wang, Dayong

    2017-01-01

    Graphene oxide (GO) can be potentially used in many medical and industrial fields. Using assay system of Caenorhabditis elegans, we identified the NLG-1/Neuroligin-mediated neuronal signaling dysregulated by GO exposure. In nematodes, GO exposure significantly decreased the expression of NLG-1, a postsynaptic cell adhesion protein. Loss-of-function mutation of nlg-1 gene resulted in a susceptible property of nematodes to GO toxicity. Rescue experiments suggested that NLG-1 could act in AIY interneurons to regulate the response to GO exposure. In the AIY interneurons, PKC-1, a serine/threonine protein kinase C (PKC) protein, was identified as the downstream target for NLG-1 in the regulation of response to GO exposure. LIN-45, a Raf protein in ERK signaling pathway, was further identified as the downstream target for PKC-1 in the regulation of response to GO exposure. Therefore, GO may dysregulate NLG-1-mediated molecular signaling in the interneurons, and a neuronal signaling cascade of NLG-1-PKC-1-LIN-45 was raised to be required for the control of response to GO exposure. More importantly, intestinal RNAi knockdown of daf-16 gene encoding a FOXO transcriptional factor in insulin signaling pathway suppressed the resistant property of nematodes overexpressing NLG-1 to GO toxicity, suggesting the possible link between neuronal NLG-1 signaling and intestinal insulin signaling in the regulation of response to GO exposure.

  5. GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain

    Science.gov (United States)

    Losi, Gabriele; Mariotti, Letizia; Carmignoto, Giorgio

    2014-01-01

    GABAergic interneurons represent a minority of all cortical neurons and yet they efficiently control neural network activities in all brain areas. In parallel, glial cell astrocytes exert a broad control of brain tissue homeostasis and metabolism, modulate synaptic transmission and contribute to brain information processing in a dynamic interaction with neurons that is finely regulated in time and space. As most studies have focused on glutamatergic neurons and excitatory transmission, our knowledge of functional interactions between GABAergic interneurons and astrocytes is largely defective. Here, we critically discuss the currently available literature that hints at a potential relevance of this specific signalling in brain function. Astrocytes can respond to GABA through different mechanisms that include GABA receptors and transporters. GABA-activated astrocytes can, in turn, modulate local neuronal activity by releasing gliotransmitters including glutamate and ATP. In addition, astrocyte activation by different signals can modulate GABAergic neurotransmission. Full clarification of the reciprocal signalling between different GABAergic interneurons and astrocytes will improve our understanding of brain network complexity and has the potential to unveil novel therapeutic strategies for brain disorders. PMID:25225102

  6. Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

    Directory of Open Access Journals (Sweden)

    Sébastien Desgent

    2012-01-01

    Full Text Available Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field.

  7. HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex

    Directory of Open Access Journals (Sweden)

    Alexi Nott

    2015-01-01

    Full Text Available An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of parvalbumin (Pv–expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2, has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv interneurons reduces inhibitory input in the visual cortex of adult mice and coincides with enhanced long-term depression that is more typical of young mice. These findings show that HDAC2 loss in Pv interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

  8. HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex.

    Science.gov (United States)

    Nott, Alexi; Cho, Sukhee; Seo, Jinsoo; Tsai, Li-Huei

    2015-01-01

    An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of Parvalbumin (Pv)-expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2), has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv-interneurons reduces inhibitory input in the visual cortex of adult mice, and coincides with enhanced long-term depression (LTD) that is more typical of young mice. These findings show that HDAC2 loss in Pv-interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

  9. Cell Type-Specific Expression of Corticotropin-Releasing Hormone-Binding Protein in GABAergic Interneurons in the Prefrontal Cortex

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    Kyle D. Ketchesin

    2017-10-01

    Full Text Available Corticotropin-releasing hormone-binding protein (CRH-BP is a secreted glycoprotein that binds CRH with very high affinity to modulate CRH receptor activity. CRH-BP is widely expressed throughout the brain, with particularly high expression in regions such as the amygdala, hippocampus, ventral tegmental area and prefrontal cortex (PFC. Recent studies suggest a role for CRH-BP in stress-related psychiatric disorders and addiction, with the PFC being a potential site of interest. However, the molecular phenotype of CRH-BP-expressing cells in this region has not been well-characterized. In the current study, we sought to determine the cell type-specific expression of CRH-BP in the PFC to begin to define the neural circuits in which this key regulator is acting. To characterize the expression of CRH-BP in excitatory and/or inhibitory neurons, we utilized dual in situ hybridization to examine the cellular colocalization of CRH-BP mRNA with vesicular glutamate transporter (VGLUT or glutamic acid decarboxylase (GAD mRNA in different subregions of the PFC. We show that CRH-BP is expressed predominantly in GABAergic interneurons of the PFC, as revealed by the high degree of colocalization (>85% between CRH-BP and GAD. To further characterize the expression of CRH-BP in this heterogenous group of inhibitory neurons, we examined the colocalization of CRH-BP with various molecular markers of GABAergic interneurons, including parvalbumin (PV, somatostatin (SST, vasoactive intestinal peptide (VIP and cholecystokinin (CCK. We demonstrate that CRH-BP is colocalized predominantly with SST in the PFC, with lower levels of colocalization in PV- and CCK-expressing neurons. Our results provide a more comprehensive characterization of the cell type-specific expression of CRH-BP and begin to define its potential role within circuits of the PFC. These results will serve as the basis for future in vivo studies to manipulate CRH-BP in a cell type-specific manner to better

  10. Prolonged response to calling songs by the L3 auditory interneuron in female crickets (Acheta domesticus): intracellular evaluation.

    Science.gov (United States)

    Navia, Benjamin; Stout, John; Atkins, Gordon

    2003-03-01

    The L3 auditory interneuron in female Acheta domesticus, produces two different responses to the male calling song: an immediate response and a prolonged response. The prolonged response exhibited spiking activity and a correlated prolonged depolarization, both of which are clearly seen in intracellular recordings. The morphology revealed by intracellular staining was clearly the L3 neuron. The amplitude of the prolonged depolarization associated with the prolonged response increased with increases in sound intensity, resulting in increased spiking rates. Both depolarization and sound presentation increased the spiking rate and the slope of pre-potentials (thus leading to spiking threshold more quickly). Injecting hyperpolarizing current had the expected opposite effect. The effects of positive current injection and sound presentation were additive, resulting in spiking rates that were approximately double the rates in response to sound alone. Short postsynaptic potentials (PSPs), whose duration ranged from 15-60 ms, which may lead to action potentials were also observed in all recordings and summated with the prolonged depolarization, increasing the probability of spiking. Copyright 2003 Wiley-Liss, Inc.

  11. Vibratory interneurons in the non-hearing cave cricket indicate evolutionary origin of sound processing elements in Ensifera.

    Science.gov (United States)

    Stritih, Natasa; Stumpner, Andreas

    2009-01-01

    Tympanal hearing organs in the front tibiae of ensiferan insects supposedly evolved from vibration-sensitive tibial organs (TO), like those in the cave cricket Troglophilus neglectus (Rhaphidophoridae). If this is true, one expects to find interneurons in the cave cricket that are homologous to auditory neurons from hearing Ensifera. Therefore, we examined the central projections of the foreleg TO of the cave cricket, as well as morphology and response properties of interneurons responding to foreleg vibration. Sensory axons of the TO adjoined to the "tympanal nerve" terminate in the equivalent portion of the ring tract neuropile in the prothoracic ganglion as corresponding receptors of crickets and weta. We found nine putatively homologous elements to sound- and/or vibration-sensitive interneurons of Ensifera--one local neuron (unpaired median, DUM), three T-fibres (TN), three descending (DN) and two ascending neurons (AN). Presumable first-order interneurons arborising in the ring tract correspond to a local auditory DUM cell of bush crickets and to TN1, DN1 and AN2 of various Ensifera, respectively. Homologues of some prominent auditory cells, the "omega" neuron(s) and the ascending neuron 1 (AN1), however, were not found. We conclude that (a) T. neglectus interneurons are morphologically primitive with respect to those of hearing taxa, (b) significant changes in the dendritic structure/synaptic connectivity have taken place during the evolution of the most specialised first-order auditory interneurons of Ensifera, (c) the data do not contradict independent evolution of hearing in Grylloidea and Tettigonoidea. Other interneurons appear morpho-physiologically conserved across hearing and non-hearing species, possibly as a part of a multimodal "alert" system.

  12. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

    Directory of Open Access Journals (Sweden)

    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  13. Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo.

    Science.gov (United States)

    Mantoan Ritter, Laura; Macdonald, Douglas C; Ritter, Georg; Escors, David; Chiara, Francesca; Cariboni, Anna; Schorge, Stephanie; Kullmann, Dimitri M; Collins, Mary

    2016-01-01

    The ability to manipulate the activity of interneurons with optogenetic tools offers the possibility of interfering with diseases caused by altered neuronal inhibition and synchrony, including epilepsy and schizophrenia. To develop vectors for therapeutic approaches, targeting optogenetic constructs to interneurons is therefore a key requirement. We investigated whether the interneuron-specific promoters glutamic acid decarboxylase (GAD)67 and cholecystokinin (CCK) allowed targeted lentiviral delivery of opsins to interneurons as a whole, or specifically CCK+ interneurons. We generated lentiviral (LV) plasmids encoding channelrhodopsin (ChR2) and halorhodopsin (NpHR) tagged with fluorophores and driven by GAD67 or CCK promoters. Adeno-associated virus (AAV) and LV vectors carrying opsins driven by pyramidal cell promoters were used as controls. We transduced neuronal cultures and rodent brain in vivo, immunostained specimens 6-8 weeks after in vivo injection and 7-14 days after in vitro transduction, and evaluated volume and specificity of expression by confocal microscopy. In vitro, 90% (19/21) of LV-CCK-NpHR2.0-EYFP expressing neurons were CCK+. In vivo, LV-GAD67-ChR2-mCherry was expressed in 2.6% (5/193), LV-GAD67-NpHR2.0-EYFP in approximately 15% (43/279) and LV-CCK-NpHR2.0-EYFP in 47% (9/19) of hippocampal GABA+ interneurons. GAD67 vectors expressed in larger volumes than CCK-driven constructs. AAV vector controls achieved the largest expression volumes. LV-CCK-NpHR2.0-EYFP may be useful for targeting CCK+ interneurons in culture. GAD67/CCK-driven lentiviral constructs are expressed in vivo, although expression is not specific for interneurons. Overall, expression levels are low compared to opsins driven by pyramidal cell promoters. A better understanding of GAD67 and CCK promoter structure or alternative techniques is required to reliably target opsins to interneurons using viral vectors. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Nox-2-mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice

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    lili qiu

    2016-10-01

    Full Text Available Postoperative cognitive decline (POCD is a common complication following anesthesia and surgery, especially in elderly patients; however, the precise mechanisms of POCD remain unclear. Here, we investigated whether nicotinamide adenine dinucleotide phosphate (NADPH oxidase mediated-abnormalities in parvalbumin (PV interneurons play an important role in the pathophysiology of POCD. The animal model was established using isoflurane anesthesia and exploratory laparotomy in sixteen-month-old male C57BL/6 mice. For interventional experiments, mice were chronically treated with the NADPH oxidase inhibitor apocynin (APO. Open field and fear conditioning behavioral tests were performed on day 6 and 7 post-surgery, respectively. In a separate experiment, brain tissue was harvested and subjected to biochemical analysis. Primary hippocampal neurons challenged with lipopolysaccharide in vitro were used to investigate the mechanisms underlying the oxidative stress-induced abnormalities in PV interneurons. Our results showed that anesthesia and surgery induced significant hippocampus-dependent memory impairment, which was accompanied by PV interneuron phenotype loss and increased expression of interleukin-1β, markers of oxidative stress, and NADPH oxidase 2 (Nox2 in the hippocampus. In addition, lipopolysaccharide exposure increased Nox2 level and decreased the expression of PV and the number of excitatory synapses onto PV interneurons in the primary hippocampal neurons. Notably, treatment with APO reversed these abnormalities. Our study suggests that Nox2-derived ROS production triggers, at least in part, anesthesia- and surgery-induced hippocampal PV interneuron phenotype loss and consequent cognitive impairment in aging mice.

  15. Trajectory of the main GABAergic interneuron populations from early development to old age in the rat primary auditory cortex

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    Lydia eOuellet

    2014-06-01

    Full Text Available In both humans and rodents, decline in cognitive function is a hallmark of the aging process, the basis for this decrease has yet to be fully characterized. However, using aged rodent models, deficits in auditory processing have been associated with significant decreases in inhibitory signaling attributed to a loss of GABAergic interneurons. Not only are these interneurons crucial for pattern detection and other large-scale population dynamics, but they have also been linked to mechanisms mediating plasticity and learning, making them a prime candidate for study and modelling of modifications to cortical communication pathways in neurodegenerative diseases. Using the rat primary auditory cortex (A1 as a model, we probed the known markers of GABAergic interneurons with immunohistological methods, using antibodies against gamma aminobutyric acid (GABA, parvalbumin (PV, somatostatin (SOM, calretinin (CR, vasoactive intestinal peptide (VIP, choline acetyltransferase (ChAT, neuropeptide Y (NPY and cholecystokinin (CCK to document the changes observed in interneuron populations across the rat’s lifespan. This analysis provided strong evidence that several but not all GABAergic neurons were affected by the aging process, showing most dramatic changes in expression of parvalbumin (PV and somatostatin (SOM expression. With this evidence, we show how understanding these trajectories of cell counts may be factored into a simple model to quantify changes in inhibitory signalling across the course of life, which may be applied as a framework for creating more advanced simulations of interneuronal implication in normal cerebral processing, normal aging, or pathological processes.

  16. Interneurons in the Honeybee Primary Auditory Center Responding to Waggle Dance-Like Vibration Pulses.

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    Ai, Hiroyuki; Kai, Kazuki; Kumaraswamy, Ajayrama; Ikeno, Hidetoshi; Wachtler, Thomas

    2017-11-01

    Female honeybees use the "waggle dance" to communicate the location of nectar sources to their hive mates. Distance information is encoded in the duration of the waggle phase (von Frisch, 1967). During the waggle phase, the dancer produces trains of vibration pulses, which are detected by the follower bees via Johnston's organ located on the antennae. To uncover the neural mechanisms underlying the encoding of distance information in the waggle dance follower, we investigated morphology, physiology, and immunohistochemistry of interneurons arborizing in the primary auditory center of the honeybee (Apis mellifera). We identified major interneuron types, named DL-Int-1, DL-Int-2, and bilateral DL-dSEG-LP, that responded with different spiking patterns to vibration pulses applied to the antennae. Experimental and computational analyses suggest that inhibitory connection plays a role in encoding and processing the duration of vibration pulse trains in the primary auditory center of the honeybee.SIGNIFICANCE STATEMENT The waggle dance represents a form of symbolic communication used by honeybees to convey the location of food sources via species-specific sound. The brain mechanisms used to decipher this symbolic information are unknown. We examined interneurons in the honeybee primary auditory center and identified different neuron types with specific properties. The results of our computational analyses suggest that inhibitory connection plays a role in encoding waggle dance signals. Our results are critical for understanding how the honeybee deciphers information from the sound produced by the waggle dance and provide new insights regarding how common neural mechanisms are used by different species to achieve communication. Copyright © 2017 the authors 0270-6474/17/3710624-12$15.00/0.

  17. Active action potential propagation but not initiation in thalamic interneuron dendrites

    Science.gov (United States)

    Casale, Amanda E.; McCormick, David A.

    2012-01-01

    Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

  18. HCN Channel Modulation of Synaptic Integration in GABAergic Interneurons in Malformed Rat Neocortex

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    John J. Hablitz

    2017-04-01

    Full Text Available Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.

  19. Interneuronal systems of the cervical spinal cord assessed with BOLD imaging at 1.5 T

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    Stracke, C.P.; Schoth, F.; Moeller-Hartmann, W.; Krings, T. [University Hospital of the University of Technology, Departments of Neuroradiology and Diagnostic Radiology, Aachen (Germany); Pettersson, L.G. [University of Goeteborg, Department of Physiology, Goeteborg (Sweden)

    2005-02-01

    The purpose of this study was to investigate if functional activity with spinal cord somatosensory stimulation can be visualized using BOLD fMRI. We investigated nine healthy volunteers using a somatosensory stimulus generator. The stimuli were applied in three different runs at the first, third, and fifth finger tip of the right hand, respectively, corresponding to dermatomes c6, c7, and c8. The stimuli gave an increase of BOLD signal (activation) in three different locations of the spinal cord and brain stem. First, activations could be seen in the spinal segment corresponding to the stimulated dermatome in seven out of nine volunteers for c6 stimulation, two out of eight for c7, and three out of eight for c8. These activations were located close to the posterior margin of the spinal cord, presumably reflecting synaptic transmission to dorsal horn interneurons. Second, activation in the medulla oblongata was evident in four subjects, most likely corresponding to the location of the nucleus cuneatus. The third location of activation, which was the strongest and most reliable observed was inside the spinal cord in the c3 and c4 segments. Activation at these spinal levels was almost invariably observed independently of the dermatome stimulated (9/9 for c6, 8/8 for c7, and 7/8 for c8 stimulation). These activations may pertain to an interneuronal system at this spinal level. The results are discussed in relation to neurophysiological studies on cervical spinal interneuronal pathways in animals and humans. (orig.)

  20. Bulbar microcircuit model predicts connectivity and roles of interneurons in odor coding.

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    Aditya Gilra

    Full Text Available Stimulus encoding by primary sensory brain areas provides a data-rich context for understanding their circuit mechanisms. The vertebrate olfactory bulb is an input area having unusual two-layer dendro-dendritic connections whose roles in odor coding are unclear. To clarify these roles, we built a detailed compartmental model of the rat olfactory bulb that synthesizes a much wider range of experimental observations on bulbar physiology and response dynamics than has hitherto been modeled. We predict that superficial-layer inhibitory interneurons (periglomerular cells linearize the input-output transformation of the principal neurons (mitral cells, unlike previous models of contrast enhancement. The linearization is required to replicate observed linear summation of mitral odor responses. Further, in our model, action-potentials back-propagate along lateral dendrites of mitral cells and activate deep-layer inhibitory interneurons (granule cells. Using this, we propose sparse, long-range inhibition between mitral cells, mediated by granule cells, to explain how the respiratory phases of odor responses of sister mitral cells can be sometimes decorrelated as observed, despite receiving similar receptor input. We also rule out some alternative mechanisms. In our mechanism, we predict that a few distant mitral cells receiving input from different receptors, inhibit sister mitral cells differentially, by activating disjoint subsets of granule cells. This differential inhibition is strong enough to decorrelate their firing rate phases, and not merely modulate their spike timing. Thus our well-constrained model suggests novel computational roles for the two most numerous classes of interneurons in the bulb.

  1. Selectivity of pyramidal cells and interneurons in the human medial temporal lobe

    Science.gov (United States)

    Mormann, Florian; Cerf, Moran; Koch, Christof; Fried, Itzhak; Quiroga, Rodrigo Quian

    2011-01-01

    Neurons in the medial temporal lobe (MTL) respond selectively to pictures of specific individuals, objects, and places. However, the underlying mechanisms leading to such degree of stimulus selectivity are largely unknown. A necessary step to move forward in this direction involves the identification and characterization of the different neuron types present in MTL circuitry. We show that putative principal cells recorded in vivo from the human MTL are more selective than putative interneurons. Furthermore, we report that putative hippocampal pyramidal cells exhibit the highest degree of selectivity within the MTL, reflecting the hierarchical processing of visual information. We interpret these differences in selectivity as a plausible mechanism for generating sparse responses. PMID:21715671

  2. Organization of projection-specific interneurons in the spinal cord of the red-eared turtle

    DEFF Research Database (Denmark)

    Nissen, Ulla Vig; Moldovan, Mihai; Hounsgaard, Jørn

    2008-01-01

    Using differential retrograde axonal tracing, we identified motoneurons (MNs) and projection-specific interneuron (IN) classes in lumbar segment D9 of the adult red-eared turtle spinal cord. We characterized the distribution of these neurons in the transverse plane, and estimated their numbers an...... of aIINs versus dIINs, of aCINs versus dCINs, and of adIINs versus adCINs. The findings are compared to the organization of lumbar spinal INs in other vertebrate species....

  3. Long-term potentiation in hippocampal oriens interneurons: postsynaptic induction, presynaptic expression and evaluation of candidate retrograde factors

    Science.gov (United States)

    Nicholson, Elizabeth; Kullmann, Dimitri M.

    2014-01-01

    Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca2+-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor. PMID:24298136

  4. Interneuron Deficit Associates Attenuated Network Synchronization to Mismatch of Energy Supply and Demand in Aging Mouse Brains

    DEFF Research Database (Denmark)

    Jessen, Sanne Barsballe; Mathiesen, Claus; Lind, Barbara Lykke

    2017-01-01

    Higher cognitive functions depend critically on synchronized network activity in the gamma range (30-100 Hz), which results from activity of fast-spiking parvalbumin-positive (PV) interneurons. Here, we examined synaptic activity in the gamma band in relation to PV interneuron activity, stimulation......-induced calcium activity in neurons and astrocytes, and cerebral blood flow and oxygen responses in the somatosensory cortex of young adult and old adult mice in vivo using electrical whisker pad stimulation. Gamma activity was reduced in old adult mice, and associated with reduced calcium activity of PV......-dependent rise in O2 use, that is, the rise in the cerebral metabolic rate of oxygen (CMRO2) evoked by excitatory postsynaptic currents almost doubled in old adult mice. We conclude that PV interneuron function and gamma activity are particularly affected in old adult mice. Alterations in neurovascular coupling...

  5. The sodium channel activator Lu AE98134 normalizes the altered firing properties of fast spiking interneurons in Dlx5/6+/- mice

    DEFF Research Database (Denmark)

    von Schoubye, Nadia Lybøl; Frederiksen, Kristen; Kristiansen, Uffe

    2018-01-01

    Mental disorders such as schizophrenia are associated with impaired firing properties of fast spiking inhibitory interneurons (FSINs) causing reduced task-evoked gamma-oscillation in prefrontal cortex. The voltage-gated sodium channel NaV1.1 is highly expressed in PV-positive interneurons, but only...

  6. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.

    Science.gov (United States)

    Kvitsiani, D; Ranade, S; Hangya, B; Taniguchi, H; Huang, J Z; Kepecs, A

    2013-06-20

    Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.

  7. Preferential expression of an AAV-2 construct in NOS-positive interneurons following intrastriatal injection.

    Science.gov (United States)

    Sin, Mihaela; Walker, Paul D; Bouhamdan, Mohamad; Quinn, John P; Bannon, Michael J

    2005-11-18

    Most CNS studies using recombinant adeno-associated virus type 2 (rAAV-2) vectors have focused on gene delivery for the purpose of gene therapy. In the present study, we examined the feasibility of using rAAV-2 vectors to study the regulation of preprotachykinin-A (PPT-A) promoter activity in striatal medium spiny projection neurons. An rAAV-2 vector incorporating a PPT promoter fragment (shown previously to confer some cell-specificity of expression in vitro) coupled to a green fluorescent protein (GFP) reporter gene was stereotaxically injected into the rat striatum. Since medium spiny projection neurons represent the predominant neuronal type (90-95%) in the striatum, we predicted that the vast majority of GFP-expressing cells would be of this phenotype. Surprisingly, the transgene was actually expressed in a similar number of medium spiny projection neurons and interneurons, while glial expression of GFP was not observed. A preponderance of GFP-expressing interneurons was immunoreactive for the marker neuronal nitric oxide synthase (nNOS). Our results suggest that viral vector-related events that occur during transduction are the determining factor in the pattern of transgene expression observed, while the influence of the transgene promoter appears to be secondary, at least under the conditions employed.

  8. Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex.

    Science.gov (United States)

    Toriumi, Kazuya; Oki, Mika; Muto, Eriko; Tanaka, Junko; Mouri, Akihiro; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2016-06-01

    We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.

  9. DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function.

    Science.gov (United States)

    Rabe Bernhardt, Nadine; Memic, Fatima; Gezelius, Henrik; Thiebes, Anja-Lena; Vallstedt, Anna; Kullander, Klas

    2012-06-15

    Coordinated limb rhythmic movements take place through organized signaling in local spinal cord neuronal networks. The establishment of these circuitries during development is dependent on the correct guidance of axons to their targets. It has previously been shown that the well-known axon guidance molecule netrin-1 is required for configuring the circuitry that provides left-right alternating coordination in fictive locomotion. The attraction of commissural axons to the midline in response to netrin-1 has been shown to involve the netrin-1 receptor DCC (deleted in Colorectal Cancer). However, the role of DCC for the establishment of CPG coordination has not yet been resolved. We show that mice carrying a null mutation of DCC displayed an uncoordinated left-right activity during fictive locomotion accompanied by a loss of interneuronal subpopulations originating from commissural progenitors. Thus, DCC plays a crucial role in the formation of spinal neuronal circuitry coordinating left-right activities. Together with the previously published results from netrin-1 deficient mice, the data presented in this study suggest a role for the most ventral originating V3 interneurons in synchronous activities over the midline. Further, it provides evidence that axon crossing in the spinal cord is more intricately controlled than in previously suggested models of DCC-netrin-1 interaction. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse.

    Science.gov (United States)

    Caldeira, Vanessa; Dougherty, Kimberly J; Borgius, Lotta; Kiehn, Ole

    2017-01-27

    Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype and progenitor domain, but does not overlap with the Shox2 non-V2a population. We also show that Hb9::Cre-derived INs include the comparatively small medial population of INs which continues to express Hb9 postnatally. When excitatory neurotransmission is selectively blocked by deleting Vglut2 from Hb9::Cre-derived INs, there is no difference in left-right and/or flexor-extensor phasing between these cords and controls, suggesting that excitatory Hb9::Cre-derived INs do not affect pattern generation. In contrast, the frequencies of locomotor activity are significantly lower in cords from Hb9::Cre-Vglut2(Δ/Δ) mice than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion.

  11. Augmented inhibition from cannabinoid sensitive interneurons diminishes CA1 output after traumatic brain injury

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    Brian Neal Johnson

    2014-12-01

    Full Text Available The neurological impairments associated with traumatic brain injury include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. To examine network activity in the hippocampal CA1 region after lateral fluid percussion injury, we used a combination of voltage sensitive dye, field potential and patch clamp recording in mouse hippocampal brain slices. When the stratum radiatum was stimulated in slices from injured mice we found decreased depolarization in stratum radiatum and increased hyperpolarization in stratum oriens, together with a decrease in the percentage of pyramidal neurons firing stimulus-evoked action potentials. Increased hyperpolarization in stratum oriens persisted when glutamatergic transmission was blocked. However, we found no changes in stratum oriens responses when the alveus was stimulated to directly activate stratum oriens. These results suggest that the increased stratum oriens hyperpolarization evoked by stratum radiatum stimulation was mediated by interneurons that have cell bodies and/or axons in stratum radiatum, and form synapses in stratum pyramidale and stratum oriens. A low concentration (100 nM of the synthetic cannabinoid WIN55,212-2,restored CA1 output in slices from injured animals. These findings support the hypothesis that increased GABAergic signaling by cannabinoid sensitive interneurons contributes to the reduced CA1 output following traumatic brain injury.

  12. Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

    Science.gov (United States)

    Choi, Yun-Sik; Lin, Stanley L.; Lee, Boyoung; Kurup, Pradeep; Cho, Hee-Yeon; Naegele, Janice R.; Lombroso, Paul J.; Obrietan, Karl

    2009-01-01

    Excitotoxic cell death is one of the precipitating events in the development of temporal lobe epilepsy. Of particular prominence is the loss of GABAergic hilar neurons. Although the molecular mechanisms responsible for the selective vulnerability of these cells are not well understood, activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway has been implicated in neuroprotective responses to excitotoxicity in other neuronal populations. Here, we report that high levels of the striatal-enriched protein tyrosine phosphatase (STEP), a key regulator of ERK/MAPK signaling, are found in vulnerable somatostatin-immunoreactive hilar interneurons. Under both control conditions and after pilocarpine-induced status epilepticus (SE), ERK/MAPK activation was repressed in STEP-immunoreactive hilar neurons. This contrasts with robust SE-induced ERK/MAPK activation in the granule cell layer of the dentate gyrus, a cell region that does not express STEP. During pilocarpine-induced SE, in vivo disruption of STEP activity allowed activation of the MAPK pathway, leading to immediate-early gene expression and significant rescue from cell death. Thus, STEP increases the sensitivity of neurons to SE-induced excitotoxicity by specifically blocking a latent neuroprotective response initiated by the MAPK pathway. These findings identify a key set of signaling events that render somatostatinergic hilar interneurons vulnerable to SE-induced cell death. PMID:17360923

  13. Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy

    DEFF Research Database (Denmark)

    Fenrich, Keith K; Skelton, Nicole; MacDermid, Victoria E

    2007-01-01

    , develop de novo axons. Our goal was to determine whether spinal commissural interneurons (CINs), axotomized by 3-4-mm midsagittal transection at C3, form de novo axons from distal dendrites. All experiments were performed on adult cats. CINs in C3 were stained with extracellular injections of Neurobiotin...

  14. Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

    Science.gov (United States)

    Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki

    2017-09-01

    Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Representation of behaviourally relevant information by blowfly motion-sensitive visual interneurons requires precise compensatory head movements

    NARCIS (Netherlands)

    Kern, R.; Hateren, J.H. van; Egelhaaf, M.

    2006-01-01

    Flying blowflies shift their gaze by saccadic turns of body and head, keeping their gaze basically fixed between saccades. For the head, this results in almost pure translational optic flow between saccades, enabling visual interneurons in the fly motion pathway to extract information about

  16. In Vivo Study of Dynamics and Stability of Dendritic Spines on Olfactory Bulb Interneurons in Xenopus laevis Tadpoles.

    Directory of Open Access Journals (Sweden)

    Yu-Bin Huang

    Full Text Available Dendritic spines undergo continuous remodeling during development of the nervous system. Their stability is essential for maintaining a functional neuronal circuit. Spine dynamics and stability of cortical excitatory pyramidal neurons have been explored extensively in mammalian animal models. However, little is known about spiny interneurons in non-mammalian vertebrate models. In the present study, neuronal morphology was visualized by single-cell electroporation. Spiny neurons were surveyed in the Xenopus tadpole brain and observed to be widely distributed in the olfactory bulb and telencephalon. DsRed- or PSD95-GFP-expressing spiny interneurons in the olfactory bulb were selected for in vivo time-lapse imaging. Dendritic protrusions were classified as filopodia, thin, stubby, or mushroom spines based on morphology. Dendritic spines on the interneurons were highly dynamic, especially the filopodia and thin spines. The stubby and mushroom spines were relatively more stable, although their stability significantly decreased with longer observation intervals. The 4 spine types exhibited diverse preferences during morphological transitions from one spine type to others. Sensory deprivation induced by severing the olfactory nerve to block the input of mitral/tufted cells had no significant effects on interneuron spine stability. Hence, a new model was established in Xenopus laevis tadpoles to explore dendritic spine dynamics in vivo.

  17. Ca2+ -Mediated Plateau Potentials in a Subpopulation of Interneurons in the Ventral Horn of the Turtle Spinal Cord

    DEFF Research Database (Denmark)

    Hounsgaard, J.; Kjaerulff, O.

    1992-01-01

    The response properties of interneurons in the ventral horn were studied in transverse slices of segments D8 to S2 from the turtle spinal cord, using the current clamp technique. In about half of the neurons the response properties were dominated by their ability to generate plateau potentials...

  18. White noise analysis of graded response in a wind-sensitive, nonspiking interneuron of the cockroach.

    Science.gov (United States)

    Kondoh, Y; Morishita, H; Arima, T; Okuma, J; Hasegawa, Y

    1991-04-01

    1. A novel approach using a Gaussian white noise as stimulus is described which allowed quantitative analysis of neuronal responses in the cercal system of the cockroach, Periplaneta americana. Cerci were stimulated by air displacement which was modulated by a sinusoidal and a white noise signal. During the stimulation, intracellular recordings were made from a uniquely identifiable, nonspiking, local interneuron which locates within the terminal abdominal ganglion. The white noise stimulation was cross-correlated with the evoked response to compute first- and second-order kernels that could define the cell's response dynamics. 2. The interneuron, cell 101, has an exceptionally large transverse neurite that connects two asymmetrical dendritic arborizations located on both sides of the ganglion. 3. The first-order Wiener kernels in cell 101 were biphasic (differentiating). The waveforms of the kernels produced by the ipsilateral and contralateral stimulations were roughly mirror images of each other: the kernels produced by wind stimuli on the side ipsilateral to the cell body of the interneuron are initially depolarized and then hyperpolarized, whereas those on the other side are initially hyperpolarized. The polarity reversal occurred along the midline of the animal's body, and no well-defined kernel was produced by a stimulus directed head on or from the tail. 4. Mean square error (MSE) between the actual response and the model prediction suggests that the linear component in cell 101 comprises half of the cell's total response (MSEs for the linear models were about 50% at preferred directions), whereas the second-order, non-linear component is insignificant. The linear component of the wind-evoked response was bandpass with the preferred frequency of 70-90 Hz. 5. Accounting for a noise, we reasonably assumed that at high frequencies the graded response in cell 101 is linearly related to a modulation of the air displacement and sensitive to the rate of change of

  19. Encoding of tactile stimuli by mechanoreceptors and interneurons of the medicinal leech

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    Jutta Kretzberg

    2016-10-01

    Full Text Available For many animals processing of tactile information is a crucial task in behavioral contexts like exploration, foraging and stimulus avoidance. The leech, having infrequent access to food, developed an energy efficient reaction to tactile stimuli, avoiding unnecessary muscle movements: The local bend behavior moves only a small part of the body wall away from an object touching the skin, while the rest of the animal remains stationary. Amazingly, the precision of this localized behavioral response is similar to the spatial discrimination threshold of the human fingertip, although the leech skin is innervated by an order of magnitude fewer mechanoreceptors and each midbody ganglion contains only 400 individually identified neurons in total. Prior studies suggested that this behavior is controlled by a three-layered feed-forward network, consisting of four mechanoreceptors (P cells, approximately 20 interneurons and 10 individually characterized motor neurons, all of which encode tactile stimulus location by overlapping, symmetrical tuning curves. Additionally, encoding of mechanical force was attributed to three types of mechanoreceptors reacting to distinct intensity ranges: T cells for touch, P cells for pressure and N cells for strong, noxious skin stimulation. In this study, we provide evidences that tactile stimulus encoding in the leech is more complex than previously thought. Combined electrophysiological, anatomical and voltage sensitive dye approaches indicate that P and T cells both play a major role in tactile information processing resulting in local bending. Our results indicate that tactile encoding neither relies on distinct force intensity ranges of different cell types, nor location encoding is restricted to spike count tuning. Instead, we propose that P and T cells form a mixed type population, which simultaneously employs temporal response features and spike counts for multiplexed encoding of touch location and force intensity

  20. Responses of Withdrawal Interneurons to Serotonin Applications in Naïve and Learned Snails Are Different

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    Tatiana K. Bogodvid

    2017-12-01

    Full Text Available Long-term changes in membrane potential after associative training were described previously in identified premotor interneurons for withdrawal of the terrestrial snail Helix. Serotonin was shown to be a major transmitter involved in triggering the long-term changes in mollusks. In the present study we compared the changes in electrophysiological characteristics of identifiable premotor interneurons for withdrawal in response to bath applications of serotonin (5-HT or serotonin precursor 5-hydroxytryptophan (5-HTP in preparations from naïve, neurotoxin-injected or associatively trained snails. It was found that 5-HT or 5-HTP applications caused a significant decrease of membrane potential in premotor interneurons of naïve snails, associatively trained snails and snails with impaired serotonergic system by injection of a selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT 1 week before the experiments. Applications of 5-HT or 5-HTP did not cause significant changes in the action potential (AP threshold potential of these neurons in naïve snails. Conversely, applications of 5-HT or 5-HTP to the premotor interneurons of previously trained or 5,7-DHT-injected snails caused a significant increase in the firing threshold potential in spite of a depolarizing shift of the resting membrane potential. Results demonstrate that responsiveness of premotor interneurons to extracellularly applied 5-HT or 5-HTP changes for days after the associative training or serotonin depletion. Similarity of the effects in trained and 5,7-DHT-injected animals may be due to massive release of serotonin elicited by 5,7-DHT injection. Our results suggest that serotonin release due to aversive conditionining or elicited by the neurotoxin administration triggers similar changes in resting membrane potential and AP threshold in response to bath applications of 5-HT or its precursor 5-HTP.

  1. Independent control of gamma and theta activity by distinct interneuron networks in the olfactory bulb.

    Science.gov (United States)

    Fukunaga, Izumi; Herb, Jan T; Kollo, Mihaly; Boyden, Edward S; Schaefer, Andreas T

    2014-09-01

    Circuits in the brain possess the ability to orchestrate activities on different timescales, but the manner in which distinct circuits interact to sculpt diverse rhythms remains unresolved. The olfactory bulb is a classic example of a place in which slow theta and fast gamma rhythms coexist. Furthermore, inhibitory interneurons that are generally implicated in rhythm generation are segregated into distinct layers, neatly separating local and global motifs. We combined intracellular recordings in vivo with circuit-specific optogenetic interference to examine the contribution of inhibition to rhythmic activity in the mouse olfactory bulb. We found that the two inhibitory circuits controlled rhythms on distinct timescales: local, glomerular networks coordinated theta activity, regulating baseline and odor-evoked inhibition, whereas granule cells orchestrated gamma synchrony and spike timing. Notably, granule cells did not contribute to baseline rhythms or sniff-coupled odor-evoked inhibition. Thus, activities on theta and gamma timescales are controlled by separate, dissociable inhibitory networks in the olfactory bulb.

  2. Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

    Directory of Open Access Journals (Sweden)

    Roger Cachope

    2012-07-01

    Full Text Available Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior.

  3. The Mechanisms of Repetitive Spike Generation in an Axonless Retinal Interneuron

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    Mark S. Cembrowski

    2012-02-01

    Full Text Available Several types of retinal interneurons exhibit spikes but lack axons. One such neuron is the AII amacrine cell, in which spikes recorded at the soma exhibit small amplitudes (5 ms. Here, we used electrophysiological recordings and computational analysis to examine the mechanisms underlying this atypical spiking. We found that somatic spikes likely represent large, brief action potential-like events initiated in a single, electrotonically distal dendritic compartment. In this same compartment, spiking undergoes slow modulation, likely by an M-type K conductance. The structural correlate of this compartment is a thin neurite that extends from the primary dendritic tree: local application of TTX to this neurite, or excision of it, eliminates spiking. Thus, the physiology of the axonless AII is much more complex than would be anticipated from morphological descriptions and somatic recordings; in particular, the AII possesses a single dendritic structure that controls its firing pattern.

  4. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    Science.gov (United States)

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous, but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABAB response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Further, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR-activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking PV basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR-activation. Together these findings identify a major, previously unrecognized, target of μOR-modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications. PMID:22016519

  5. Ivy and neurogliaform interneurons are a major target of μ-opioid receptor modulation.

    Science.gov (United States)

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-10-19

    μ-Opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin-expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABA(B) response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that, across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Furthermore, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking parvalbumin basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR activation. Together, these findings identify a major, previously unrecognized, target of μOR modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications.

  6. Convergence of ipsi- and contralateral muscle afferents on common interneurons mediating reciprocal inhibition of ankle plantarflexors in humans

    DEFF Research Database (Denmark)

    Mrachacz-Kersting, Natalie; Geertsen, Svend S.; Stevenson, Andrew James Thomas

    2017-01-01

    Recent studies have shown that afferents arising from muscle receptors located on one side can affect the activity of muscles on the contralateral side. In animal preparations, evidence supports that afferent pathways originating from one limb converge onto interneurons mediating disynaptic...... reciprocal Ia inhibition of the opposite limb. This study was designed to investigate whether this pathway is similar in humans to that described in animals. Thirteen healthy volunteers participated in one of two experiments. In experiment 1, the effects of ipsilateral posterior tibial nerve (i...... induced a significantly greater inhibition compared to their separate effects. These data provide evidence of convergence on common inhibitory interneurons by muscle afferents activated by iPTN and cCPN stimulation during sitting. Since the inhibition elicited by cCPN stimulation is known to be mediated...

  7. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon.

    Science.gov (United States)

    Stemme, Torben; Iliffe, Thomas M; Bicker, Gerd; Harzsch, Steffen; Koenemann, Stefan

    2012-09-05

    Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin) combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral olfactory neuropils with a glomerular organization

  8. Serotonin immunoreactive interneurons in the brain of the Remipedia: new insights into the phylogenetic affinities of an enigmatic crustacean taxon

    Directory of Open Access Journals (Sweden)

    Stemme Torben

    2012-09-01

    Full Text Available Abstract Background Remipedia, a group of homonomously segmented, cave-dwelling, eyeless arthropods have been regarded as basal crustaceans in most early morphological and taxonomic studies. However, molecular sequence information together with the discovery of a highly differentiated brain led to a reconsideration of their phylogenetic position. Various conflicting hypotheses have been proposed including the claim for a basal position of Remipedia up to a close relationship with Malacostraca or Hexapoda. To provide new morphological characters that may allow phylogenetic insights, we have analyzed the architecture of the remipede brain in more detail using immunocytochemistry (serotonin, acetylated α-tubulin, synapsin combined with confocal laser-scanning microscopy and image reconstruction techniques. This approach allows for a comprehensive neuroanatomical comparison with other crustacean and hexapod taxa. Results The dominant structures of the brain are the deutocerebral olfactory neuropils, which are linked by the olfactory globular tracts to the protocerebral hemiellipsoid bodies. The olfactory globular tracts form a characteristic chiasm in the center of the brain. In Speleonectes tulumensis, each brain hemisphere contains about 120 serotonin immunoreactive neurons, which are distributed in distinct cell groups supplying fine, profusely branching neurites to 16 neuropilar domains. The olfactory neuropil comprises more than 300 spherical olfactory glomeruli arranged in sublobes. Eight serotonin immunoreactive neurons homogeneously innervate the olfactory glomeruli. In the protocerebrum, serotonin immunoreactivity revealed several structures, which, based on their position and connectivity resemble a central complex comprising a central body, a protocerebral bridge, W-, X-, Y-, Z-tracts, and lateral accessory lobes. Conclusions The brain of Remipedia shows several plesiomorphic features shared with other Mandibulata, such as deutocerebral

  9. Characterisation of type I and type II nNOS-expressing interneurons in the barrel cortex of mouse

    Directory of Open Access Journals (Sweden)

    Quentin ePerrenoud

    2012-06-01

    Full Text Available In the neocortex, neuronal Nitric Oxide-Synthase (nNOS is essentially expressed in two sets of GABAergic neurons: type I neurons displaying a high expression and type II neurons displaying a weaker expression. Using immunocytochemistry on mice expressing GFP under the control of the glutamic acid decarboxylase 67k (GAD67 promoter we studied the distribution of type I and type II neurons in the barrel cortex and their expression of parvalbumin (PV, somatostatin (SOM and vasoactive intestinal peptide (VIP. We found that type I neurons accumulated in deeper layers and expressed SOM (91.5% while type II neurons concentrated in layer II/III and VI and expressed PV (17.7%, SOM (18.7% and VIP (10.2%. We then characterised 42 nNOS transcribing neurons ex vivo, using whole-cell recordings coupled to singe-cell RT-PCR and biocytin labelling. Unsupervised cluster analysis of this sample disclosed four classes. One cluster (n=7 corresponded to large, deep layer neurons, displaying a high expression of SOM (85.7% and were thus very likely to correspond to type I neurons. The three other clusters were neurogliaform-like interneurons (n=19, deep layer neurons transcribing PV or SOM (n=9 and neurons transcribing VIP (n=7, matching the features of type II cells. Finally, we performed nNOS immunohistochemistry on two mouse lines in which GFP/YFP labelling revealed the expression of two specific developmental genes (Lhx6 and 5-HT3A. We found that type I neurons expressed Lhx6 but never 5-HT3A, indicating that they originate in the medial ganglionic eminence (MGE. Type II neurons expressed Lhx6 (63% and 5-HT3A (34.4% supporting that they derive either from the MGE or from the caudal ganglionic eminence (CGE and the entopeduncular preoptic area (AEP/PO. Together, our results support the view that type I neurons form a particular class of SOM-expressing neurons while type II neurons are heterogeneous and comprise at least three classes.

  10. Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.

    Science.gov (United States)

    Tong, Leslie M; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K; Yoon, Seo Yeon; Wang, Max M; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L R; Alvarez-Buylla, Arturo; Huang, Yadong

    2014-07-16

    Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases. Copyright © 2014 the authors 0270-6474/14/349506-10$15.00/0.

  11. Immunofluorescent visualization of mouse interneuron subtypes [v2; ref status: indexed, http://f1000r.es/4qq

    Directory of Open Access Journals (Sweden)

    Simon Molgaard

    2014-11-01

    Full Text Available The activity of excitatory neurons is controlled by a highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, an antibody review database, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for

  12. Genetic dissection of Gata2 selective functions during specification of V2 interneurons in the developing spinal cord.

    Science.gov (United States)

    Francius, Cédric; Ravassard, Philippe; Hidalgo-Figueroa, María; Mallet, Jacques; Clotman, Frédéric; Nardelli, Jeannette

    2015-07-01

    Motor activities are controlled by neural networks in the ventral spinal cord and consist in motor neurons and a set of distinct cardinal classes of spinal interneurons. These interneurons arise from distinct progenitor domains (p0-p3) delineated according to a transcriptional code. Neural progenitors of each domain express a unique combination of transcription factors (TFs) that largely contribute to determine the fate of four classes of interneurons (V0-V3) and motor neurons. In p2 domain, at least four subtypes of interneurons namely V2a, V2b, V2c, and Pax6(+) V2 are generated. Although genetic and molecular mechanisms that specify V2a and V2b are dependent on complex interplay between several TFs including Nkx6.1, Irx3, Gata2, Foxn4, and Ascl1, and signaling pathways such as Notch and TGF-β, the sequence order of the activation of these regulators and their respective contribution are not completely elucidated yet. Here, we provide evidence by loss- or gain-of-function experiments that Gata2 is necessary for the normal development of both V2a and V2b neurons. We demonstrate that Nkx6.1 and Dll4 positively regulate the activation of Gata2 and Foxn4 in p2 progenitors. Gata2 also participates in the maintenance of p2 domain by repressing motor neuron differentiation and exerting a feedback control on patterning genes. Finally, Gata2 promotes the selective activation of V2b program at the expense of V2a fate. Thus our results provide new insights on the hierarchy and complex interactions between regulators of V2 genetic program. © 2014 Wiley Periodicals, Inc.

  13. Immunohistochemical visualization of mouse interneuron subtypes [v1; ref status: indexed, http://f1000r.es/4em

    Directory of Open Access Journals (Sweden)

    Simon Molgaard

    2014-10-01

    Full Text Available The activity of excitatory neurons is controlled by a small, but highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for studying the

  14. Audition in the praying mantis, Mantis religiosa L.: identification of an interneuron mediating ultrasonic hearing.

    Science.gov (United States)

    Yager, D D; Hoy, R R

    1989-08-01

    1. The praying mantis possesses a single ear located in the ventral midline of the metathorax. We have studied the mantis' auditory nervous system using both extracellular and intracellular techniques and have identified anatomically and physiologically a mirror-image pair of interneurons (MR-501-T3) in the metathoracic ganglion that mediates ultrasonic hearing. 2. MR-501-T3 is tuned broadly to ultrasound with best sensitivity (55-60 dB SPL) between 25 and 45 kHz. Its tuning matches closely that of the whole tympanal nerve. 3. The physiological responses of MR-501-T3 are characterized by: (1) a phasic-tonic firing pattern with a distinctive initial burst at 500-800 spikes/s; (2) minimum latencies of 8-12 ms; (3) no spontaneous activity; (4) sigmoid intensity response curves with a small (10 dB) dynamic range; (5) accurate coding of stimulus duration and of repetition rates up to 60 pps. 4. The ascending axon of MR-501-T3 conducts action potentials at 4 m/s, a rate comparable with some giant fiber systems. 5. MR-501-T3 shows no directional capability. Sound from right and left produce identical responses in both cells of the pair. Neither cutting one tympanal nerve nor removing one hemi-ear leads to different responses in the two cells indicating that they must receive a common input, either from the auditory afferents or from interneurons. We present evidence that the two cells are not directly connected. 6. MR-501-T3 is a large, symmetrical cell with its processes primarily in the intermediate neuropil (lateral ring tract). Its integration segment crosses the midline in the supramedian commissure, and the cell body lies dorsally near the entrance of the leg nerve. The axon travels in the dorsal lateral tract and is one of the largest (17 microns) in the connective. 7. Given the strong anatomical similarities between MR-501-T3 and the G and B cells of the locust, these cells may be homologous. 8. We present arguments based on our physiological results and existing

  15. Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice.

    Science.gov (United States)

    Drexel, Meinrad; Romanov, Roman A; Wood, James; Weger, Stefan; Heilbronn, Regine; Wulff, Peer; Tasan, Ramon O; Harkany, Tibor; Sperk, Günther

    2017-08-23

    Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present

  16. Calretinin periglomerular interneurons in mice olfactory bulb: cells of few words

    Directory of Open Access Journals (Sweden)

    Alex Fogli Iseppe

    2016-10-01

    Full Text Available Within the olfactory bulb (OB, periglomerular (PG cells consist of various types of interneurons, generally classified by their chemical properties such as neurotransmitter and calcium binding proteins.Calretinin (CR characterizes morphologically and functionally the more numerous and one of the less known subpopulation of PG cells in the OB. Using of transgenic mice expressing eGFP under the CR promoter, we have tried to obtain the first functional characterization of these cells. Electrophysiological recordings were made in these cells using the patch-clamp technique in thin slices. Using ion substitution methods and specific blockers, we dissected the main voltage-dependent conductances present, obtaining a complete kinetic description for each of them.The more peculiar property of these cells from the electrophysiological point of view is the presence only of a single K-current, the IA - there is no trace of delayed rectifier or of Ca-dependent K-current. Other currents identified, isolated and fully characterised are two inward currents, a fast sodium current and a small L-type calcium current, and an inward rectifier, h-type cationic current. As a consequence of the peculiar complement of voltage-dependent conductances present in these cells, and in particular the absence of delayed-rectifier potassium currents, under the functional point of view these cells present two interesting properties.First, in response to prolonged depolarisations, after the inactivation of the A-current, these cells behave as a purely ohmic elements, showing no outward rectification. Second, the CR cells studied can respond only with a single action potential to excitatory inputs; since they send inhibitory synapses to projection neurones, they seem to be designed to inhibit responses of the main neurones to isolated, random excitatory signals, losing their vetoing effect for more structured, repetitive excitatory signals, as result from odour detection

  17. Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves.

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    Funk, Chadd M; Peelman, Kayla; Bellesi, Michele; Marshall, William; Cirelli, Chiara; Tononi, Giulio

    2017-09-20

    During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated. SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the

  18. Soft-diet feeding impairs neural transmission between mitral cells and interneurons in the mouse olfactory bulb.

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    Noguchi, Tomohiro; Utsugi, Chizuru; Kashiwayanagi, Makoto

    2017-11-01

    (Objective) The subventricular zone in mice generates a lot of neuroblasts even during adulthood. These neuroblasts migrate to the olfactory bulb and differentiate into inhibitory interneurons such as granule cells and periglomerular cells. Olfactory sensory neurons receive information from various odorants and transmit it to the olfactory bulb. Our previous study showed that soft-diet feeding impairs neurogenesis in the subventricular zone, in turn leading to the reduction of odor-induced behaviors and Fos-immunoreactivities, the latter of which are markers of neural activity, at the olfactory bulb after exposure to odors. Release of GABA from inhibitory interneurons at the olfactory bulb induces inhibitory currents at the mitral cells, which are output neurons from the olfactory bulb. (Design) In the present study, we measured spontaneous inhibitory postsynaptic currents (sIPSCs) at the mitral cells of mice fed a soft diet in order to explore the effects of changes in texture of diets on neural function at the olfactory bulb. (Results) The soft-diet feeding extended the intervals between sIPSCs and reduced their peak amplitudes. (Conclusions) The present results suggest that soft-diet feeding in mice attenuates the neural functions of inhibitory interneurons at the olfactory bulb. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. V1 and V2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion

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    Zhang, Jingming; Lanuza, Guillermo M.; Britz, Olivier; Wang, Zhi; Siembab, Valerie C.; Zhang, Ying; Velasquez, Tomoko; Alvarez, Francisco J.; Frank, Eric; Goulding, Martyn

    2014-01-01

    SUMMARY The reciprocal activation of flexor and extensor muscles constitutes the fundamental mechanism that tetrapod vertebrates use for locomotion and limb-driven reflex behaviors. This aspect of motor coordination is controlled by inhibitory neurons in the spinal cord; however, the identity of the spinal interneurons that serve this function is not known. Here we show that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally-located inhibitory neurons, V1 and V2b interneurons (INs). Abrogating V1 and V2b IN-derived neurotransmission in the isolated spinal cord results in a synchronous pattern of L2 flexor-related and L5 extensor-related locomotor activity. Mice lacking V1 and V2b inhibition are unable to articulate their limb joints and display marked deficits in limb-driven reflex movements. Taken together, these findings identify V1- and V2b-derived neurons as the core interneuronal components of the limb central pattern generator (CPG) that coordinate flexor-extensor motor activity. PMID:24698273

  20. Netrin-1-dependent spinal interneuron subtypes are required for the formation of left-right alternating locomotor circuitry.

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    Rabe, Nadine; Gezelius, Henrik; Vallstedt, Anna; Memic, Fatima; Kullander, Klas

    2009-12-16

    Neuronal circuits in the spinal cord that produce the rhythmic and coordinated activities necessary for limb movements are referred to as locomotor central pattern generators (CPGs). The identities and preceding development of neurons essential for coordination between left and right limbs are not yet known. We show that the ventral floor plate chemoattractant Netrin-1 preferentially guides dorsally originating subtypes of commissural interneurons, the majority of which are inhibitory. In contrast, the excitatory and ventralmost V3 subtype of interneurons have a normal number of commissural fibers in Netrin-1 mutant mice, thus being entirely independent of Netrin-1-mediated attraction. This selective loss of commissural fibers in Netrin-1 mutant mice resulted in an abnormal circuitry manifested by a complete switch from alternating to synchronous fictive locomotor activity suggesting that the most ventral-originating excitatory commissural interneurons are an important component of a left-right synchrony circuit in the locomotor CPG. Thus, during development, Netrin-1 plays a critical role for the establishment of a functional balanced CPG.

  1. Plastic changes in striatal fast-spiking interneurons following hemicerebellectomy and environmental enrichment.

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    De Bartolo, Paola; Gelfo, Francesca; Burello, Lorena; De Giorgio, Andrea; Petrosini, Laura; Granato, Alberto

    2011-09-01

    Recent findings suggest marked interconnections between the cerebellum and striatum, thus challenging the classical view of their segregated operation in motor control. Therefore, this study was aimed at further investigating this issue by analyzing the effects of hemicerebellectomy (HCb) on density and dendritic length of striatal fast-spiking interneurons (FSi). First, we analyzed the plastic rearrangements of striatal FSi morphology in hemicerebellectomized animals reared in standard conditions. Then, since environmental enrichment (EE) induces structural changes in experimental models of brain disease, we evaluated FSi morphology in lesioned animals exposed to an enriched environment after HCb. Although HCb did not affect FSi density, it progressively shrank dendritic branching of striatal FSi of both sides. These plastic changes, already evident 15 days after the cerebellar ablation, became very marked 30 days after the lesion. Such a relevant effect was completely abolished by postoperative enrichment. EE not only counteracted shrinkage of FSi dendritic arborization but also provoked a progressive increase in dendritic length which surpassed that of the controls as the enrichment period lengthened. These data confirm that the cerebellum and striatum are more interconnected than previously retained. Furthermore, cerebellar damage likely evokes a striatal response through cortical mediation. The EE probably modifies HCb-induced plastic changes in the striatum by increasing the efficiency of the cortical circuitry. This is the first study describing the morphological rearrangement of striatal FSi following a cerebellar lesion; it provides the basis for further studies aimed at investigating the mechanisms underlying cerebello-striatal "talking."

  2. Dendritic signaling in inhibitory interneurons: local tuning via group I metabotropic glutamate receptors

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    Olivier eCamiré

    2012-07-01

    Full Text Available Communication between neurons is achieved by rapid signal transduction via highly specialized structural elements known as synaptic contacts. In addition, numerous extrasynaptic mechanisms provide a flexible platform for the local regulation of synaptic signals. For example, peri- and extrasynaptic signaling through the group I metabotropic glutamate receptors (mGluRs can be involved in the highly compartmentalized regulation of dendritic ion conductances, the induction of input-specific synaptic plasticity, and the local release of retrograde messengers. Therefore, extrasynaptic mechanisms appear to play a key role in the local tuning of dendritic computations. Here, we review recent findings on the role of group I mGluRs in the dendritic signaling of inhibitory interneurons. We propose that group I mGluRs provide a dual-mode signaling device that integrates different patterns of neural activity. By implementing distinct forms of intrinsic and synaptic regulation, group I mGluRs may be responsible for the local fine-tuning of dendritic function.

  3. The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

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    Sonia eDuchemin

    2012-08-01

    Full Text Available Following the discovery of the vasorelaxant properties of nitric oxide (NO by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow. Anatomically, axons, dendrites or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting cerebral blood flow as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e. neuronal, glial and vascular cells also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.

  4. A spiking network model of cerebellar Purkinje cells and molecular layer interneurons exhibiting irregular firing

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    William eLennon

    2014-12-01

    Full Text Available While the anatomy of the cerebellar microcircuit is well studied, how it implements cerebellar function is not understood. A number of models have been proposed to describe this mechanism but few emphasize the role of the vast network Purkinje cells (PKJs form with the molecular layer interneurons (MLIs – the stellate and basket cells. We propose a model of the MLI-PKJ network composed of simple spiking neurons incorporating the major anatomical and physiological features. In computer simulations, the model reproduces the irregular firing patterns observed in PKJs and MLIs in vitro and a shift toward faster, more regular firing patterns when inhibitory synaptic currents are blocked. In the model, the time between PKJ spikes is shown to be proportional to the amount of feedforward inhibition from an MLI on average. The two key elements of the model are: (1 spontaneously active PKJs and MLIs due to an endogenous depolarizing current, and (2 adherence to known anatomical connectivity along a parasagittal strip of cerebellar cortex. We propose this model to extend previous spiking network models of the cerebellum and for further computational investigation into the role of irregular firing and MLIs in cerebellar learning and function.

  5. Neurog1 Genetic Inducible Fate Mapping (GIFM) Reveals the Existence of Complex Spatiotemporal Cyto-Architectures in the Developing Cerebellum.

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    Obana, Edwin A; Lundell, Travis G; Yi, Kevin J; Radomski, Kryslaine L; Zhou, Qiong; Doughty, Martin L

    2015-06-01

    Neurog1 is a pro-neural basic helix-loop-helix (bHLH) transcription factor expressed in progenitor cells located in the ventricular zone and subsequently the presumptive white matter tracts of the developing mouse cerebellum. We used genetic inducible fate mapping (GIFM) with a transgenic Neurog1-CreER allele to characterize the contributions of Neurog1 lineages to cerebellar circuit formation in mice. GIFM reveals Neurog1-expressing progenitors are fate-mapped to become Purkinje cells and all GABAergic interneuron cell types of the cerebellar cortex but not glia. The spatiotemporal sequence of GIFM is unique to each neuronal cell type. GIFM on embryonic days (E) 10.5 to E12.5 labels Purkinje cells with different medial-lateral settling patterns depending on the day of tamoxifen delivery. GIFM on E11.5 to P7 labels interneurons and the timing of tamoxifen administration correlates with the final inside-to-outside resting position of GABAergic interneurons in the cerebellar cortex. Proliferative status and long-term BrdU retention of GIFM lineages reveals Purkinje cells express Neurog1 around the time they become post-mitotic. In contrast, GIFM labels mitotic and post-mitotic interneurons. Neurog1-CreER GIFM reveals a correlation between the timing of Neurog1 expression and the spatial organization of GABAergic neurons in the cerebellar cortex with possible implications for cerebellar circuit assembly.

  6. A multi-compartment model for interneurons in the dorsal lateral geniculate nucleus.

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    Geir Halnes

    2011-09-01

    Full Text Available GABAergic interneurons (INs in the dorsal lateral geniculate nucleus (dLGN shape the information flow from retina to cortex, presumably by controlling the number of visually evoked spikes in geniculate thalamocortical (TC neurons, and refining their receptive field. The INs exhibit a rich variety of firing patterns: Depolarizing current injections to the soma may induce tonic firing, periodic bursting or an initial burst followed by tonic spiking, sometimes with prominent spike-time adaptation. When released from hyperpolarization, some INs elicit rebound bursts, while others return more passively to the resting potential. A full mechanistic understanding that explains the function of the dLGN on the basis of neuronal morphology, physiology and circuitry is currently lacking. One way to approach such an understanding is by developing a detailed mathematical model of the involved cells and their interactions. Limitations of the previous models for the INs of the dLGN region prevent an accurate representation of the conceptual framework needed to understand the computational properties of this region. We here present a detailed compartmental model of INs using, for the first time, a morphological reconstruction and a set of active dendritic conductances constrained by experimental somatic recordings from INs under several different current-clamp conditions. The model makes a number of experimentally testable predictions about the role of specific mechanisms for the firing properties observed in these neurons. In addition to accounting for the significant features of all experimental traces, it quantitatively reproduces the experimental recordings of the action-potential- firing frequency as a function of injected current. We show how and why relative differences in conductance values, rather than differences in ion channel composition, could account for the distinct differences between the responses observed in two different neurons, suggesting

  7. Dichotomous Effects of Mu Opioid Receptor Activation on Striatal Low-Threshold Spike Interneurons

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    Rasha Elghaba

    2017-12-01

    Full Text Available Striatal low-threshold spike interneurons (LTSIs are tonically active neurons that express GABA and nitric oxide synthase and are involved in information processing as well as neurovascular coupling. While mu opioid receptors (MORs and their ligand encephalin are prominent in the striatum, their action on LTSIs has not been investigated. We addressed this issue carrying out whole-cell recordings in transgenic mice in which the NPY-expressing neurons are marked with green fluorescent protein (GFP. The MOR agonist (D-Ala(2, N-MePhe(4, Gly-ol-enkephalin (DAMGO produced dual effects on subpopulations of LTSIs. DAMGO caused inhibitory effects, accompanied by decreases of spontaneous firing, in 62% of LTSIs, while depolarizing effects (accompanied by an increase in spontaneous firing were observed in 23% of LTSIs tested. The dual effects of DAMGO persisted in the presence of tetrodotoxin (TTX, a sodium channel blocker or in the presence of the nicotinic acetylcholine receptor antagonist mecamylamine. However, in the presence of either the GABAA receptor antagonist picrotoxin or the muscarinic cholinergic receptor antagonist atropine, DAMGO only elicited inhibitory effects on LTSIs. Furthermore, we found that DAMGO decreased the amplitude and frequency of spontaneous GABAergic events. Unexpectedly, these effects of DAMGO on spontaneous GABAergic events disappeared after blocking of the muscarinic and nicotinic cholinergic blockers, showing that GABA inputs to LTSIs are not directly modulated by presynaptic MORs. These finding suggest that activation of MORs affect LTSIs both directly and indirectly, through modulation of GABAergic and cholinergic tones. The complex balance between direct and indirect effects determines the net effect of DAMGO on LTSIs.

  8. Octopaminergic modulation of temporal frequency coding in an identified optic flow-processing interneuron

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    Kit D. Longden

    2010-11-01

    Full Text Available Flying generates predictably different patterns of optic flow compared with other locomotor states. A sensorimotor system tuned to rapid responses and a high bandwidth of optic flow would help the animal to avoid wasting energy through imprecise motor action. However, neural processing that covers a higher input bandwidth itself comes at higher energetic costs which would be a poor investment when the animal was not flying. How does the blowfly adjust the dynamic range of its optic flow-processing neurons to the locomotor state? Octopamine (OA is a biogenic amine central to the initiation and maintenance of flight in insects. We used an OA agonist chlordimeform (CDM to simulate the widespread OA release during flight and recorded the effects on the temporal frequency coding of the H2 cell. This cell is a visual interneuron known to be involved in flight stabilization reflexes. The application of CDM resulted in i an increase in the cell's spontaneous activity, expanding the inhibitory signalling range ii an initial response gain to moving gratings (20 – 60 ms post-stimulus that depended on the temporal frequency of the grating and iii a reduction in the rate and magnitude of motion adaptation that was also temporal frequency-dependent. To our knowledge, this is the first demonstration that the application of a neuromodulator can induce velocity-dependent alterations in the gain of a wide-field optic flow-processing neuron. The observed changes in the cell’s response properties resulted in a 33% increase of the cell’s information rate when encoding random changes in temporal frequency of the stimulus. The increased signalling range and more rapid, longer lasting responses employed more spikes to encode each bit, and so consumed a greater amount of energy. It appears that for the fly investing more energy in sensory processing during flight is more efficient than wasting energy on under-performing motor control.

  9. Persistent, generalized hypersensitivity of olfactory bulb interneurons after olfactory fear generalization.

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    Kass, Marley D; McGann, John P

    2017-11-08

    Generalization of fear from previously threatening stimuli to novel but related stimuli can be beneficial, but if fear overgeneralizes to inappropriate situations it can produce maladaptive behaviors and contribute to pathological anxiety. Appropriate fear learning can selectively facilitate early sensory processing of threat-predictive stimuli, but it is unknown if fear generalization has similarly generalized neurosensory consequences. We performed in vivo optical neurophysiology to visualize odor-evoked neural activity in populations of periglomerular interneurons in the olfactory bulb 1 day before, 1 day after, and 1 month after each mouse underwent an olfactory fear conditioning paradigm designed to promote generalized fear of odors. Behavioral and neurophysiological changes were assessed in response to a panel of odors that varied in similarity to the threat-predictive odor at each time point. After conditioning, all odors evoked similar levels of freezing behavior, regardless of similarity to the threat-predictive odor. Freezing significantly correlated with large changes in odor-evoked periglomerular cell activity, including a robust, generalized facilitation of the response to all odors, broadened odor tuning, and increased neural responses to lower odor concentrations. These generalized effects occurred within 24 h of a single conditioning session, persisted for at least 1 month, and were detectable even in the first moments of the brain's response to odors. The finding that generalized fear includes altered early sensory processing of not only the threat-predictive stimulus but also novel though categorically-similar stimuli may have important implications for the etiology and treatment of anxiety disorders with sensory sequelae. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Excitation-transcription coupling in parvalbumin-positive interneurons employs a novel CaM Kinase-dependent pathway distinct from excitatory neurons

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    Cohen, Samuel M.; Ma, Huan; Kuchibhotla, Kishore V.; Watson, Brendon O.; Buzsáki, György; Froemke, Robert C.; Tsien, Richard W.

    2016-01-01

    Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. Here, we report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease. PMID:27041500

  11. Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons.

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    Richard Andersson

    Full Text Available BACKGROUND: Gamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well. METHODOLOGY/PRINCIPAL FINDINGS: To address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast-spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power. CONCLUSIONS/SIGNIFICANCE: We conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This

  12. [Structural and functional reorganization of the interneuronal contacts of the cerebral cortex after a single convulsive paroxysm].

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    Savchenko, Iu N; Ereniev, S I; Semchenko, V V; Stepanov, S S

    1987-01-01

    Using the technique of contrasting the cerebral tissue with phosphotungstic acid, the authors studied the structural and functional status of interneuronal contacts of the molecular layer of the sensomotor cortex in the brain of Krushinsky-Molodkina rats following convulsive sound stimulation and the subsequent audiogenic convulsive paroxysm. Marked reduction in the general number of synapses 4 h after the attack was attended by transformation of some flat functionally mature contacts into concave ones, which reflects the activation of the synaptic pool. The relative levels of concave and flat mature contacts returned to the initial level 8 to 24 h later.

  13. Cortical interneurons migrating on a pure substrate of N-cadherin exhibit fast synchronous centrosomal and nuclear movements and reduced ciliogenesis

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    Camilla eLuccardini

    2015-08-01

    Full Text Available The embryonic development of the cortex involves a phase of long distance migration of interneurons born in the basal telencephalon. Interneurons first migrate tangentially and then reorient their trajectories radially to enter the developing cortex. We have shown that migrating interneurons can assemble a primary cilium, which maintains the centrosome to the plasma membrane and processes signals to control interneuron trajectory (Baudoin et al., 2012. In the developing cortex, N-cadherin is expressed by migrating interneurons and by cells in their migratory pathway. N-cadherin promotes the motility and maintains the polarity of tangentially migrating interneurons (Luccardini et al., 2013. Because N-cadherin is an important factor that regulates the migration of MGE cells in vivo, we further characterized the motility and polarity of MGE cells on a substrate that only comprises this protein. MGE cells migrating on a N-cadherin substrate were seven times faster than on a laminin substrate and two times faster than on a substrate of cortical cells. A primary cilium was much less frequently observed on MGE cells migrating on N-cadherin than on laminin. Nevertheless, the mature centriole frequently docked to the plasma membrane in MGE cells migrating on N-cadherin, suggesting that plasma membrane docking is a basic feature of the centrosome in migrating MGE cells. On the N-cadherin substrate, centrosomal and nuclear movements were remarkably synchronous and the centrosome remained near the nucleus. Interestingly, MGE cells with cadherin invalidation presented centrosomal movements no longer coordinated with nuclear movements. In summary, MGE cells migrating on a pure substrate of N-cadherin show fast, coordinated nuclear and centrosomal movements, and rarely present a primary cilium.

  14. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.

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    Laura Leung

    Full Text Available Apolipoprotein (apo E4 is the major genetic risk factor for Alzheimer's disease (AD. ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive--but not NPY- or parvalbumin-positive-interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype.

  15. Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

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    Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

    2017-02-03

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K(+) concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

  16. Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC.

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    Rao, S G; Williams, G V; Goldman-Rakic, P S

    1999-04-01

    Studies on the cellular mechanisms of working memory demonstrated that neurons in dorsolateral prefrontal cortex (dPFC) exhibit directionally tuned activity during an oculomotor delayed response. To determine the particular contributions of pyramidal cells and interneurons to spatial tuning in dPFC, we examined both individually and in pairs the tuning properties of regular-spiking (RS) and fast-spiking (FS) units that represent putative pyramidal cells and interneurons, respectively. Our main finding is that FS units possess spatially tuned sensory, motor, and delay activity (i. e., "memory fields") similar to those found in RS units. Furthermore, when recorded simultaneously at the same site, the majority of neighboring neurons, whether FS or RS, displayed isodirectional tuning, i.e., they shared very similar tuning angles for the sensory and delay phases of the task. As the trial entered the response phase of the task, many FS units shifted their direction of tuning and became cross-directional to adjacent RS units by the end of the trial. These results establish that a large part of inhibition in prefrontal cortex is spatially oriented rather than being untuned and simply regulating the threshold response of pyramidal cell output. Moreover, the isodirectional tuning between adjacent neurons supports a functional microcolumnar organization in dPFC for spatial memory fields similar to that found in other areas of cortex for sensory receptive fields.

  17. Local Optogenetic Induction of Fast (20-40 Hz Pyramidal-Interneuron Network Oscillations in the In Vitro and In Vivo CA1 Hippocampus: Modulation by CRF and Enforcement of Perirhinal Theta Activity

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    Julien eDine

    2016-04-01

    Full Text Available The neurophysiological processes that can cause theta-to-gamma frequency range (4-80 Hz network oscillations in the rhinal cortical-hippocampal system and the potential connectivity-based interactions of such forebrain rhythms are a topic of intensive investigation. Here, using selective Channelrhodopsin-2 (ChR2 expression in mouse forebrain glutamatergic cells, we were able to locally, temporally precisely, and reliably induce fast (20-40 Hz field potential oscillations in hippocampal area CA1 in vitro (at 25°C and in vivo (i.e., slightly anaesthetized NEX-Cre-ChR2 mice. As revealed by pharmacological analyses and patch-clamp recordings from pyramidal cells and GABAergic interneurons in vitro, these light-triggered oscillations can exclusively arise from sustained suprathreshold depolarization (~200 ms or longer and feedback inhibition of CA1 pyramidal neurons, as being mandatory for prototypic pyramidal-interneuron network (P-I oscillations. Consistently, the oscillations comprised rhythmically occurring population spikes (generated by pyramidal cells and their frequency increased with increasing spectral power. We further demonstrate that the optogenetically driven CA1 oscillations, which remain stable over repeated evocations, are impaired by the stress hormone corticotropin-releasing factor (CRF, 125 nM in vitro and, even more remarkably, found that they are accompanied by concurrent states of enforced theta activity in the memory-associated perirhinal cortex (PrC in vivo. The latter phenomenon most likely derives from neurotransmission via a known, but poorly studied excitatory CA1PrC pathway. Collectively, our data provide evidence for the existence of a prototypic (CRF-sensitive P-I gamma rhythm generator in area CA1 and suggest that CA1 P-I oscillations can rapidly up-regulate theta activity strength in hippocampus-innervated rhinal networks, at least in the PrC.

  18. NPR-9, a Galanin-Like G-Protein Coupled Receptor, and GLR-1 Regulate Interneuronal Circuitry Underlying Multisensory Integration of Environmental Cues in Caenorhabditis elegans.

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    Jason C Campbell

    2016-05-01

    Full Text Available C. elegans inhabit environments that require detection of diverse stimuli to modulate locomotion in order to avoid unfavourable conditions. In a mammalian context, a failure to appropriately integrate environmental signals can lead to Parkinson's, Alzheimer's, and epilepsy. Provided that the circuitry underlying mammalian sensory integration can be prohibitively complex, we analyzed nematode behavioral responses in differing environmental contexts to evaluate the regulation of context dependent circuit reconfiguration and sensorimotor control. Our work has added to the complexity of a known parallel circuit, mediated by interneurons AVA and AIB, that integrates sensory cues and is responsible for the initiation of backwards locomotion. Our analysis of the galanin-like G-protein coupled receptor NPR-9 in C. elegans revealed that upregulation of galanin signaling impedes the integration of sensory evoked neuronal signals. Although the expression pattern of npr-9 is limited to AIB, upregulation of the receptor appears to impede AIB and AVA circuits to broadly prevent backwards locomotion, i.e. reversals, suggesting that these two pathways functionally interact. Galanin signaling similarly plays a broadly inhibitory role in mammalian models. Moreover, our identification of a mutant, which rarely initiates backwards movement, allowed us to interrogate locomotory mechanisms underlying chemotaxis. In support of the pirouette model of chemotaxis, organisms that did not exhibit reversal behavior were unable to navigate towards an attractant peak. We also assessed ionotropic glutamate receptor GLR-1 cell-specifically within AIB and determined that GLR-1 fine-tunes AIB activity to modify locomotion following reversal events. Our research highlights that signal integration underlying the initiation and fine-tuning of backwards locomotion is AIB and NPR-9 dependent, and has demonstrated the suitability of C. elegans for analysis of multisensory integration

  19. Functional α7β2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid β peptides

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    Liu Qiang

    2012-12-01

    Full Text Available Abstract Background β-amyloid (Aβ accumulation is described as a hallmark of Alzheimer’s disease (AD. Aβ perturbs a number of synaptic components including nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs, which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric α7β2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Aβ exposure. To extend our previous work, we evaluated the expression and pharmacology of α7β2-nAChRs in hippocampal interneurons and their sensitivity to Aβ. Results GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional α7β2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-β-erythroidine (DHβE, a nAChR β2* subunit selective blocker, and α7 and β2 subunit interaction using immunoprecipitation assay. In addition, α7β2-nAChRs were sensitive to 1 nM oligomeric Aβ. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. Conclusion These findings suggest that Aβ modulation of cholinergic signaling in hippocampal GABAergic interneurons via α7β2-nAChRs could be an early and critical event in Aβ-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.

  20. Postsynaptic GABABRs Inhibit L-Type Calcium Channels and Abolish Long-Term Potentiation in Hippocampal Somatostatin Interneurons.

    Science.gov (United States)

    Booker, Sam A; Loreth, Desiree; Gee, Annabelle L; Watanabe, Masahiko; Kind, Peter C; Wyllie, David J A; Kulik, Ákos; Vida, Imre

    2018-01-02

    Inhibition provided by local GABAergic interneurons (INs) activates ionotropic GABAA and metabotropic GABAB receptors (GABABRs). Despite GABABRs representing a major source of inhibition, little is known of their function in distinct IN subtypes. Here, we show that, while the archetypal dendritic-inhibitory somatostatin-expressing INs (SOM-INs) possess high levels of GABABR on their somato-dendritic surface, they fail to produce significant postsynaptic inhibitory currents. Instead, GABABRs selectively inhibit dendritic CaV1.2 (L-type) Ca2+ channels on SOM-IN dendrites, leading to reduced calcium influx and loss of long-term potentiation at excitatory input synapses onto these INs. These data provide a mechanism by which GABABRs can contribute to disinhibition and control the efficacy of extrinsic inputs to hippocampal networks. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Population-specific regulation of Chmp2b by Lbx1 during onset of synaptogenesis in lateral association interneurons.

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    Jun Xu

    Full Text Available Chmp2b is closely related to Vps2, a key component of the yeast protein complex that creates the intralumenal vesicles of multivesicular bodies. Dominant negative mutations in Chmp2b cause autophagosome accumulation and neurodegenerative disease. Loss of Chmp2b causes failure of dendritic spine maturation in cultured neurons. The homeobox gene Lbx1 plays an essential role in specifying postmitotic dorsal interneuron populations during late pattern formation in the neural tube. We have discovered that Chmp2b is one of the most highly regulated cell-autonomous targets of Lbx1 in the embryonic mouse neural tube. Chmp2b was expressed and depended on Lbx1 in only two of the five nascent, Lbx1-expressing, postmitotic, dorsal interneuron populations. It was also expressed in neural tube cell populations that lacked Lbx1 protein. The observed population-specific expression of Chmp2b indicated that only certain population-specific combinations of sequence specific transcription factors allow Chmp2b expression. The cell populations that expressed Chmp2b corresponded, in time and location, to neurons that make the first synapses of the spinal cord. Chmp2b protein was transported into neurites within the motor- and association-neuropils, where the first synapses are known to form between E11.5 and E12.5 in mouse neural tubes. Selective, developmentally-specified gene expression of Chmp2b may therefore be used to endow particular neuronal populations with the ability to mature dendritic spines. Such a mechanism could explain how mammalian embryos reproducibly establish the disynaptic cutaneous reflex only between particular cell populations.

  2. Sparing of descending axons rescues interneuron plasticity in the lumbar cord to allow adaptive learning after thoracic spinal cord injury

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    Christopher Nelson Hansen

    2016-03-01

    Full Text Available This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI. Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX. This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI. To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm. In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days or late (42 days after midthoracic SCI in a rodent model. Early after SCI or TX at 7d, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between

  3. Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus.

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    Ruzicka, W Brad; Subburaju, Sivan; Coyle, Joseph T; Benes, Francine M

    2018-01-15

    Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email

  4. Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury.

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    Hansen, Christopher N; Faw, Timothy D; White, Susan; Buford, John A; Grau, James W; Basso, D Michele

    2016-01-01

    This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI). Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX). This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI). To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm (ILP). In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days) or late (42 days) after midthoracic SCI in a rodent model. Early after SCI or TX at 7 days, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between spared

  5. Interneurons and proprioneurons in the adult human spinal grey matter and in the general somatic and visceral afferent cranial nerve nuclei.

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    Abdel-Maguid, T E; Bowsher, D

    1984-01-01

    Using the classification of Abdel-Maguid & Bowsher (1984), interneurons of the dorsal horn of the grey matter of the human spinal cord and medulla oblongata were found to belong to only three 'families' of neurons, out of a possible thirteen. This is in itself one of the justifications for the method of classification. Functional identification of these human neurons has been made on the basis of topological, morphological and projectional comparison with known cells in other mammalian specie...

  6. Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

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    Patrick Aldrin-Kirk

    Full Text Available Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable

  7. Adolescent GBR12909 exposure induces oxidative stress, disrupts parvalbumin-positive interneurons, and leads to hyperactivity and impulsivity in adult mice.

    Science.gov (United States)

    Khan, Asma; de Jong, Loek A W; Kamenski, Mary E; Higa, Kerin K; Lucero, Jacinta D; Young, Jared W; Behrens, M Margarita; Powell, Susan B

    2017-03-14

    The adolescent period in mammals is a critical period of brain maturation and thus represents a time of susceptibility to environmental insult, e.g. psychosocial stress and/or drugs of abuse, which may cause lasting impairments in brain function and behavior and even precipitate symptoms in at-risk individuals. One likely effect of these environmental insults is to increase oxidative stress in the developing adolescent brain. Indeed, there is increasing evidence that redox dysregulation plays an important role in the development of schizophrenia and other neuropsychiatric disorders and that GABA interneurons are particularly susceptible to alterations in oxidative stress. The current study sought to model this adolescent neurochemical "stress" by exposing mice to the dopamine transporter inhibitor GBR12909 (5mg/kg; IP) during adolescence (postnatal day 35-44) and measuring the resultant effect on locomotor behavior and probabilistic reversal learning as well as GABAergic interneurons and oxidative stress in adulthood. C57BL6/J mice exposed to GBR12909 showed increased activity in a novel environment and increased impulsivity as measured by premature responding in the probabilistic reversal learning task. Adolescent GBR12909-exposed mice also showed decreased parvalbumin (PV) immunoreactivity in the prefrontal cortex, which was accompanied by increased oxidative stress in PV+ neurons. These findings indicate that adolescent exposure to a dopamine transporter inhibitor results in loss of PV in GABAergic interneurons, elevations in markers of oxidative stress, and alterations in behavior in adulthood. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice

    Science.gov (United States)

    Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

    2014-01-01

    Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women. PMID:24991763

  9. Interneurons and proprioneurons in the adult human spinal grey matter and in the general somatic and visceral afferent cranial nerve nuclei.

    Science.gov (United States)

    Abdel-Maguid, T E; Bowsher, D

    1984-08-01

    Using the classification of Abdel-Maguid & Bowsher (1984), interneurons of the dorsal horn of the grey matter of the human spinal cord and medulla oblongata were found to belong to only three 'families' of neurons, out of a possible thirteen. This is in itself one of the justifications for the method of classification. Functional identification of these human neurons has been made on the basis of topological, morphological and projectional comparison with known cells in other mammalian species. Among the cells identified are gelatinosal interneurons and Renshaw cells of laminae VII and VIII. Neurons belonging to the same 'family' as Waldeyer cells of lamina I continue around the outer edge of the grey matter, their dendrites forming a part of the boundary between grey and white matter. Interneurons with small and very small dendrite fields lie on interlaminar boundaries and have mediolaterally oriented dendrites, in contrast to the craniocaudally oriented dendritic field of most dorsal horn neurons. If such dendrites lying along interlaminar boundaries are also found to exist in other species, it may explain the abrupt change in physiological characteristics which is found on passing an electrode from one lamina to another.

  10. Npas4 regulates Mdm2 and thus Dcx in experience-dependent dendritic spine development of newborn olfactory bulb interneurons.

    Science.gov (United States)

    Yoshihara, Sei-Ichi; Takahashi, Hiroo; Nishimura, Nobushiro; Kinoshita, Masahito; Asahina, Ryo; Kitsuki, Michiko; Tatsumi, Kana; Furukawa-Hibi, Yoko; Hirai, Hirokazu; Nagai, Taku; Yamada, Kiyofumi; Tsuboi, Akio

    2014-08-07

    Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB). Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs), although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  11. [Interneuronal relationships in the basolateral amygdala of cats trained for choice in the quality of food reinforcement].

    Science.gov (United States)

    Merzhanova, G Kh; Dolbakian, E E; Partev, A Z

    1997-01-01

    The alimentary instrumental conditioned bar-pressing reflex was elaborated in cats by the method of "active choice" of either short-delayed reinforcement with bread-meat mixture of delayed more valuable reinforcement with meat. The animals differed in behavior strategy: some animals preferred bar-pressing with the long delay (the so-called "self-control" group), other animals pressed the bar with short delay (the so-called "impulsive" group). The multiunit activity in the basolateral amygdala was recorded with chronically implanted nichrome microelectrodes. The interactions between the spike trains of the neighbouring neurons selected from the multiunit activity were evaluated by means of statistical crosscorrelation analysis. It was shown that the number of correlations between the discharges of neurons was significantly higher in the "impulsive" cats. In both groups the number of cross-correlations was maximal in cases of a difficult choice, i.e., during the omission of the conditioned bar-pressing response. In "impulsive" cats the number of interneuronal correlations was highest with the latencies in the range of 0-30 msec. We suggest that the basolateral amygdala is involved in the system of structures which determine the individual-typological characteristics of animals.

  12. Npas4 Regulates Mdm2 and thus Dcx in Experience-Dependent Dendritic Spine Development of Newborn Olfactory Bulb Interneurons

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    Sei-ichi Yoshihara

    2014-08-01

    Full Text Available Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB. Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs, although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience.

  13. Repeated Blockade of NMDA Receptors during Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex

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    Jitao eLi

    2016-03-01

    Full Text Available Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg, a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV-, calbindin (CB- and calretinin (CR-positive neurons in mPFC were analyzed at either 24 hours or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.

  14. Transplanted Human Stem Cell-Derived Interneuron Precursors Mitigate Mouse Bladder Dysfunction and Central Neuropathic Pain after Spinal Cord Injury.

    Science.gov (United States)

    Fandel, Thomas M; Trivedi, Alpa; Nicholas, Cory R; Zhang, Haoqian; Chen, Jiadong; Martinez, Aida F; Noble-Haeusslein, Linda J; Kriegstein, Arnold R

    2016-10-06

    Neuropathic pain and bladder dysfunction represent significant quality-of-life issues for many spinal cord injury patients. Loss of GABAergic tone in the injured spinal cord may contribute to the emergence of these symptoms. Previous studies have shown that transplantation of rodent inhibitory interneuron precursors from the medial ganglionic eminence (MGE) enhances GABAergic signaling in the brain and spinal cord. Here we look at whether transplanted MGE-like cells derived from human embryonic stem cells (hESC-MGEs) can mitigate the pathological effects of spinal cord injury. We find that 6 months after transplantation into injured mouse spinal cords, hESC-MGEs differentiate into GABAergic neuron subtypes and receive synaptic inputs, suggesting functional integration into host spinal cord. Moreover, the transplanted animals show improved bladder function and mitigation of pain-related symptoms. Our results therefore suggest that this approach may be a valuable strategy for ameliorating the adverse effects of spinal cord injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.

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    Nomura, Toshihiro; Musial, Timothy F; Marshall, John J; Zhu, Yiwen; Remmers, Christine L; Xu, Jian; Nicholson, Daniel A; Contractor, Anis

    2017-11-22

    Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin

  16. Balanced plasticity and stability of the electrical properties of a molluscan modulatory interneuron after classical conditioning: a computational study

    Directory of Open Access Journals (Sweden)

    Dimitris Vavoulis

    2010-05-01

    Full Text Available The Cerebral Giant Cells (CGCs are a pair of identified modulatory interneurons in the Central Nervous System of the pond snail Lymnaea stagnalis with an important role in the expression of both unconditioned and conditioned feeding behavior. Following single-trial food-reward classical conditioning, the membrane potential of the CGCs becomes persistently depolarized. This depolarization contributes to the conditioned response by facilitating sensory cell to command neuron synapses, which results in the activation of the feeding network by the conditioned stimulus. Despite the depolarization of the membrane potential, which enables the CGGs to play a key role in learning-induced network plasticity, there is no persistent change in the tonic firing rate or shape of the action potentials, allowing these neurons to retain their normal network function in feeding. In order to understand the ionic mechanisms of this novel combination of plasticity and stability of intrinsic electrical properties, we first constructed and validated a Hodgkin-Huxley-type model of the CGCs. We then used this model to elucidate how learning-induced changes in a somal persistent sodium and a delayed rectifier potassium current lead to a persistent depolarization of the CGCs whilst maintaining their firing rate. Including in the model an additional increase in the conductance of a high-voltage-activated calcium current allowed the spike amplitude and spike duration also to be maintained after conditioning. We conclude therefore that a balanced increase in three identified conductances is sufficient to explain the electrophysiological changes found in the CGCs after classical conditioning.

  17. Interaction between Purkinje cells and inhibitory interneurons may create adjustable output waveforms to generate timed cerebellar output.

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    Simon Hong

    Full Text Available We develop a new model that explains how the cerebellum may generate the timing in classical delay eyeblink conditioning. Recent studies show that both Purkinje cells (PCs and inhibitory interneurons (INs have parallel signal processing streams with two time scales: an AMPA receptor-mediated fast process and a metabotropic glutamate receptor (mGluR-mediated slow process. Moreover, one consistent finding is an increased excitability of PC dendrites (in Larsell's lobule HVI in animals when they acquire the classical delay eyeblink conditioning naturally, in contrast to in vitro studies, where learning involves long-term depression (LTD. Our model proposes that the delayed response comes from the slow dynamics of mGluR-mediated IP3 activation, and the ensuing calcium concentration change, and not from LTP/LTD. The conditioned stimulus (tone, arriving on the parallel fibers, triggers this slow activation in INs and PC spines. These excitatory (from PC spines and inhibitory (from INs signals then interact at the PC dendrites to generate variable waveforms of PC activation. When the unconditioned stimulus (puff, arriving on the climbing fibers, is coupled frequently with this slow activation the waveform is amplified (due to an increased excitability and leads to a timed pause in the PC population. The disinhibition of deep cerebellar nuclei by this timed pause causes the delayed conditioned response. This suggested PC-IN interaction emphasizes a richer role of the INs in learning and also conforms to the recent evidence that mGluR in the cerebellar cortex may participate in slow motor execution. We show that the suggested mechanism can endow the cerebellar cortex with the versatility to learn almost any temporal pattern, in addition to those that arise in classical conditioning.

  18. Ovarian cycle-linked plasticity of δ-GABAA receptor subunits in hippocampal interneurons affects γ oscillations in vivo

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    Albert Miklos Barth

    2014-08-01

    Full Text Available GABAA receptors containing δ subunits (δ-GABAARs are GABA-gated ion channels with extra- and perisynaptic localization, strong sensitivity to neurosteroids (NS, and a high degree of plasticity. In selective brain regions they are expressed on specific principal cells and interneurons (INs, and generate a tonic conductance that controls neuronal excitability and oscillations. Plasticity of δ-GABAARs in principal cells has been described during states of altered NS synthesis including acute stress, puberty, ovarian cycle, pregnancy and the postpartum period, with direct consequences on neuronal excitability and network dynamics. The defining network events implicated in cognitive function, memory formation and encoding are γ oscillations (30-120 Hz, a well-timed loop of excitation and inhibition between principal cells and PV-expressing INs (PV+INs. The δ-GABAARs of INs can modify γ oscillations, and a lower expression of δ-GABAARs on INs during pregnancy alters γ frequency recorded in vitro. The ovarian cycle is another physiological event with large fluctuations in NS levels and δ-GABAARs. Stages of the cycle are paralleled by swings in memory performance, cognitive function, and mood in both humans and rodents. Here we show δ-GABAARs changes during the mouse ovarian cycle in hippocampal cell types, with enhanced expression during diestrus in principal cells and specific INs. The plasticity of δ-GABAARs on PV-INs decreases the magnitude of γ oscillations continuously recorded in area CA1 throughout several days in vivo during diestrus and increases it during estrus. Such recurring changes in γ magnitude were not observed in non-cycling wild-type (WT females, cycling females lacking δ-GABAARs only on PV-INs (PV-Gabrd-/-, and in male mice during a time course equivalent to the ovarian cycle. Our findings may explain the impaired memory and cognitive performance experienced by women with premenstrual syndrome (PMS or premenstrual

  19. Segmental organization of vestibulospinal inputs to spinal interneurons mediating crossed activation of thoracolumbar motoneurons in the neonatal mouse.

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    Kasumacic, Nedim; Lambert, François M; Coulon, Patrice; Bras, Helene; Vinay, Laurent; Perreault, Marie-Claude; Glover, Joel C

    2015-05-27

    Vestibulospinal pathways activate contralateral motoneurons (MNs) in the thoracolumbar spinal cord of the neonatal mouse exclusively via axons descending ipsilaterally from the vestibular nuclei via the lateral vestibulospinal tract (LVST; Kasumacic et al., 2010). Here we investigate how transmission from the LVST to contralateral MNs is mediated by descending commissural interneurons (dCINs) in different spinal segments. We test the polysynaptic nature of this crossed projection by assessing LVST-mediated ventral root (VR) response latencies, manipulating synaptic responses pharmacologically, and tracing the pathway transynaptically from hindlimb extensor muscles using rabies virus (RV). Longer response latencies in contralateral than ipsilateral VRs, near-complete abolition of LVST-mediated calcium responses in contralateral MNs by mephenesin, and the absence of transsynaptic RV labeling of contralateral LVST neurons within a monosynaptic time window all indicate an overwhelmingly polysynaptic pathway from the LVST to contralateral MNs. Optical recording of synaptically mediated calcium responses identifies LVST-responsive ipsilateral dCINs that exhibit segmental differences in proportion and dorsoventral distribution. In contrast to thoracic and lower lumbar segments, in which most dCINs are LVST responsive, upper lumbar segments stand out because they contain a much smaller and more ventrally restricted subpopulation of LVST-responsive dCINs. A large proportion of these upper lumbar LVST-responsive dCINs project to contralateral L5, which contains many of the hindlimb extensor MNs activated by the LVST. A selective channeling of LVST inputs through segmentally and dorsoventrally restricted subsets of dCINs provides a mechanism for targeting vestibulospinal signals differentially to contralateral trunk and hindlimb MNs in the mammalian spinal cord. Copyright © 2015 the authors 0270-6474/15/358158-12$15.00/0.

  20. The subcellular distribution of T-type Ca2+ channels in interneurons of the lateral geniculate nucleus.

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    Allken, Vaneeda; Chepkoech, Joy-Loi; Einevoll, Gaute T; Halnes, Geir

    2014-01-01

    Inhibitory interneurons (INs) in the lateral geniculate nucleus (LGN) provide both axonal and dendritic GABA output to thalamocortical relay cells (TCs). Distal parts of the IN dendrites often enter into complex arrangements known as triadic synapses, where the IN dendrite plays a dual role as postsynaptic to retinal input and presynaptic to TC dendrites. Dendritic GABA release can be triggered by retinal input, in a highly localized process that is functionally isolated from the soma, but can also be triggered by somatically elicited Ca(2+)-spikes and possibly by backpropagating action potentials. Ca(2+)-spikes in INs are predominantly mediated by T-type Ca(2+)-channels (T-channels). Due to the complex nature of the dendritic signalling, the function of the IN is likely to depend critically on how T-channels are distributed over the somatodendritic membrane (T-distribution). To study the relationship between the T-distribution and several IN response properties, we here run a series of simulations where we vary the T-distribution in a multicompartmental IN model with a realistic morphology. We find that the somatic response to somatic current injection is facilitated by a high T-channel density in the soma-region. Conversely, a high T-channel density in the distal dendritic region is found to facilitate dendritic signalling in both the outward direction (increases the response in distal dendrites to somatic input) and the inward direction (the soma responds stronger to distal synaptic input). The real T-distribution is likely to reflect a compromise between several neural functions, involving somatic response patterns and dendritic signalling.

  1. Looming detection by identified visual interneurons during larval development of the locust Locusta migratoria.

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    Simmons, Peter J; Sztarker, Julieta; Rind, F Claire

    2013-06-15

    Insect larvae clearly react to visual stimuli, but the ability of any visual neuron in a newly hatched insect to respond selectively to particular stimuli has not been directly tested. We characterised a pair of neurons in locust larvae that have been extensively studied in adults, where they are known to respond selectively to objects approaching on a collision course: the lobula giant motion detector (LGMD) and its postsynaptic partner, the descending contralateral motion detector (DCMD). Our physiological recordings of DCMD axon spikes reveal that at the time of hatching, the neurons already respond selectively to objects approaching the locust and they discriminate between stimulus approach speeds with differences in spike frequency. For a particular approaching stimulus, both the number and peak frequency of spikes increase with instar. In contrast, the number of spikes in responses to receding stimuli decreases with instar, so performance in discriminating approaching from receding stimuli improves as the locust goes through successive moults. In all instars, visual movement over one part of the visual field suppresses a response to movement over another part. Electron microscopy demonstrates that the anatomical substrate for the selective response to approaching stimuli is present in all larval instars: small neuronal processes carrying information from the eye make synapses both onto LGMD dendrites and with each other, providing pathways for lateral inhibition that shape selectivity for approaching objects.

  2. Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons.

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    Albayram, Önder; Passlick, Stefan; Bilkei-Gorzo, Andras; Zimmer, Andreas; Steinhäuser, Christian

    2016-04-01

    A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired-pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning.

  3. Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex.

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    Man Jiang

    Full Text Available Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca²⁺ at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca²⁺ concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.

  4. Inter-neuronal correlation distinguishes mechanisms of direction selectivity in cortical circuit models

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    Baker, Pamela M.; Bair, Wyeth

    2012-01-01

    Direction selectivity is a fundamental physiological property that arises from V1 circuitry, yet basic questions of how direction selective (DS) receptive fields are constructed remain unanswered. We built a set of simple, plausible neuronal circuits that produce DS cells via different mechanisms and tested these circuits to determine how they can be distinguished experimentally. Our models consisted of populations of spiking units representing physiological cell classes ranging from LGN cells to V1 complex DS cells. They differed in network architecture and DS mechanism: including linear summation of non-DS simple cell inputs or nonlinear pairwise combinations of non-DS inputs. The circuits also varied in the location of the DS time delay and whether the DS interaction was facilitatory or suppressive. We tested the models with visual stimuli often employed experimentally, including sinusoidal gratings and flashed bars, and computed shuffle-corrected cross-correlograms (CCGs) of spike trains from pairs of units that would be accessible to extracellular recording. We found that CCGs revealed fundamental features of the DS models, including the location of signal delays in the DS circuit and the sign (facilitatory or suppressive) of DS interactions. We also found that correlation was strongly stimulus-dependent, changing with direction and temporal frequency in a manner that generalized across model architectures. Our models make specific predictions for designing, optimizing and interpreting electrophysiology experiments aimed at resolving DS circuitry and provide new insights into mechanisms that could underlie stimulus-dependent correlation. The models are available and easy to explore at www.iModel.org. PMID:22745482

  5. Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism.

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    Oblak, Adrian L; Rosene, Douglas L; Kemper, Thomas L; Bauman, Margaret L; Blatt, Gene J

    2011-06-01

    Autism is a developmental disorder with prenatal origins, currently estimated to affect 1 in 91 children in the United States. Social-emotional deficits are a hallmark of autism and early neuropathology studies have indicated involvement of the limbic system. Imaging studies demonstrate abnormal activation of the posterior cingulate cortex (PCC), a component of the limbic system. Abnormal activation has also been noted in the fusiform gyrus (FFG), a region important for facial recognition and a key element in social interaction. A potential imbalance between excitatory and inhibitory interneurons in the cortex may contribute to altered information processing in autism. Furthermore, reduced numbers of GABA receptors have previously been reported in the autistic brain. Thionin-stained sections were used to qualitatively assess cytoarchitectonic patterning and quantitatively determine the density of neurons and immunohistochemistry was used to determine the densities of a subset of GABAergic interneurons utilizing parvalbumin-and calbindin-immunoreactivity. In autism, the PCC displayed altered cytoarchitecture with irregularly distributed neurons, poorly demarcated layers IV and V, and increased presence of white matter neurons. In contrast, no neuropathology was observed in the FFG. There was no significant difference in the density of thionin, parvalbumin, or calbindin interneurons in either region and there was a trend towards a reduced density of calbindin neurons in the PCC. This study highlights the presence of abnormal findings in the PCC, which appear to be developmental in nature and could affect the local processing of social-emotional behaviors as well as functioning of interrelated areas. Copyright © 2011, International Society for Autism Research, Wiley Periodicals, Inc.

  6. Roles of molecular layer interneurons in sensory information processing in mouse cerebellar cortex Crus II in vivo.

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    Chun-Ping Chu

    Full Text Available BACKGROUND: Cerebellar cortical molecular layer interneurons (MLIs play essential roles in sensory information processing by the cerebellar cortex. However, recent experimental and modeling results are questioning traditional roles for molecular layer inhibition in the cerebellum. METHODS AND MAIN RESULTS: Synaptic responses of MLIs and Purkinje cells (PCs, evoked by air-puff stimulation of the ipsilateral whisker pad were recorded from cerebellar cortex Crus II in urethane-anesthetized ICR mice by in vivo whole-cell patch-clamp recording techniques. Under current-clamp (I = 0, air-puff stimuli were found to primarily produce inhibition in PCs. In MLIs, this stimulus evoked spike firing regardless of whether they made basket-type synaptic connections or not. However, MLIs not making basket-type synaptic connections had higher rates of background activity and also generated spontaneous spike-lets. Under voltage-clamp conditions, excitatory postsynaptic currents (EPSCs were recorded in MLIs, although the predominant response of recorded PCs was an inhibitory postsynaptic potential (IPSP. The latencies of EPSCs were similar for all MLIs, but the time course and amplitude of EPSCs varied with depth in the molecular layer. The highest amplitude, shortest duration EPSCs were recorded from MLIs deep in the molecular layer, which also made basket-type synaptic connections. Comparing MLI to PC responses, time to peak of PC IPSP was significantly slower than MLI recorded EPSCs. Blocking GABA(A receptors uncovered larger EPSCs in PCs whose time to peak, half-width and 10-90% rising time were also significantly slower than in MLIs. Biocytin labeling indicated that the MLIs (but not PCs are dye-coupled. CONCLUSIONS: These findings indicate that tactile face stimulation evokes rapid excitation in MLIs and inhibition occurring at later latencies in PCs in mouse cerebellar cortex Crus II. These results support previous suggestions that the lack of

  7. Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations

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    Li Hao

    2012-02-01

    Full Text Available Abstract Background Cortical GABAergic interneurons (INs are generated in the medial ganglionic eminence (MGE and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel and within cortex. Results During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex. Conclusions Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE

  8. Roles of Molecular Layer Interneurons in Sensory Information Processing in Mouse Cerebellar Cortex Crus II In Vivo

    Science.gov (United States)

    Chu, Chun-Ping; Bing, Yan-Hua; Liu, Heng; Qiu, De-Lai

    2012-01-01

    Background Cerebellar cortical molecular layer interneurons (MLIs) play essential roles in sensory information processing by the cerebellar cortex. However, recent experimental and modeling results are questioning traditional roles for molecular layer inhibition in the cerebellum. Methods and Main Results Synaptic responses of MLIs and Purkinje cells (PCs), evoked by air-puff stimulation of the ipsilateral whisker pad were recorded from cerebellar cortex Crus II in urethane-anesthetized ICR mice by in vivo whole-cell patch-clamp recording techniques. Under current-clamp (I = 0), air-puff stimuli were found to primarily produce inhibition in PCs. In MLIs, this stimulus evoked spike firing regardless of whether they made basket-type synaptic connections or not. However, MLIs not making basket-type synaptic connections had higher rates of background activity and also generated spontaneous spike-lets. Under voltage-clamp conditions, excitatory postsynaptic currents (EPSCs) were recorded in MLIs, although the predominant response of recorded PCs was an inhibitory postsynaptic potential (IPSP). The latencies of EPSCs were similar for all MLIs, but the time course and amplitude of EPSCs varied with depth in the molecular layer. The highest amplitude, shortest duration EPSCs were recorded from MLIs deep in the molecular layer, which also made basket-type synaptic connections. Comparing MLI to PC responses, time to peak of PC IPSP was significantly slower than MLI recorded EPSCs. Blocking GABAA receptors uncovered larger EPSCs in PCs whose time to peak, half-width and 10–90% rising time were also significantly slower than in MLIs. Biocytin labeling indicated that the MLIs (but not PCs) are dye-coupled. Conclusions These findings indicate that tactile face stimulation evokes rapid excitation in MLIs and inhibition occurring at later latencies in PCs in mouse cerebellar cortex Crus II. These results support previous suggestions that the lack of parallel fiber

  9. NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder.

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    Liu, Fang-Fang; Yang, Lin-Dong; Sun, Xiao-Ru; Zhang, Hui; Pan, Wei; Wang, Xing-Ming; Yang, Jian-Jun; Ji, Mu-Huo; Yuan, Hong-Mei

    2016-12-01

    Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4-hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS.

  10. Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males.

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    Holland, Freedom H; Ganguly, Prabarna; Potter, David N; Chartoff, Elena H; Brenhouse, Heather C

    2014-04-30

    Early life stress exposure (ELS) yields risk for psychiatric disorders that might occur though a population-specific mechanism that impacts prefrontal cortical development. Sex differences in ELS effects are largely unknown and are also essential to understand social and cognitive development. ELS can cause dysfunction within parvalbumin (PVB)-containing inhibitory interneurons in the prefrontal cortex and in several prefrontal cortex-mediated behaviors including social interaction. Social behavior deficits are often the earliest observed changes in psychiatric disorders, therefore the time-course and causation of social interaction deficits after ELS are important to determine. PVB interneuron dysfunction can disrupt social behavior, and has been correlated in males with elevated markers of oxidative stress and inflammation, such as cyclooxygenase-2 after ELS. Here, we measured the effects of maternal separation ELS on social interaction behaviors in males and females. Prefrontal cortex PVB and cyclooxygenase-2 were also measured in juveniles and adolescents using Western blots. ELS led to social interaction alterations earlier in females than males. Sexually dimorphic behavioral changes were consistent with prefrontal cortex PVB loss after ELS. PVB levels were decreased in ELS-exposed juvenile females, while males exposed to ELS do not display parvalbumin decreases until adolescence. Early behavioral and PVB changes in females did not appear to be mediated through cyclooxygenase-2, since levels were not affected in ELS females. Therefore, these data suggest that ELS affects males and females differently and with distinct developmental profiles. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Acetylcholine-Based Entropy in Response Selection: A Model of How Striatal Interneurons Modulate Exploration, Exploitation, and Response Variability in Decision Making

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    Andrea eStocco

    2012-02-01

    Full Text Available The basal ganglia play a fundamental role in decision making. Their contribution is typically modeled within a reinforcement learning framework, with the basal ganglia learning to select the options associated with highest value and their dopamine inputs conveying performance feedback. This basic framework, however, does not account for the role of cholinergic interneurons in the striatum, and does not easily explain certain dynamic aspects of decision-making and skill acquisition like the generation of exploratory actions. This paper describes BABE (Basal ganglia Acetylcholine-Based Entropy, a model of the acetylcholine system in the striatum that provides a unified explanation for these phenomena. According to this model, cholinergic interneurons in the striatum control the level of variability in behavior by modulating the number of possible responses that are considered by the basal ganglia, as well as the level of competition between them. This mechanism provides a natural way to account for the role of basal ganglia in generating behavioral variability during the acquisition of certain cognitive skills, as well as for modulating exploration and exploitation in decision making. Compared to a typical reinforcement learning model, BABE showed a greater modulation of response variability in the face of changes in the reward contingencies, allowing for faster learning (and re-learning of option values. Finally, the paper discusses the possible applications of the model to other domains.

  12. Major amyloid-β-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex.

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    Pacheco-Quinto, Javier; Eckman, Christopher B; Eckman, Elizabeth A

    2016-12-01

    Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for Aβ degradation is consistent with the possibility that Aβ may have a physiological function related to the regulation of inhibitory signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Prolonged response to calling songs by the L3 auditory interneuron in female crickets (Acheta domesticus): possible roles in regulating phonotactic threshold and selectiveness for call carrier frequency.

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    Bronsert, Michael; Bingol, Hilary; Atkins, Gordon; Stout, John

    2003-03-01

    L3, an auditory interneuron in the prothoracic ganglion of female crickets (Acheta domesticus) exhibited two kinds of responses to models of the male's calling song (CS): a previously described, phasically encoded immediate response; a more tonically encoded prolonged response. The onset of the prolonged response required 3-8 sec of stimulation to reach its maximum spiking rate and 6-20 sec to decay once the calling song ceased. It did not encode the syllables of the chirp. The prolonged response was sharply selective for the 4-5 kHz carrier frequency of the male's calling songs and its threshold tuning matched the threshold tuning of phonotaxis, while the immediate response of the same neuron was broadly tuned to a wide range of carrier frequencies. The thresholds for the prolonged response covaried with the changing phonotactic thresholds of 2- and 5-day-old females. Treatment of females with juvenile hormone reduced the thresholds for both phonotaxis and the prolonged response by equivalent amounts. Of the 3 types of responses to CSs provided by the ascending L1 and L3 auditory interneurons, the threshold for L3's prolonged response, on average, best matched the same females phonotactic threshold. The prolonged response was stimulated by inputs from both ears while L3's immediate response was driven only from its axon-ipsilateral ear. The prolonged response was not selective for either the CS's syllable period or chirp rate. Copyright 2003 Wiley-Liss, Inc.

  14. Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: a role for estradiol.

    Science.gov (United States)

    Wu, YeeWen Candace; Du, Xin; van den Buuse, Maarten; Hill, Rachel A

    2014-07-01

    Gender differences in the neurodevelopmental disorder, schizophrenia, have been described for nearly all features of the illness. Reduced hippocampal expression of the GABAergic interneuron marker, parvalbumin (PV), and GABA synthesizing enzyme, GAD67, are consistently reported in schizophrenia. However, little is known of the expression patterns of hippocampal PV and GAD67 during adolescence and their interaction with sex steroid hormones during adolescent development. This study examined the effects of altered sex steroid hormone levels during adolescence on protein levels of PV, GAD67 and estrogen receptors (ERα/β) in the hippocampus of mice. Protein expression of PV and GAD67 was measured in the dorsal (DHP) and ventral (VHP) hippocampus of female and male C57Bl/6 mice by Western blot in a week by week analysis from pre-pubescence to adulthood (week 3-12). Fluorescent immunohistochemistry (IHC) was used to investigate the relationship between ERs and PV(+) cells in the hippocampus of female mice at young adulthood (week 10-11). To further examine the role of sex steroid hormones on PV and GAD67 expression, gonadectomy and hormone replacement was done at 5 weeks of age. Female mice showed a significant gradual increase in PV expression from 3 to 12 weeks of age in the DHP and VHP which correlated with serum 17β-estradiol levels. Fluorescent IHC showed approximately 30-50% co-localization of ER-α in PV(+) cells in the female DHP and VHP (dentate gryus/hilus and CA1-CA3). Adolescent ovariectomy significantly reduced PV expression in the DHP but not VHP of female mice, while 17β-estradiol replacement prevented this deficit in DHP PV levels. ER-α expression, but not ER-β, was also reduced in the DHP following ovariectomy with no significant effect of 17β-estradiol replacement. In contrast to female mice, male mice did not show any significant changes in hippocampal PV/GAD67 expression throughout adolescent development. Furthermore, adolescent castration and

  15. Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms.

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    Ferguson, Katie A; Huh, Carey Y L; Amilhon, Bénédicte; Williams, Sylvain; Skinner, Frances K

    2013-01-01

    The coupling of high frequency oscillations (HFOs; >100 Hz) and theta oscillations (3-12 Hz) in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+) interneurons may play an essential role in these oscillations due to their extensive connections with neighboring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms. We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence. Network simulations produce coherent firing at high frequencies (>90 Hz) for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms.

  16. Experimentally constrained CA1 fast-firing parvalbumin-positive interneuron network models exhibit sharp transitions into coherent high frequency rhythms

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    Katie A Ferguson

    2013-10-01

    Full Text Available The coupling of high frequency oscillations (HFOs; >100 Hz and theta oscillations (3-12 Hz in the CA1 region of rats increases during REM sleep, indicating that it may play a role in memory processing. However, it is unclear whether the CA1 region itself is capable of providing major contributions to the generation of HFOs, or if they are strictly driven through input projections. Parvalbumin-positive (PV+ interneurons may play an essential role in these oscillations due to their extensive connections with neighbouring pyramidal cells, and their characteristic fast-spiking. Thus, we created mathematical network models to investigate the conditions under which networks of CA1 fast-spiking PV+ interneurons are capable of producing high frequency population rhythms.We used whole-cell patch clamp recordings of fast-spiking, PV+ cells in the CA1 region of an intact hippocampal preparation in vitro to derive cellular properties, from which we constrained an Izhikevich-type model. Novel, biologically constrained network models were constructed with these individual cell models, and we investigated networks across a range of experimentally determined excitatory inputs and inhibitory synaptic strengths. For each network, we determined network frequency and coherence.Network simulations produce coherent firing at high frequencies (> 90 Hz for parameter ranges in which PV-PV inhibitory synaptic conductances are necessarily small and external excitatory inputs are relatively large. Interestingly, our networks produce sharp transitions between random and coherent firing, and this sharpness is lost when connectivity is increased beyond biological estimates. Our work suggests that CA1 networks may be designed with mechanisms for quickly gating in and out of high frequency coherent population rhythms, which may be essential in the generation of nested theta/high frequency rhythms.

  17. The effects of anodal transcranial direct current stimulation and patterned electrical stimulation on spinal inhibitory interneurons and motor function in patients with spinal cord injury.

    Science.gov (United States)

    Yamaguchi, Tomofumi; Fujiwara, Toshiyuki; Tsai, Yun-An; Tang, Shuen-Chang; Kawakami, Michiyuki; Mizuno, Katsuhiro; Kodama, Mitsuhiko; Masakado, Yoshihisa; Liu, Meigen

    2016-06-01

    Supraspinal excitability and sensory input may play an important role for the modulation of spinal inhibitory interneurons and functional recovery among patients with incomplete spinal cord injury (SCI). Here, we investigated the effects of anodal transcranial direct current stimulation (tDCS) combined with patterned electrical stimulation (PES) on spinal inhibitory interneurons in patients with chronic incomplete SCI and in healthy individuals. Eleven patients with incomplete SCI and ten healthy adults participated in a single-masked, sham-controlled crossover study. PES involved stimulating the common peroneal nerve with a train of ten 100 Hz pulses every 2 s for 20 min. Anodal tDCS (1 mA) was simultaneously applied to the primary motor cortex that controls the tibialis anterior muscle. We measured reciprocal inhibition and presynaptic inhibition of a soleus H-reflex by stimulating the common peroneal nerve prior to tibial nerve stimulation, which elicits the H-reflex. The inhibition was assessed before, immediately after, 10 min after and 20 min after the stimulation. Compared with baseline, simultaneous application of anodal tDCS with PES significantly increased changes in disynaptic reciprocal inhibition and long-latency presynaptic inhibition in both healthy and SCI groups for at least 20 min after the stimulation (all, p stimulation (p = 0.004). In conclusion, anodal tDCS combined with PES could induce spinal plasticity and improve ankle movement in patients with incomplete SCI.

  18. Using a Semi-Automated Strategy to Develop Multi-Compartment Models That Predict Biophysical Properties of Interneuron-Specific 3 (IS3) Cells in Hippocampus.

    Science.gov (United States)

    Guet-McCreight, Alexandre; Camiré, Olivier; Topolnik, Lisa; Skinner, Frances K

    2016-01-01

    Determining how intrinsic cellular properties govern and modulate neuronal input-output processing is a critical endeavor for understanding microcircuit functions in the brain. However, lack of cellular specifics and nonlinear interactions prevent experiments alone from achieving this. Building and using cellular models is essential in these efforts. We focus on uncovering the intrinsic properties of mus musculus hippocampal type 3 interneuron-specific (IS3) cells, a cell type that makes GABAergic synapses onto specific interneuron types, but not pyramidal cells. While IS3 cell morphology and synaptic output have been examined, their voltage-gated ion channel profile and distribution remain unknown. We combined whole-cell patch-clamp recordings and two-photon dendritic calcium imaging to examine IS3 cell membrane and dendritic properties. Using these data as a target reference, we developed a semi-automated strategy to obtain multi-compartment models for a cell type with unknown intrinsic properties. Our approach is based on generating populations of models to capture determined features of the experimental data, each of which possesses unique combinations of channel types and conductance values. From these populations, we chose models that most closely resembled the experimental data. We used these models to examine the impact of specific ion channel combinations on spike generation. Our models predict that fast delayed rectifier currents should be present in soma and proximal dendrites, and this is confirmed using immunohistochemistry. Further, without A-type potassium currents in the dendrites, spike generation is facilitated at more distal synaptic input locations. Our models will help to determine the functional role of IS3 cells in hippocampal microcircuits.

  19. The multimodal antidepressant vortioxetine may facilitate pyramidal cell firing by inhibition of 5-HT3 receptor expressing interneurons: An in vitro study in rat hippocampus slices.

    Science.gov (United States)

    Dale, Elena; Grunnet, Morten; Pehrson, Alan L; Frederiksen, Kristen; Larsen, Peter H; Nielsen, Jacob; Stensbøl, Tine B; Ebert, Bjarke; Yin, Haolan; Lu, Dunguo; Liu, Huiquing; Jensen, Thomas N; Yang, Charles R; Sanchez, Connie

    2017-12-21

    The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling. Copyright © 2017. Published by Elsevier B.V.

  20. [Dendritic arborization patterns of interneurons labeled with a lectin, Vicia villosa, in rat cerebral cortex: studies by intracellular injection of lucifer yellow using aldehyde-fixed slices].

    Science.gov (United States)

    Ojima, H

    1993-04-01

    In order to characterize the dendritic field of a number of interneurons in the cerebral cortex, the labeling of extracellular sugar chains which define a subset of interneurons was combined with the subsequent intracellular filling of dyes in aldehyde-fixed tissue. Neurons whose cell body had been outlined by a lectin, Vicia villosa (VVA), which recognizes terminal N-acetylgalactosamine, were intracellularly injected with a fluorescent tracer, Lucifer yellow (LY), in the rat parietal cortex under direct visualization. After immunohistochemical detection of LY, somal morphology and the dendritic fields of injected neurons were reconstructed from serial sections and characterized in each of the layers II/III, IV, V and VI. Multipolar, flask-shaped and bitufted somata were VVA-positive. Multipolar neurons with round soma and spherical dendritic field were found in layers II/III, IV and V, while those with vertically elongated dendritic fields were found in layer VI. Cell bodies were located roughly in the center of the spherical or cylindrical dendritic fields. Neurons with apparently multipolar but flask- or pear-shaped soma were found frequently in layer IV, and much less frequently in layer II/III and VI. The majority of the dendrites originated from the neck portion of flask and formed a roughly spherical dendritic field with the cell body located more or less eccentrically. Some neurons in layer IV had an oval, somewhat vertically elongated soma and displayed a typical bitufted dendritic arborization pattern with vertically elongated dendritic fields. The overall dendritic field sizes of the cells gradually increased at deeper layers of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Similar distribution changes of GABAergic interneuron subpopulations in contrast to the different impact on neurogenesis between developmental and adult-stage hypothyroidism in the hippocampal dentate gyrus in rats.

    Science.gov (United States)

    Shiraki, Ayako; Akane, Hirotoshi; Ohishi, Takumi; Wang, Liyun; Morita, Reiko; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-10-01

    Hypothyroidism affects neurogenesis. The present study was performed to clarify the sensitivity of neurogenesis-related cellular responses in the hippocampal dentate gyrus between developmental and adult-stage hypothyroidism. An exposure study of methimazole (MMI) as an anti-thyroid agent at 0, 50, 200 ppm in the drinking water was performed using pregnant rats from gestation day 10 to postnatal day (PND) 21 (developmental hypothyroidism) and adult male rats by setting an identical exposure period from PND 46 through to PND 77 (adult-stage hypothyroidism). Offspring with developmental hypothyroidism were killed at PND 21 or PND 77, and animals with adult-stage hypothyroidism were killed at PND 77. Proliferation and apoptosis were unchanged in the dentate subgranular zone by either developmental or adult-stage hypothyroidism. With regard to precursor granule cells, a sustained reduction of paired box 6-positive stem or early progenitor cells and a transient reduction of doublecortin-positive late-stage progenitor cells were observed after developmental hypothyroidism with MMI at 50 and 200 ppm. These cells were unchanged by adult-stage hypothyroidism. With regard to γ-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus, the number of parvalbumin-positive cells was decreased and the number of calretinin-positive cells was increased after both developmental and adult-stage hypothyroidism with MMI at 50 and 200 ppm. Fluctuations in GABAergic interneuron numbers with developmental hypothyroidism continued through to PND 77 with 200 ppm MMI. Considering the roles of GABAergic interneuron subpopulations in neurogenesis and neuronal differentiation, subpopulation changes in GABAergic interneurons by hypothyroidism may be the signature of aberrant neurogenesis even at the adult stage.

  2. Hippocampal cholinergic interneurons visualized with the choline acetyltransferase promoter: anatomical distribution, intrinsic membrane properties, neurochemical characteristics, and capacity for cholinergic modulation

    Directory of Open Access Journals (Sweden)

    Feng eYi

    2015-03-01

    Full Text Available Release of acetylcholine (ACh in the hippocampus (HC occurs during exploration, arousal, and learning. Although the medial septum-diagonal band of Broca (MS-DBB is the major extrinsic source of cholinergic input to the HC, cholinergic neurons intrinsic to the HC also exist but remain poorly understood. Here, ChAT-tauGFP and ChAT-CRE/Rosa26YFP (ChAT-Rosa mice were examined in HC. The HC of ChAT-tauGFP mice was densely innervated with GFP-positive axons, often accompanied by large GFP-positive structures, some of which were Neurotrace/DAPI-negative and likely represent large axon terminals. In the HC of ChAT-Rosa mice, ChAT-YFP cells were Neurotrace-positive and more abundant in CA3 and dentate gyrus than CA1 with partial overlapping with calretinin/VIP. Moreover, an anti-ChAT antibody consistently showed ChAT immunoreactivity in ChAT-YFP cells from MS-DBB but rarely from HC. Furthermore, ChAT-YFP cells from CA1 stratum radiatum/stratum lacunosum moleculare (SR/SLM exhibited a stuttering firing phenotype but a delayed firing phenotype in stratum pyramidale (SP of CA3. Input resistance and capacitance were also different between CA1 SR/LM and CA3 SP ChAT-YFP cells. Bath application of ACh increased firing frequency in all ChAT-YFP cells; however, cholinergic modulation was larger in CA1 SR/SLM than CA3 SP ChAT-YFP cells. Finally, CA3 SP ChAT-YFP cells exhibited a wider AP half-width and weaker cholinergic modulation than YFP-negative CA3 pyramidal cells. Consistent with CRE expression in a subpopulation of principal cells, optogenetic stimulation evoked glutamatergic postsynaptic currents in CA1 SR/SLM interneurons. In conclusion, the presence of fluorescently labeled hippocampal cells common to both ChAT-Rosa and ChAT-tauGFP mice are in good agreement with previous reports on the existence of cholinergic interneurons, but both transgenic mouse lines exhibited unexpected anatomical features that departed considerably from earlier observations.

  3. Interneurons and beta-amyloid in the olfactory bulb, anterior olfactory nucleus and olfactory tubercle in APPxPS1 transgenic mice model of Alzheimer's disease.

    Science.gov (United States)

    Saiz-Sanchez, Daniel; De La Rosa-Prieto, Carlos; Ubeda-Bañon, Isabel; Martinez-Marcos, Alino

    2013-09-01

    Impaired olfaction has been described as an early symptom in Alzheimer's disease (AD). Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Given that interneuron populations are crucial in olfactory information processing, we have quantitatively analyzed somatostatin- (SOM), parvalbumin- (PV), and calretinin-expressing (CR) cells in the olfactory bulb, anterior olfactory nucleus, and olfactory tubercle in PS1 x APP double transgenic mice model of AD. The experiments were performed in wild type and double transgenic homozygous animal groups of 2, 4, 6, and 8 months of age to analyze early stages of the pathology. In addition, beta-amyloid (Aβ) expression and its correlation with SOM cells have been quantified under confocal microscopy. The results indicate increasing expressions of Aβ with aging as well as an early fall of SOM and CR expression, whereas PV was decreased later in the disease progression. These observations evidence an early, preferential vulnerability of SOM and CR cells in rostral olfactory structures during AD that may be useful to unravel neural basis of olfactory deficits associated to this neurodegenerative disorder. Copyright © 2013 Wiley Periodicals, Inc.

  4. Calcium Imaging Reveals Coordinated Simple Spike Pauses in Populations of Cerebellar Purkinje Cells

    Directory of Open Access Journals (Sweden)

    Jorge E. Ramirez

    2016-12-01

    Full Text Available The brain’s control of movement is thought to involve coordinated activity between cerebellar Purkinje cells. The results reported here demonstrate that somatic Ca2+ imaging is a faithful reporter of Na+-dependent “simple spike” pauses and enables us to optically record changes in firing rates in populations of Purkinje cells in brain slices and in vivo. This simultaneous calcium imaging of populations of Purkinje cells reveals a striking spatial organization of pauses in Purkinje cell activity between neighboring cells. The source of this organization is shown to be the presynaptic gamma-Aminobutyric acid producing (GABAergic network, and blocking ionotropic gamma-Aminobutyric acid receptor (GABAARs abolishes the synchrony. These data suggest that presynaptic interneurons synchronize (inactivity between neighboring Purkinje cells, and thereby maximize their effect on downstream targets in the deep cerebellar nuclei.

  5. Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.

    Science.gov (United States)

    Yuan, Qiang; Yang, Feng; Xiao, Yixin; Tan, Shawn; Husain, Nilofer; Ren, Ming; Hu, Zhonghua; Martinowich, Keri; Ng, Julia S; Kim, Paul J; Han, Weiping; Nagata, Koh-Ichi; Weinberger, Daniel R; Je, H Shawn

    2016-08-15

    Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown. We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy. A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures. Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in behavior and plasticity of L2 interneurons in the brain of Drosophila melanogaster.

    Science.gov (United States)

    Kijak, Ewelina; Pyza, Elżbieta

    2017-01-01

    Drosophila melanogaster is a common model used to study circadian rhythms in behavior and circadian clocks. However, numerous circadian rhythms have also been detected in non-clock neurons, especially in the first optic neuropil (lamina) of the fly's visual system. Such rhythms have been observed in the number of synapses and in the structure of interneurons, which exhibit changes in size and shape in a circadian manner. Although the patterns of these changes are known, the mechanism remains unclear. In the present study, we investigated the role of the TOR signaling pathway and autophagy in regulating circadian rhythms based on the behavior and structural plasticity of the lamina L2 monopolar cell dendritic trees. In addition, we examined the cyclic expression of the TOR signaling pathway (Tor, Pi3K class 1, Akt1) and autophagy (Atg5 and Atg7) genes in the fly's brain. We observed that Tor, Atg5 and Atg7 exhibit rhythmic expressions in the brain of wild-type flies in day/night conditions (LD 12:12) that are abolished in per01 clock mutants. The silencing of Tor in per expressing cells shortens a period of the locomotor activity rhythm of flies. In addition, silencing of the Tor and Atg5 genes in L2 cells disrupts the circadian plasticity of the L2 cell dendritic trees measured in the distal lamina. In turn, silencing of the Atg7 gene in L2 cells changes the pattern of this rhythm. Our results indicate that the TOR signaling pathway and autophagy are involved in the regulation of circadian rhythms in the behavior and plasticity of neurons in the brain of adult flies.

  7. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Science.gov (United States)

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

    2017-01-01

    ABSTRACT Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal. PMID:28138095

  8. Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion

    Directory of Open Access Journals (Sweden)

    Kathrin eHoppenrath

    2016-03-01

    Full Text Available Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV fast-spiking interneurons (FSIs, evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs of FSIs start to grow around postnatal day 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo – in vitro whole-cell patch clamp recordings from pre-labelled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28 and older animals (PD40-62. Slices of verum iTBS-treated rats further showed higher rates of spontaneous EPSCs. Based on these and previous findings we conclude that FSIs are particularly sensitive to theta-burst stimulation during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

  9. Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion.

    Science.gov (United States)

    Hoppenrath, Kathrin; Härtig, Wolfgang; Funke, Klaus

    2016-01-01

    Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo-in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28) and older animals (PD40-62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

  10. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    Directory of Open Access Journals (Sweden)

    David Ladrón de Guevara-Miranda

    2017-03-01

    Full Text Available Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV+ and neuropeptide Y (NPY+ interneurons and adult neurogenesis (cell proliferation and immature neurons] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

  11. Dendritic distributions of Ih channels in experimentally-derived multi-compartment models of oriens-lacunosum/moleculare (O-LM hippocampal interneurons

    Directory of Open Access Journals (Sweden)

    Vladislav eSekulic

    2015-02-01

    Full Text Available The O-LM cell type mediates feedback inhibition onto hippocampal pyramidal cells and gates information flow in the CA1. Its functions depend on the presence of voltage-gated channels (VGCs, which affect its integrative properties and response to synaptic input. Given the challenges associated with determining densities and distributions of VGCs on interneuron dendrites, we take advantage of computational modeling to consider different possibilities. In this work, we focus on hyperpolarization-activated channels (h-channels in O-LM cells. While h-channels are known to be present in O-LM cells, it is unknown whether they are present on their dendrites. In previous work, we used ensemble modeling techniques with experimental data to obtain insights into potentially important conductance balances. We found that the best O-LM models that included uniformly distributed h-channels in the dendrites could not fully capture the sag response. This led us to examine activation kinetics and non-uniform distributions of h-channels in the present work. In tuning our models, we found that different kinetics and non-uniform distributions could better reproduce experimental O-LM cell responses. In contrast to CA1 pyramidal cells where higher conductance densities of h-channels occur in more distal dendrites, decreasing conductance densities of h-channels away from the soma were observed in O-LM models. Via an illustrative scenario, we showed that having dendritic h-channels clearly speeds up back-propagating action potentials in O-LM cells, unlike when h-channels are present only in the soma. Although the present results were morphology-dependent, our work shows that it should be possible to determine the distributions and characteristics of O-LM cells with recordings and morphologies from the same cell. We hypothesize that h-channels are distributed in O-LM cell dendrites and endow them with particular synaptic integration properties that shape information flow

  12. Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: potential roles in GABAergic interneuron pathology.

    Science.gov (United States)

    Schubert, Klaus Oliver; Föcking, Melanie; Cotter, David R

    2015-09-01

    Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein-endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Data on characterizing the gene expression patterns of neuronal ceroid lipofuscinosis genes: CLN1, CLN2, CLN3, CLN5 and their association to interneuron and neurotransmission markers: Parvalbumin and Somatostatin

    Directory of Open Access Journals (Sweden)

    Helena M. Minye

    2016-09-01

    Full Text Available The article contains raw and analyzed data related to the research article “Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain” (Fabritius et al., 2014 [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development. Immunohistochemistry was used to identify known interneuronal markers for neurotransmission and cell proliferation: parvalbumin, somatostatin subpopulations of interneurons. Non-radioactive in-situ hybridization detected CLN5 mRNA in the hippocampus. Throughout the development strong expression of CLN genes were identified in the germinal epithelium and in ventricle regions, cortex, hippocampus, and cerebellum. This provides supportive evidence that CLN1, CLN2, CLN3 and CLN5 genes may be involved in synaptic pruning.

  14. Data on characterizing the gene expression patterns of neuronal ceroid lipofuscinosis genes: CLN1, CLN2, CLN3, CLN5 and their association to interneuron and neurotransmission markers: Parvalbumin and Somatostatin.

    Science.gov (United States)

    Minye, Helena M; Fabritius, Anna-Liisa; Vesa, Jouni; Peltonen, Leena

    2016-09-01

    The article contains raw and analyzed data related to the research article "Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain" (Fabritius et al., 2014) [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development. Immunohistochemistry was used to identify known interneuronal markers for neurotransmission and cell proliferation: parvalbumin, somatostatin subpopulations of interneurons. Non-radioactive in-situ hybridization detected CLN5 mRNA in the hippocampus. Throughout the development strong expression of CLN genes were identified in the germinal epithelium and in ventricle regions, cortex, hippocampus, and cerebellum. This provides supportive evidence that CLN1, CLN2, CLN3 and CLN5 genes may be involved in synaptic pruning.

  15. Android Emotions Revealed

    DEFF Research Database (Denmark)

    Vlachos, Evgenios; Schärfe, Henrik

    2012-01-01

    in which case an android robot like the Geminoid|DK –a duplicate of an Original person- reveals emotions convincingly; when following an empirical perspective, or when following a theoretical one. The methodology includes the processes of acquiring the empirical data, and gathering feedback on them. Our...

  16. Revealing the programming process

    DEFF Research Database (Denmark)

    Bennedsen, Jens; Caspersen, Michael Edelgaard

    2005-01-01

    One of the most important goals of an introductory programming course is that the students learn a systematic approach to the development of computer programs. Revealing the programming process is an important part of this; however, textbooks do not address the issue -- probably because...... the textbook medium is static and therefore ill-suited to expose the process of programming. We have found that process recordings in the form of captured narrated programming sessions are a simple, cheap, and efficient way of providing the revelation.We identify seven different elements of the programming...

  17. TypeScript revealed

    CERN Document Server

    Maharry, Dan

    2013-01-01

    TypeScript Revealed is a quick 100-page guide to Anders Hejlsberg's new take on JavaScript. With this brief, fast-paced introduction to TypeScript, .NET, Web and Windows 8 application developers who are already familiar with JavaScript will easily get up to speed with TypeScript and decide whether or not to start incorporating it into their own development. TypeScript is 'JavaScript for Application-scale development'; a superset of JavaScript that brings to it an additional object-oriented-like syntax familiar to .NET programmers that compiles down into simple, clean JavaScript that any browse

  18. Mysterious Blob Galaxies Revealed

    Science.gov (United States)

    2005-01-01

    [figure removed for brevity, see original site] [figure removed for brevity, see original site] Figure 1Figure 2Figure 3 This image composite shows a giant galactic blob (red, figure 2) and the three merging galaxies NASA's Spitzer Space Telescope discovered within it (yellow, figure 3). Blobs are intensely glowing clouds of hot hydrogen gas that envelop faraway galaxies. They are about 10 times as large as the galaxies they surround. Visible-light images like the one shown in figure 2, reveal the vast extent of blobs, but don't provide much information about their host galaxies. Using its heat-seeking infrared eyes, Spitzer was able to see the dusty galaxies tucked inside one well-known blob located 11 billion light-years away. The findings reveal three monstrously bright galaxies, trillions of times brighter than the Sun, in the process of merging together (figure 3). Spitzer also observed three other blobs located in the same cosmic neighborhood, all of which were found to be glaringly bright. One of these blobs is also known to be a galactic merger, only between two galaxies instead of three. It remains to be seen whether the final two blobs studied also contain mergers. The Spitzer data were acquired by its multiband imaging photometer. The visible-light image was taken by the Blanco Telescope at the Cerro Tololo Inter-American Observatory, Chile.

  19. Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets

    Science.gov (United States)

    Ganley, Robert P.; Iwagaki, Noboru; del Rio, Patricia; Baseer, Najma; Dickie, Allen C.; Boyle, Kieran A.; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda

    2015-01-01

    The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to “unclassified” cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn. PMID:25972186

  20. Comparison of Ca2+ transients and [Ca2+]i in the dendrites and boutons of non-fast-spiking GABAergic hippocampal interneurons using two-photon laser microscopy and high- and low-affinity dyes

    Science.gov (United States)

    Kisfali, Máté; Lőrincz, Tibor; Vizi, E Sylvester

    2013-01-01

    Using two-photon laser microscopy, high- and low-affinity dyes and patch clamp electrophysiology, we successfully measured somatic stimulation-evoked Ca2+ transients simultaneously in the dendrites and axonal boutons of the same non-fast-spiking GABAergic interneurons in acute slice preparations obtained from hippocampal area CA1. The advantage of the acute preparation is that both neuronal connections and anatomy are maintained. Calculated as unperturbed values, the amplitudes of Ca2+ transients and changes in [Ca2+]i in response to somatic single or burst stimulation were much higher in boutons (428 nm/AP) than in dendrites (49 nm/AP), leading to the conclusion that the much greater influx of Ca2+ observed in terminals might be due to a higher density of N-type voltage-sensitive Ca2+ channels compared to the L-type channels present in dendrites. Whereas the decay of Ca2+ transients recorded in dendrites was primarily mono-exponential, the decay in boutons was bi-exponential, as indicated by an initial fast phase, followed by a much slower reduction in fluorescence intensity. The extrusion of Ca2+ was much faster in boutons than in dendrites. To avoid saturation effects and the flawed conversion of fluorescence measures of [Ca2+]i, we assessed the limits of [Ca2+] measurements (which ranged between 6 and 82% of the applied dye saturation) when high- and low-affinity dyes were applied at different concentrations. When two APs were delivered at a high frequency (>3 Hz) of stimulation, the low-affinity indicators OGB-6F (KD= 3.0 μm) and OGB-5N (KD= 20 μm) were able to accurately reflect the changes in ΔF/F produced by the consecutive APs. There was no difference in the endogenous buffer capacity (κE), which can shape Ca2+ signals, calculated in dendrites (κE= 354) or boutons (κE= 458). PMID:23981718

  1. Identification and structural characterization of interneurons of the Drosophila brain by monoclonal antibodies of the würzburg hybridoma library.

    Directory of Open Access Journals (Sweden)

    Beatriz Blanco Redondo

    Full Text Available Several novel synaptic proteins have been identified by monoclonal antibodies (mAbs of the Würzburg hybridoma library generated against homogenized Drosophila brains, e.g. cysteine string protein, synapse-associated protein of 47 kDa, and Bruchpilot. However, at present no routine technique exists to identify the antigens of mAbs of our library that label only a small number of cells in the brain. Yet these antibodies can be used to reproducibly label and thereby identify these cells by immunohistochemical staining. Here we describe the staining patterns in the Drosophila brain for ten mAbs of the Würzburg hybridoma library. Besides revealing the neuroanatomical structure and distribution of ten different sets of cells we compare the staining patterns with those of antibodies against known antigens and GFP expression patterns driven by selected Gal4 lines employing regulatory sequences of neuronal genes. We present examples where our antibodies apparently stain the same cells in different Gal4 lines suggesting that the corresponding regulatory sequences can be exploited by the split-Gal4 technique for transgene expression exclusively in these cells. The detection of Gal4 expression in cells labeled by mAbs may also help in the identification of the antigens recognized by the antibodies which then in addition to their value for neuroanatomy will represent important tools for the characterization of the antigens. Implications and future strategies for the identification of the antigens are discussed.

  2. What changes in neural oscillations can reveal about developmental cognitive neuroscience: language development as a case in point.

    Science.gov (United States)

    Maguire, Mandy J; Abel, Alyson D

    2013-10-01

    EEG is a primary method for studying temporally precise neuronal processes across the lifespan. Most of this work focuses on event related potentials (ERPs); however, using time-locked time frequency analysis to decompose the EEG signal can identify and distinguish multiple changes in brain oscillations underlying cognition (Bastiaansen et al., 2010). Further this measure is thought to reflect changes in inter-neuronal communication more directly than ERPs (Nunez and Srinivasan, 2006). Although time frequency has elucidated cognitive processes in adults, applying it to cognitive development is still rare. Here, we review the basics of neuronal oscillations, some of what they reveal about adult cognitive function, and what little is known relating to children. We focus on language because it develops early and engages complex cortical networks. Additionally, because time frequency analysis of the EEG related to adult language comprehension has been incredibly informative, using similar methods with children will shed new light on current theories of language development and increase our understanding of how neural processes change over the lifespan. Our goal is to emphasize the power of this methodology and encourage its use throughout developmental cognitive neuroscience. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Immunohistochemical visualization of mouse interneuron subtypes

    DEFF Research Database (Denmark)

    Jensen, Simon Mølgaard; Ulrichsen, Maj; Boggild, Simon

    2014-01-01

    on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections...

  4. [Vulvar oedema revealing systemic mastocytosis].

    Science.gov (United States)

    Deveza, E; Locatelli, F; Girardin, M; Valmary-Degano, S; Daguindau, E; Aubin, F; Humbert, P; Pelletier, F

    2015-11-01

    Systemic mastocytosis is characterised by abnormal proliferation of mast cells in various organs. We report an original case of systemic mastocytosis revealed by vulvar oedema. A 24-year-old patient was examined in the dermatology department for vulvar oedema appearing during sexual intercourse. She presented vasomotor dysfunction of the lower limbs, urticaria on the trunk on exertion, diarrhoea and bone pains. Laboratory tests showed serum tryptase of 29.7μg and plasma histamine at twice the normal value. Myelogram results showed infiltration by dysmorphic mast cells. Screening for c-kit D816V mutation was positive. Duodenal biopsies revealed mast-cell clusters with aggregation involving over 15 mast cells. CD2 staining was inconclusive and CD25 staining could not be done. Trabecular osteopenia was found, and we thus made a diagnosis of indolent systemic mastocytosis (ISM variant Ia) as per the WHO 2008 criteria. Symptomatic treatment was initiated (antiH1, H2, antileukotrienes) and clinical and laboratory follow-up was instituted. The cutaneous signs leading to diagnosis in this patient of systemic mastocytosis involving several organs were seemingly minimal signs associated with mastocyte degranulation. This is the third recorded case of mastocytosis revealed by vulvar oedema and the first case revealing systemic involvement. The two previously reported cases of vulvar oedema revealed cutaneous mastocytosis alone. Mastocytosis, whether systemic or cutaneous, must be included among the differential diagnoses considered in the presence of vulvar oedema. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Revealing and Concealing in Antiquity

    DEFF Research Database (Denmark)

    Secrecy and the act of concealing and revealing knowledge effectually segregate the initiated and the uninitiated. The act of sharing or hiding knowledge plays a central role in all human relations private or public, political or religious. This volume explores the concept of secrecy and its impl...

  6. [Cervicofacial cellulitis revealing cutaneous lymphomas].

    Science.gov (United States)

    Benbouzid, M A; Bencheikh, R; Benhammou, A; El Edghiri, H; Boulaich, M; Essakali, L; Kzadri, M

    2007-06-01

    The cervicofacial localization of cutaneous lymphomas is rare. These lymphomas usually present as a long-lasting and treatment-refractory papule or nodule. Lymphomas can also be revealed by cervicofacial cellulitis. We report 2 cases of cervicofacial cellulitis revealing a cutaneous lymphoma. The diagnosis was proved by multiple biopsies, performed because there was no clinical improvement in spite of an aggressive and adequate antibiotherapy. Our 2 patients were treated by radio and chemotherapy. Cutaneous lymphomas are lymphocytic proliferations stemming from cutaneous lymphoid tissue, without nodal, medullary, or visceral localization. Their clinical presentation is quite polymorphic, and cellulitis is one of the modes of revelation, especially forehead and neck localization. They have no portal of entry and are resistant to treatment. The diagnosis relies on histology, and biopsies must be performed if there is a suspicion of lymphoma. The treatment is radio and chemotherapy, and the evolution depends on the tumoral stage.

  7. Decision Making and Revealed Preference

    DEFF Research Database (Denmark)

    de la Rosa, Leonidas Enrique

    If our decision-making processes are to some extent shaped by evolutionary pressures and our environment is different from that to which we adapted, some of our choices will not be in our best interest. But revealed preference is the only tool that we have so far to conduct a normative analysis. ....... Given advances in evolutionary psychology and neuroscience, I propose one way to model those evolutionary pressures that will hopefully prove useful in expanding normative economics.......If our decision-making processes are to some extent shaped by evolutionary pressures and our environment is different from that to which we adapted, some of our choices will not be in our best interest. But revealed preference is the only tool that we have so far to conduct a normative analysis...

  8. Urticarial vasculitis reveals unsuspected thyroiditis.

    Science.gov (United States)

    Ferreira, Olga; Mota, Alberto; Baudrier, Teresa; Azevedo, Filomena

    2012-01-01

    A 38-year-old woman presented with erythematous, violaceous plaques with a serpiginous and unusual appearance located on the left shoulder, left thigh, and right buttock, evolving for 5 days, which eventually became generalized. A skin biopsy revealed leukocytoclastic vasculitis and a diagnosis of urticarial vasculitis was made. The complete blood count, biochemistry, complement levels, and other immunological test results were unremarkable. However, antithyroid antibody titers were increased. Despite having normal thyroid function tests and an absence of specific symptoms, the patient underwent a thyroid ultrasound, which revealed features of thyroiditis, and was subsequently referred to an endocrinologist. Several diseases can be associated with urticarial vasculitis, namely infections and autoimmune connective-tissue disorders such as systemic lupus erythematosus and Sjögren syndrome. Thyroiditis is an uncommon association.

  9. Transparency masters for mathematics revealed

    CERN Document Server

    Berman, Elizabeth

    1980-01-01

    Transparency Masters for Mathematics Revealed focuses on master diagrams that can be used for transparencies for an overhead projector or duplicator masters for worksheets. The book offers information on a compilation of master diagrams prepared by John R. Stafford, Jr., audiovisual supervisor at the University of Missouri at Kansas City. Some of the transparencies are designed to be shown horizontally. The initial three masters are number lines and grids that can be used in a mathematics course, while the others are adaptations of text figures which are slightly altered in some instances. The

  10. To Reveal Thy Heart Perchance to Reveal the World

    Directory of Open Access Journals (Sweden)

    Robert B. Faux

    2005-05-01

    Full Text Available Ronald PELIAS, a professor of speech communications, employs a variety of writing methods as examples of alternative ways to do research and to share with the reader a seldom seen and seldom considered aspect of academic life: Heart. In the early chapters of the book, PELIAS sets out to establish a way to place his Heart in the foreground; baring his emotional vulnerability, his humanness, his being in the world. Later chapters of the book encompass an autoethnographic study of academic life in which the previously revealed Heart is placed in context. In this review essay I discuss PELIAS' book in relation to the larger literature on autoethnography and subjectivist research; I follow this by discussing the need for and usefulness of such alternative methods using PELIAS' autoethnography of academic life as a context. URN: urn:nbn:de:0114-fqs050279

  11. Communication Games Reveal Preparation Contextuality

    Science.gov (United States)

    Hameedi, Alley; Tavakoli, Armin; Marques, Breno; Bourennane, Mohamed

    2017-12-01

    A communication game consists of distributed parties attempting to jointly complete a task with restricted communication. Such games are useful tools for studying limitations of physical theories. A theory exhibits preparation contextuality whenever its predictions cannot be explained by a preparation noncontextual model. Here, we show that communication games performed in operational theories reveal the preparation contextuality of that theory. For statistics obtained in a particular family of communication games, we show a direct correspondence with correlations in spacelike separated events obeying the no-signaling principle. Using this, we prove that all mixed quantum states of any finite dimension are preparation contextual. We report on an experimental realization of a communication game involving three-level quantum systems from which we observe a strong violation of the constraints of preparation noncontextuality.

  12. Plan competitions reveal entrepreneurial talent

    Energy Technology Data Exchange (ETDEWEB)

    Madison, Alison L.

    2011-05-15

    Monthly economic diversity column for Tri-City Herald business section. Excerpt below: There’s something to be said for gaining valuable real-world experience in a structured, nurturing environment. Take for instance learning to scuba dive in the comfort of my resort pool rather than immediately hanging out with sharks while I figure out little things like oxygen tanks and avoiding underwater panic attacks. Likewise, graduate students are getting some excellent, supportive real-world training through university business plan competitions. These competitions are places where smart minds, new technologies, months of preparation and coaching, and some healthy pre-presentation jitters collide to reveal not only solid new business ideas, but also some promising entrepreneurial talent. In fact, professionals from around our region descend upon college campuses every spring to judge these events, which help to bridge the gap between academics and the real technology and business-driven economy.

  13. Revealing Non-Covalent Interactions

    Science.gov (United States)

    Johnson, Erin R.; Keinan, Shahar; Mori-Sánchez, Paula; Contreras-García, Julia; Cohen, Aron J.; Yang, Weitao

    2010-01-01

    Molecular structure does not easily identify the intricate non-covalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect non-covalent interactions in real space, based on the electron density and its derivatives. Our approach reveals underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of non-bonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands. PMID:20394428

  14. Hubble Images Reveal Jupiter's Auroras

    Science.gov (United States)

    1996-01-01

    These images, taken by the Hubble Space Telescope, reveal changes in Jupiter's auroral emissions and how small auroral spots just outside the emission rings are linked to the planet's volcanic moon, Io. The images represent the most sensitive and sharply-detailed views ever taken of Jovian auroras.The top panel pinpoints the effects of emissions from Io, which is about the size of Earth's moon. The black-and-white image on the left, taken in visible light, shows how Io and Jupiter are linked by an invisible electrical current of charged particles called a 'flux tube.' The particles - ejected from Io (the bright spot on Jupiter's right) by volcanic eruptions - flow along Jupiter's magnetic field lines, which thread through Io, to the planet's north and south magnetic poles. This image also shows the belts of clouds surrounding Jupiter as well as the Great Red Spot.The black-and-white image on the right, taken in ultraviolet light about 15 minutes later, shows Jupiter's auroral emissions at the north and south poles. Just outside these emissions are the auroral spots. Called 'footprints,' the spots are created when the particles in Io's 'flux tube' reach Jupiter's upper atmosphere and interact with hydrogen gas, making it fluoresce. In this image, Io is not observable because it is faint in the ultraviolet.The two ultraviolet images at the bottom of the picture show how the auroral emissions change in brightness and structure as Jupiter rotates. These false-color images also reveal how the magnetic field is offset from Jupiter's spin axis by 10 to 15 degrees. In the right image, the north auroral emission is rising over the left limb; the south auroral oval is beginning to set. The image on the left, obtained on a different date, shows a full view of the north aurora, with a strong emission inside the main auroral oval.The images were taken by the telescope's Wide Field and Planetary Camera 2 between May 1994 and September 1995.This image and other images and data

  15. Tadpole begging reveals high quality.

    Science.gov (United States)

    Dugas, M B; Strickler, S A; Stynoski, J L

    2017-05-01

    Parents can benefit from allocating limited resources nonrandomly among offspring, and offspring solicitation (i.e. begging) is often hypothesized to evolve because it contains information valuable to choosy parents. We tested the predictions of three 'honest begging' hypotheses - Signal of Need, Signal of Quality and Signal of Hunger - in the tadpoles of a terrestrial frog (Oophaga pumilio). In this frog, mothers provision tadpoles with trophic eggs, and when mothers visit, tadpoles perform a putative begging signal by stiffening their bodies and vibrating rapidly. We assessed the information content of intense tadpole begging with an experimental manipulation of tadpole condition (need/quality) and food deprivation (hunger). This experiment revealed patterns consistent with the Signal of Quality hypothesis and directly counter to predictions of Signal of Need and Signal of Hunger. Begging effort and performance were higher in more developed and higher condition tadpoles and declined with food deprivation. Free-living mothers were unlikely to feed tadpoles of a nonbegging species experimentally cross-fostered with their own, and allocated larger meals to more developed tadpoles and those that vibrated at higher speed. Mother O. pumilio favour their high-quality young, and because their concurrent offspring are reared in separate nurseries, must do so by making active allocation decisions. Our results suggest that these maternal choices are based at least in part on offspring signals, indicating that offspring solicitation can evolve to signal high quality. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  16. Focus groups reveal consumer ambivalence.

    Science.gov (United States)

    1983-01-01

    According to qualitative research, Salvadoreans are ambivalent about the use of contraceptives. Since complete responsibility for management of the CSM project was accepted by the Association Demografica Salvadorena (ADS), the agency which operates the contraceptive social marketing project in El Salvador, in November 1980, the need for decisions in such areas as product price increases, introduction of new condom brands, promotion of the vaginal foaming tablet, and assessment of product sales performance had arisen. The ICSMP funded market research, completed during 1983, was intended to provide the data on which such decisions by ADS could be based. The qualitative research involved 8 focus groups, comprised of men and women, aged 18-45, contraceptive users and nonusers, from the middle and lower socioeconomic strata of the city of San Salvador and other suburban areas. In each group a moderator led discussion of family planning and probed respondents for specific attitudes, knowledge, and behavior regarding the use of contraceptives. To assess attitudes at a more emotional level, moderators asked respondents to "draw" their ideas on certain issues. A marked discrepancy was revealed between respondents' intellectual responses to the issues raised in group discussion, as opposed to their feelings expressed in the drawings. Intellectually, participants responded very positively to family planning practice, but when they were asked to draw their perceptions, ambivalent feelings emerged. Drawings of both the user and the nonuser convey primarily negative aspects for either choice. The user is tense and moody toward her children; the nonuser loses her attractiveness and "dies." Figures also show drawings of some of the attitudes of single and married male participants. 1 drawing shows an incomplete and a complete circle, symbolizing a sterilized man (incomplete) and a nonsterilized man (complete). Another picture depicts a chained man who has lost his freedom

  17. Revealing conceptual understanding of international business

    NARCIS (Netherlands)

    Ashley, S.; Schaap, H.; Bruijn, E. de

    2017-01-01

    This study aims to identify an adequate approach for revealing conceptual understanding in higher professional education. Revealing students’ conceptual understanding is an important step towards developing effective curricula, assessment and aligned teaching strategies to enhance conceptual

  18. Revealing conceptual understanding of international business

    NARCIS (Netherlands)

    Ashley, S.M.; Schaap, H.; de Bruijn, E.

    2016-01-01

    This study aims to identify an adequate approach for revealing conceptual understanding in higher professional education. Revealing students’ conceptual understanding is an important step towards developing effective curricula, assessment and aligned teaching strategies to enhance conceptual

  19. Puerto Rico Revealed Preference Survey Data 2004

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Revealed preference models provide insights into recreational angler behavior and the economic value of recreational fishing trips. Revealed preference data is...

  20. Revealing Conceptual Understanding of International Business

    Science.gov (United States)

    Ashley, Sue; Schaap, Harmen; de Bruijn, Elly

    2017-01-01

    This study aims to identify an adequate approach for revealing conceptual understanding in higher professional education. Revealing students' conceptual understanding is an important step towards developing effective curricula, assessment and aligned teaching strategies to enhance conceptual understanding in higher education. Essays and concept…

  1. [Cholangitis revealing an intrahepatic Osler's disease].

    Science.gov (United States)

    Asma, Kochlef; Dalila, Gargouri; Olfa, Bousnina; Malika, Romani; Afef, Kilani; Najet, BelHadg; Jamel, Kharrat; Abdeljabbar, Gorbel; Sarra, Shili; Chiraz, Jemli; Mohamed, Habib Daghfous; Slim, Khlifi; Anis, Ben Maamer; Abdelmajid, Letaïef

    2005-08-01

    Osler Weber Rendu Disease is an hereditary haemorrhagic télangectasia habitually revealed by reccurent bleeding (epistaxis). Hepatic involvement in Osler disease is found in 8 to 31%, manifested by cholestasis. We report an original observation of a cholangitis revealing Osler disease.

  2. Cell-Type-Specific Circuit Connectivity of Hippocampal CA1 Revealed through Cre-Dependent Rabies Tracing

    Directory of Open Access Journals (Sweden)

    Yanjun Sun

    2014-04-01

    Full Text Available We developed and applied a Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to specific CA1 neuron types in the mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, the entorhinal cortex (EC, the medial septum (MS, and, unexpectedly, the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons, whereas inhibitory neurons receive a great majority of inputs from GABAergic MS neurons. Both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons received much stronger input than SOM+ neurons from CA3, the EC, and the MS. Thus, rabies tracing identifies hippocampal circuit connections and maps how the different input sources to CA1 are distributed with different strengths on each of its constituent cell types.

  3. REVEAL: Software Documentation and Platform Migration

    Science.gov (United States)

    Wilson, Michael A.; Veibell, Victoir T.

    2011-01-01

    The Research Environment for Vehicle Embedded Analysis on Linux (REVEAL) is reconfigurable data acquisition software designed for network-distributed test and measurement applications. In development since 2001, it has been successfully demonstrated in support of a number of actual missions within NASA's Suborbital Science Program. Improvements to software configuration control were needed to properly support both an ongoing transition to operational status and continued evolution of REVEAL capabilities. For this reason the project described in this report targets REVEAL software source documentation and deployment of the software on a small set of hardware platforms different from what is currently used in the baseline system implementation. This presentation specifically describes the actions taken over a ten week period by two undergraduate student interns and serves as an overview of the content of the final report for that internship.

  4. [Cervical Pott's disease revealed by retropharyngeal abscesses].

    Science.gov (United States)

    Benhammou, A; Bencheikh, R; Benbouzid, M-A; Boulaich, M; Essakali, L; Kzadri, M

    2007-12-01

    Retropharyngeal abscesses are exceptional in adults. The etiologies are numerous, cervical spine tuberculosis is one of them. We report two cases of cervical Pott's disease revealed by a retropharyngeal abscess. The clinical presentation was non-specific, dominated by oropharyngeal obstruction. Radiological findings suggested the diagnosis, showing a retropharyngeal collection with vertebral osteolysis. The bacteriological and histological assessment confirmed the diagnosis. The evolution was favorable after treatment by antituberculosis drugs. Vertebral tuberculosis is rare. Cervical involvement is exceptional, and retropharyngeal abscesses can be the revealing feature of this condition. Symptoms are not specific. The diagnosis is based on radiological and bacteriological assessment. Treatment with antituberculosis drugs leads to a good outcome.

  5. Revealed preference analysis of noncooperative household consumption

    NARCIS (Netherlands)

    Cherchye, L.J.H.; Demuynck, T.; de Rock, B.

    2011-01-01

    We develop a revealed preference approach to analyse non-unitary household consumption behaviour that is not cooperative (or Pareto efficient). We derive global necessary and sufficient conditions for data consistency with the model. We show that the conditions can be verified by means of relatively

  6. Revealed preference tests for collective household behavior

    NARCIS (Netherlands)

    Cherchye, L.J.H.; de Rock, B.; Vermeulen, F.M.P.; Verriest, E.; Molina, J.A.

    2011-01-01

    This chapter contains a state of the art of revealed preference tests for consistency of observed household behavior with Pareto efficiency. These tests are entirely nonparametric, since they do not require any assumptions regarding the parametric form of individual preferences or the intrahousehold

  7. Hypoglycemia revealing arachnoidocele in infant | Jellouli | Pan ...

    African Journals Online (AJOL)

    Arachnoidocele is characterized by the herniation of the subarachnoid space within the sella turcica, associated with some degree of flattening of the pituitary ... An exploration of the pituitary was requested, finding an achievement of the cortical axis revealed by the occurrence of multiple episodes of hypoglycemia with ...

  8. Genetic variation and geographical differentiation revealed using ...

    Indian Academy of Sciences (India)

    [Zhang L., Lu S., Sun D., and Peng J. 2015 Genetic variation and geographical differentiation revealed using ISSR markers in tung tree,. Vernicia fordii. J. Genet. 94, e5–e9. Online only: http://www.ias.ac.in/jgenet/OnlineResources/94/e5.pdf]. Introduction. Tung tree, Vernicia fordii is an oil-bearing woody plant species of ...

  9. Commentary: Revealing the workings of universal grammar

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 28; Issue 5. Commentary: Revealing the workings of universal grammar. Mohinish Shukla. Volume 28 Issue 5 September 2003 pp 535-537. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/jbsc/028/05/0535-0537. Author Affiliations.

  10. Systemic lupus erythematous revealed by cytomegalovirus infection ...

    African Journals Online (AJOL)

    Cytomegalovirus (CMV) infection have been described as exacerbing systemic lupus erythematous (SLE). The role of CMV in starting off SLE remains object of debate. We report a severe presentation of SLE revealed by CMV infection with hemophogocytic syndrome. A 22 old women without a history of systemic disease ...

  11. [Mastitis revealing Churg-Strauss syndrome].

    Science.gov (United States)

    Dannepond, C; Le Fourn, E; de Muret, A; Ouldamer, L; Carmier, D; Machet, L

    2014-01-01

    Churg-Strauss syndrome often involves the skin, and this may sometimes reveal the disease. A 25-year-old woman was referred to a gynaecologist for inflammation of the right breast with breast discharge. Cytological analysis of the liquid showed numerous inflammatory cells, particularly polymorphonuclear eosinophils and neutrophils. Ultrasound examination of the breast was consistent with galactophoritis. CRP was normal, and hypereosinophilia was seen. The patient was subsequently referred to a dermatology unit. Skin examination revealed inflammation of the entire breast, which was painful, warm and erythematous; the border was oedematous with blisters. Necrotic lesions were also present on the thumbs and knees. Skin biopsy of the breast showed a dermal infiltrate with abundant infiltrate of polymorphonuclear eosinophils, including patchy necrosis and intraepidermal vesicles. Histological examination of a biopsy sample from a thumb revealed eosinophilic granuloma and leukocytoclastic vasculitis. The patient was also presenting asthma, pulmonary infiltrates and mononeuropathy at L3, consistent with Churg-Strauss syndrome. Breast involvement in Churg-Strauss syndrome is very rare (only one other case has been reported). This is the first case in which the breast condition revealed the disease. Cutaneous involvement of the breast is, however, also compatible with Wells' cellulitis. The lesions quickly disappeared with 1mg/kg/d oral prednisolone. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  12. Genetic relationship among Musa genotypes revealed by ...

    African Journals Online (AJOL)

    Genetic relationship among Musa genotypes revealed by microsatellite markers. NAP Abdullah, GB Saleh, ETS Putra, ZB Wahab. Abstract. A banana germplasm was established containing 44 Musa genotypes collected from various locations in Malaysia. To detect their genetic variation and to rule out duplicates among ...

  13. Revealed Preference Theory, Rationality, and Neoclassical ...

    African Journals Online (AJOL)

    Revealed Preference Theory (Samuelson 1938) is an attempt to establish economic theory as a genuine empirical science by ridding it of nonempirical psychological concepts. Samuelson's goal was to rid economic theory of the last vestiges of utility analysis. Samuelson structured his theory on a set of preference axioms ...

  14. Bilateral stellate neuroretinitis revealing a pheochromocytoma ...

    African Journals Online (AJOL)

    Fundus examination showed bilateral stellate neuroretinitis. Physical examination revealed a malignant hypertension of 210/150mmHg. Magnetic resonance imaging identified a left suprarenal mass, whereas urinary catecholamine level was abnormally high which supported a diagnosis of pheochromocytoma.The patient ...

  15. Eye Movements Reveal Dynamics of Task Control

    Science.gov (United States)

    Mayr, Ulrich; Kuhns, David; Rieter, Miranda

    2013-01-01

    With the goal to determine the cognitive architecture that underlies flexible changes of control settings, we assessed within-trial and across-trial dynamics of attentional selection by tracking of eye movements in the context of a cued task-switching paradigm. Within-trial dynamics revealed a switch-induced, discrete delay in onset of…

  16. Open chromatin reveals the functional maize genome

    Science.gov (United States)

    Every cellular process mediated through nuclear DNA must contend with chromatin. As results from ENCODE show, open chromatin assays can efficiently integrate across diverse regulatory elements, revealing functional non-coding genome. In this study, we use a MNase hypersensitivity assay to discover o...

  17. Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

    Science.gov (United States)

    Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith; Venkataraju, Kannan Umadevi; Bota, Mihail; García Del Molino, Luis Carlos; Fitzgerald, Greg; Ram, Keerthi; He, Miao; Levine, Jesse Maurica; Mitra, Partha; Huang, Z Josh; Wang, Xiao-Jing; Osten, Pavel

    2017-10-05

    The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Cell-specific STORM superresolution imaging reveals nanoscale organization of cannabinoid signaling

    Science.gov (United States)

    Szabó, Szilárd I.; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G.; Henstridge, Christopher M.; Balla, Gyula Y.; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

    2014-01-01

    A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell-type-, and subcellular compartment-specific manner. We therefore developed a novel approach combining cell-specific physiological and anatomical characterization with superresolution imaging, and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically-projecting GABAergic interneurons possess increased CB1 receptor number, active-zone complexity, and receptor/effector ratio compared to dendritically-projecting interneurons, in agreement with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked dramatic CB1-downregulation in a dose-dependent manner. Full receptor recovery required several weeks after cessation of Δ9-tetrahydrocannabinol treatment. These findings demonstrate that cell-type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits, and identify novel molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction. PMID:25485758

  19. Expression weighted cell type enrichments reveal genetic and cellular nature of major brain disorders

    Directory of Open Access Journals (Sweden)

    Nathan Gerald Skene

    2016-01-01

    Full Text Available The cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimer’s disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimer’s and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesised that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimer’s disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.

  20. Septic sacroiliitis revealing an infectious endocarditis

    Science.gov (United States)

    Mahfoudhi, Madiha; Hariz, Anis; Turki, Sami; Kheder, Adel

    2014-01-01

    We report the case of a 43-year-old man admitted for right hip ache and fever. Physical examination revealed a fever, an ache at the manipulation of the sacroiliac joint and a limitation of abduction and external rotation of the right hip. There was no murmur in cardiac auscultation. No anomaly was found at the conventional radiographs of the sacroiliac joint, while the pelvic MRI confirmed a right sacroiliitis. A sacroiliac puncture with a study of synovial fluid demonstrated the presence of Streptococcus viridans. The blood culture revealed the same germ. Transthoracic and transoesophageal echocardiography confirmed infectious endocarditis with vegetation in the mitral valve. He received penicillin G and gentamicin relayed by pristinamycin because of an allergy to penicillin G with a total duration of treatment of 40 days. His symptoms and the laboratory and radiological tests abnormalities resolved totally with no recurrence. PMID:25123569

  1. Septic sacroiliitis revealing an infectious endocarditis.

    Science.gov (United States)

    Mahfoudhi, Madiha; Hariz, Anis; Turki, Sami; Kheder, Adel

    2014-08-14

    We report the case of a 43-year-old man admitted for right hip ache and fever. Physical examination revealed a fever, an ache at the manipulation of the sacroiliac joint and a limitation of abduction and external rotation of the right hip. There was no murmur in cardiac auscultation. No anomaly was found at the conventional radiographs of the sacroiliac joint, while the pelvic MRI confirmed a right sacroiliitis. A sacroiliac puncture with a study of synovial fluid demonstrated the presence of Streptococcus viridans. The blood culture revealed the same germ. Transthoracic and transoesophageal echocardiography confirmed infectious endocarditis with vegetation in the mitral valve. He received penicillin G and gentamicin relayed by pristinamycin because of an allergy to penicillin G with a total duration of treatment of 40 days. His symptoms and the laboratory and radiological tests abnormalities resolved totally with no recurrence. 2014 BMJ Publishing Group Ltd.

  2. Revealing the Anatomy of Vote Trading

    CERN Document Server

    Guerrero, Omar A

    2016-01-01

    Cooperation in the form of vote trading, also known as logrolling, is central for law-making processes, shaping the development of democratic societies. Empirical evidence of logrolling is scarce and limited to highly specific situations because existing methods are not easily applicable to broader contexts. We have developed a general and scalable methodology for revealing a network of vote traders, allowing us to measure logrolling on a large scale. Analysis on more than 9 million votes spanning 40 years in the U.S. Congress reveals a higher logrolling prevalence in the Senate and an overall decreasing trend over recent congresses, coincidental with high levels of political polarization. Our method is applicable in multiple contexts, shedding light on many aspects of logrolling and opening new doors in the study of hidden cooperation.

  3. Revealed Comparative Advantage in the Internal Market

    OpenAIRE

    Widgrén, Mika

    2005-01-01

    This paper investigates comparative advantage and its development across selected Asian, American and European countries between 1996 and 2002. In doing so, we calculate the Balassa index of revealed comparative advantage using industry data at the HS 4-digit level. The major part of the analysis concentrates on the factor intensities of the sample countries’ comparative advantage and the overlap between them in the Internal Market. The paper shows that there is clearly some convergence in te...

  4. Comparative genomics reveals novel biochemical pathways.

    Science.gov (United States)

    Piskur, Jure; Schnackerz, Klaus D; Andersen, Gorm; Björnberg, Olof

    2007-08-01

    How well do we understand which enzymes are involved in the primary metabolism of the cell? A recent study using comparative genomics and postgenomics approaches revealed a novel pathway in the most studied organism, Escherichia coli. The analysis of a new operon consisting of seven previously uncharacterized genes thought to be involved in the degradation of nucleic acid precursors shows the impact of comparative genomics on the discovery of novel pathways and enzymes.

  5. Hyposplenism revealed by Plasmodium malariae infection

    OpenAIRE

    Hommel, Benjamin; Galloula, Alexandre; Simon, Anne; Buffet, Pierre

    2013-01-01

    International audience; BACKGROUND: Hyposplenism, due to splenectomy, inherited red blood cell disorders or acquired conditions such as celiac disease, has an important impact on the severity of malaria, especially in non-immune patients. Conversely, that malaria may reveal functional hyposplenism has not been described previously. METHODS: A 31-year old gardener was diagnosed with an uncomplicated attack of Plasmodium malariae 11 years after leaving the endemic area. In addition to trophozoi...

  6. Mediastinal Mature Teratoma Revealed by Empyema

    Directory of Open Access Journals (Sweden)

    Mohammed Raoufi

    2016-01-01

    Full Text Available Teratomas are germ cell tumors, manifested with a great variety of clinical features; the most common extragonadal site is the anterior mediastinum. In this case, we report the patient with a large mature mediastinal teratoma with several components of ectodermal and endothermal epithelium. A 24-year-old female patient presented with history of persistent chest pain and progressively aggravating dyspnea for the previous 3 months. A chest X-ray showed a large opacity of the entire left hemithorax. Transcutaneous needle aspiration revealed a purulent fluid. The tube thoracostomy was introduced and the effusion was evacuated. Some weeks later, patient was seen in emergency for persistent cough and lateral chest pain. CT scan revealed a mass of the left hemithorax. The mass showed heterogeneous density, without compressing mediastinum great vessels and left hilar structures. Lipase value was elevated in needle aspiration. The patient underwent a total resection of the mediastinum mass via a left posterolateral thoracotomy. Microscopy revealed a mature teratoma with cystic structures. The patient subsequently made a full recovery. This case provide benign mediastinal teratoma with total atelectasis of left lung and elevated lipase value in needle transcutaneous aspiration; this event is explained by pancreatic component in the cystic tumor. Total removal of the tumor is adequate treatment for this type of teratoma and the prognosis is excellent.

  7. Hyposplenism revealed by Plasmodium malariae infection.

    Science.gov (United States)

    Hommel, Benjamin; Galloula, Alexandre; Simon, Anne; Buffet, Pierre

    2013-08-02

    Hyposplenism, due to splenectomy, inherited red blood cell disorders or acquired conditions such as celiac disease, has an important impact on the severity of malaria, especially in non-immune patients. Conversely, that malaria may reveal functional hyposplenism has not been described previously. A 31-year old gardener was diagnosed with an uncomplicated attack of Plasmodium malariae 11 years after leaving the endemic area. In addition to trophozoites and schizonts, thick and thin smears also showed Howell-Jolly bodies, pointing to functional hyposplenism. This was later confirmed by the presence of a calcified spleen in the context of S/β + sickle-cell syndrome in a patient previously unaware of this condition. Malaria may reveal hyposplenism. Although Howell-Jolly bodies are morphologically similar to nuclei of young Plasmodium trophozoite, distinction on smears is based on the absence of cytoplasm and irregular size of Howell-Jolly bodies. In the patient reported here, hyposplenism was revealed by the occurrence of P. malariae infection relatively late in life. Timely diagnosis of hyposplenism resulted in the implementation of appropriate measures to prevent overwhelming infection with capsulated bacteria. This observation highlights the importance of diagnosing hyposplenism in patients with malaria despite the morphological similarities between ring nuclei and Howell-Jolly bodies on thick smears.

  8. [Dermohypodermitis on the face revealing TIBOLA].

    Science.gov (United States)

    Gaston, J; Durox, H; Sparsa, A; Bonnetblanc, J-M; Doffoel-Hantz, V

    2011-05-01

    Tick-borne lymphadenopathy (TIBOLA) is an emerging rickettsiosis in Europe, transmitted by the Dermacentor tick. This syndrome is defined as the association of an inoculation eschar on the scalp that may be surrounded by an erythema scalp, fever, and painful cervical lymphadenopathy in colder months. Children and women are at higher risk for TIBOLA. We report the case of a 9 year-old French child with an acute hemifacial edema and erythema revealing TIBOLA. Early empirical antibiotic therapy should be prescribed in any suspected TIBOLA, before confirmation of the diagnosis. The recommended treatment is doxycycline or macrolide. Copyright © 2011. Published by Elsevier SAS.

  9. Changes in Pluto's Atmosphere Revealed by Occultations

    Science.gov (United States)

    Sicardy, Bruno; Widemann, Thomas; Lellouch, Emmanuel; Veillet, Christian; Colas, Francois; Roques, Francoise; Beisker, Wolfgang; Kretlow, Mike; Cuillandre, Jean-Charles; Hainaut, Olivier

    After the discovery and study of Pluto's tenuous atmosphere in 1985 and 1988 with stellar occultations 14 years were necessary before two other occultations by the planet could be observed on 20 July 2002 and 21 August 2002 from Northern Chile with a portable telescope and from CFHT in Hawaii respectively. These occultations reveal drastric changes in Pluto's nitrogen atmosphere whose pressure increased by a factor two or more since 1988. In spite of an increasing distance to the Sun (and a correlated decrease of solar energy input at Pluto) this increase can be explained by the fact that Pluto's south pole went from permanent darkness to permanent illumination between 1988 and 2002. This might cause the sublimation of the south polar cap and the increase of pressure which could go on till 2015 according to current nitrogen cycle models. Furthermore we detect temperature contrasts between the polar and the equatorial regions probed on Pluto possibly caused by different diurnally averaged insolations at those locations. Finally spikes observed in the light curves reveal a dynamical activity in Pluto's atmosphere.

  10. [Severe pulmonary embolism revealed by status epilepticus].

    Science.gov (United States)

    Allou, N; Coolen-Allou, N; Delmas, B; Cordier, C; Allyn, J

    2016-12-01

    High-risk pulmonary embolism (PE) is associated with high mortality rate (>50%). In some cases, diagnosis of PE remains a challenge with atypical presentations like in this case report with a PE revealed by status epilepticus. We report the case of a 40-year-old man without prior disease, hospitalized in ICU for status epilepticus. All paraclinical examinations at admission did not show any significant abnormalities (laboratory tests, cardiologic and neurological investigations). On day 1, he presented a sudden circulatory collapse and echocardiography showed right intra-auricular thrombus. He was treated by thrombolysis and arteriovenous extracorporeal membrane oxygenation. After stabilization, computed tomography showed severe bilateral PE. He developed multi-organ failure and died 4days after admission. Pulmonary embolism revealed by status epilepticus has rarely been reported and is associated with poor prognosis. Physicians should be aware and think of the possibility of PE in patients with status epilepticus without any history or risk factors of seizure and normal neurological investigations. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Tuning afferent synapses of hippocampal interneurons by neuropeptide Y

    DEFF Research Database (Denmark)

    Ledri, Marco; Sørensen, Andreas Toft; Erdelyi, Ferenc

    2011-01-01

    extrahippocampal afferents. Various excitatory and inhibitory afferent and efferent synapses of the hippocampal CCK basket cells express serotoninergic, cholinergic, cannabinoid, and benzodiazepine sensitive receptors, all contributing to their functional plasticity. We explored whether CCK basket cells...

  12. Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons.

    Directory of Open Access Journals (Sweden)

    Loïs S Miraucourt

    Full Text Available Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCgamma. Selective inhibition of PKCgamma as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCgamma-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCgamma might provide a new tool for alleviating allodynia in the clinical setting.

  13. High Stimulus-Related Information in Barrel Cortex Inhibitory Interneurons.

    Directory of Open Access Journals (Sweden)

    Vicente Reyes-Puerta

    2015-06-01

    Full Text Available The manner in which populations of inhibitory (INH and excitatory (EXC neocortical neurons collectively encode stimulus-related information is a fundamental, yet still unresolved question. Here we address this question by simultaneously recording with large-scale multi-electrode arrays (of up to 128 channels the activity of cell ensembles (of up to 74 neurons distributed along all layers of 3-4 neighboring cortical columns in the anesthetized adult rat somatosensory barrel cortex in vivo. Using two different whisker stimulus modalities (location and frequency we show that individual INH neurons--classified as such according to their distinct extracellular spike waveforms--discriminate better between restricted sets of stimuli (≤6 stimulus classes than EXC neurons in granular and infra-granular layers. We also demonstrate that ensembles of INH cells jointly provide as much information about such stimuli as comparable ensembles containing the ~20% most informative EXC neurons, however presenting less information redundancy - a result which was consistent when applying both theoretical information measurements and linear discriminant analysis classifiers. These results suggest that a consortium of INH neurons dominates the information conveyed to the neocortical network, thereby efficiently processing incoming sensory activity. This conclusion extends our view on the role of the inhibitory system to orchestrate cortical activity.

  14. Select interneuron clusters determine female sexual receptivity in Drosophila.

    Science.gov (United States)

    Sakurai, Akira; Koganezawa, Masayuki; Yasunaga, Kei-ichiro; Emoto, Kazuo; Yamamoto, Daisuke

    2013-01-01

    Female Drosophila with the spinster mutation repel courting males and rarely mate. Here we show that the non-copulating phenotype can be recapitulated by the elimination of spinster functions from either spin-A or spin-D neuronal clusters, in the otherwise wild-type (spinster heterozygous) female brain. Spin-D corresponds to the olfactory projection neurons with dendrites in the antennal lobe VA1v glomerulus that is fruitless-positive, sexually dimorphic and responsive to fly odour. Spin-A is a novel local neuron cluster in the suboesophageal ganglion, which is known to process contact chemical pheromone information and copulation-related signals. A slight reduction in spinster expression to a level with a minimal effect is sufficient to shut off female sexual receptivity if the dominant-negative mechanistic target of rapamycin is simultaneously expressed, although the latter manipulation alone has only a marginal effect. We propose that spin-mediated mechanistic target of rapamycin signal transduction in these neurons is essential for females to accept the courting male.

  15. Select interneuron clusters determine female sexual receptivity in Drosophila

    OpenAIRE

    Sakurai, Akira; Koganezawa, Masayuki; Yasunaga, Kei-ichiro; Emoto, Kazuo; Yamamoto, Daisuke

    2013-01-01

    Female Drosophila with the spinster mutation repel courting males and rarely mate. Here we show that the non-copulating phenotype can be recapitulated by the elimination of spinster functions from either spin-A or spin-D neuronal clusters, in the otherwise wild-type (spinster heterozygous) female brain. Spin-D corresponds to the olfactory projection neurons with dendrites in the antennal lobe VA1v glomerulus that is fruitless-positive, sexually dimorphic and responsive to fly odour. Spin-A is...

  16. Wegener Granulomatosis Revealed by Pleural Effusion

    Science.gov (United States)

    Toffart, Anne-Claire; Arbib, François; Lantuejoul, Sylvie; Roux, Jean-François; Bland, Vincent; Ferretti, Gilbert; Diab, Samia

    2009-01-01

    Pulmonary signs are common in Wegener's granulomatosis (WG). However, an initial presentation including pleural effusion has not been described. We describe a case of WG in which pleural effusion was the first clinical manifestation. A 45-year-old man with dorsal pain presented with pleural thickening and effusion, and a visible nodule on a thoracic scan. A dense chronic inflammatory infiltrate was obtained by pleural biopsy and an open lung biopsy revealed necrotizing granulomatous vasculitis. Serologies were positive for antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies. A diagnosis of WG was conducted and the patient was started on cyclophosphamide and methylprednisolone as an initial treatment, with a favorable evolution. Although pleural effusion is rarely described in WG, this pathology must be considered in the presence of this clinical manifestation. PMID:20168982

  17. Wegener Granulomatosis Revealed by Pleural Effusion

    Directory of Open Access Journals (Sweden)

    Anne-Claire Toffart

    2009-01-01

    Full Text Available Pulmonary signs are common in Wegener's granulomatosis (WG. However, an initial presentation including pleural effusion has not been described. We describe a case of WG in which pleural effusion was the first clinical manifestation. A 45-year-old man with dorsal pain presented with pleural thickening and effusion, and a visible nodule on a thoracic scan. A dense chronic inflammatory infiltrate was obtained by pleural biopsy and an open lung biopsy revealed necrotizing granulomatous vasculitis. Serologies were positive for antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies. A diagnosis of WG was conducted and the patient was started on cyclophosphamide and methylprednisolone as an initial treatment, with a favorable evolution. Although pleural effusion is rarely described in WG, this pathology must be considered in the presence of this clinical manifestation.

  18. Revealing effective classifiers through network comparison

    Science.gov (United States)

    Gallos, Lazaros K.; Fefferman, Nina H.

    2014-11-01

    The ability to compare complex systems can provide new insight into the fundamental nature of the processes captured, in ways that are otherwise inaccessible to observation. Here, we introduce the n-tangle method to directly compare two networks for structural similarity, based on the distribution of edge density in network subgraphs. We demonstrate that this method can efficiently introduce comparative analysis into network science and opens the road for many new applications. For example, we show how the construction of a “phylogenetic tree” across animal taxa according to their social structure can reveal commonalities in the behavioral ecology of the populations, or how students create similar networks according to the University size. Our method can be expanded to study many additional properties, such as network classification, changes during time evolution, convergence of growth models, and detection of structural changes during damage.

  19. Social patterns revealed through random matrix theory

    Science.gov (United States)

    Sarkar, Camellia; Jalan, Sarika

    2014-11-01

    Despite the tremendous advancements in the field of network theory, very few studies have taken weights in the interactions into consideration that emerge naturally in all real-world systems. Using random matrix analysis of a weighted social network, we demonstrate the profound impact of weights in interactions on emerging structural properties. The analysis reveals that randomness existing in particular time frame affects the decisions of individuals rendering them more freedom of choice in situations of financial security. While the structural organization of networks remains the same throughout all datasets, random matrix theory provides insight into the interaction pattern of individuals of the society in situations of crisis. It has also been contemplated that individual accountability in terms of weighted interactions remains as a key to success unless segregation of tasks comes into play.

  20. Neutron Imaging Reveals Internal Plant Hydraulic Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Jeffrey [ORNL; Bilheux, Hassina Z [ORNL; Kang, Misun [ORNL; Voisin, Sophie [ORNL; Cheng, Chu-Lin [ORNL; Horita, Jusuke [ORNL; Perfect, Edmund [ORNL

    2013-01-01

    Many terrestrial ecosystem processes are constrained by water availability and transport within the soil. Knowledge of plant water fluxes is thus critical for assessing mechanistic processes linked to biogeochemical cycles, yet resolution of root structure and xylem water transport dynamics has been a particularly daunting task for the ecologist. Through neutron imaging, we demonstrate the ability to non-invasively monitor individual root functionality and water fluxes within Zea mays L. (maize) and Panicum virgatum L. (switchgrass) seedlings growing in a sandy medium. Root structure and growth were readily imaged by neutron radiography and neutron computed tomography. Seedlings were irrigated with water or deuterium oxide and imaged through time as a growth lamp was cycled on to alter leaf demand for water. Sub-millimeter scale resolution reveals timing and magnitudes of root water uptake, redistribution within the roots, and root-shoot hydraulic linkages, relationships not well characterized by other techniques.

  1. Revealing effective classifiers through network comparison

    CERN Document Server

    Gallos, Lazaros K

    2014-01-01

    The ability to compare complex systems can provide new insight into the fundamental nature of the processes captured in ways that are otherwise inaccessible to observation. Here, we introduce the $n$-tangle method to directly compare two networks for structural similarity, based on the distribution of edge density in network subgraphs. We demonstrate that this method can efficiently introduce comparative analysis into network science and opens the road for many new applications. For example, we show how the construction of a phylogenetic tree across animal taxa according to their social structure can reveal commonalities in the behavioral ecology of the populations, or how students create similar networks according to the University size. Our method can be expanded to study a multitude of additional properties, such as network classification, changes during time evolution, convergence of growth models, and detection of structural changes during damage.

  2. Hidden acoustic information revealed by intentional nonlinearity

    Science.gov (United States)

    Dowling, David R.

    2017-11-01

    Acoustic waves are omnipresent in modern life and are well described by the linearized equations of fluid dynamics. Once generated, acoustic waves carry and collect information about their source and the environment through which they propagate, respectively, and this information may be retrieved by analyzing recordings of these waves. Because of this, acoustics is the primary means for observation, surveillance, reconnaissance, and remote sensing in otherwise opaque environments, such as the Earth's oceans and crust, and the interior of the human body. For such information-retrieval tasks, acoustic fields are nearly always interrogated within their recorded frequency range or bandwidth. However, this frequency-range restriction is not general; acoustic fields may also carry (hidden) information at frequencies outside their bandwidth. Although such a claim may seem counter intuitive, hidden acoustic-field information can be revealed by re-introducing a marquee trait of fluid dynamics: nonlinearity. In particular, an intentional quadratic nonlinearity - a form of intra-signal heterodyning - can be used to obtain acoustic field information at frequencies outside a recorded acoustic field's bandwidth. This quadratic nonlinearity enables a variety of acoustic remote sensing applications that were long thought to be impossible. In particular, it allows the detrimental effects of sparse recordings and random scattering to be suppressed when the original acoustic field has sufficient bandwidth. In this presentation, the topic is developed heuristically, with a just brief exposition of the relevant mathematics. Hidden acoustic field information is then revealed from simulated and measured acoustic fields in simple and complicated acoustic environments involving frequencies from a few Hertz to more than 100 kHz, and propagation distances from tens of centimeters to hundreds of kilometers. Sponsored by ONR, NAVSEA, and NSF.

  3. Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus.

    Science.gov (United States)

    Patton, Andrew P; Chesham, Johanna E; Hastings, Michael H

    2016-09-07

    The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional-translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuronal, circuit-level coupling. The aim of this study was to combine pharmacological and genetic manipulations to push the SCN clockwork toward its limits and, by doing so, probe cell-autonomous and emergent, circuit-level properties. Circadian oscillation of mouse SCN organotypic slice cultures was monitored as PER2::LUC bioluminescence. SCN of three genetic backgrounds-wild-type, short-period CK1ε(Tau/Tau) mutant, and long-period Fbxl3(Afh/Afh) mutant-all responded reversibly to pharmacological manipulation with period-altering compounds: picrotoxin, PF-670462 (4-[1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinamine dihydrochloride), and KNK437 (N-Formyl-3,4-methylenedioxy-benzylidine-gamma-butyrolactam). This revealed a remarkably wide operating range of sustained periods extending across 25 h, from ≤17 h to >42 h. Moreover, this range was maintained at network and single-cell levels. Development of a new technique for formal analysis of circadian waveform, first derivative analysis (FDA), revealed internal phase patterning to the circadian oscillation at these extreme periods and differential phase sensitivity of the SCN to genetic and pharmacological manipulations. For example, FDA of the CK1ε(Tau/Tau) mutant SCN treated with the CK1ε-specific inhibitor PF-4800567 (3-[(3-Chlorophenoxy)methyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride) revealed that period acceleration in the mutant is due to inappropriately phased

  4. [Neuropsychiatric symptoms revealing pseudohypoparathyroidism with Fahr's syndrome].

    Science.gov (United States)

    Otheman, Y; Khalloufi, H; Benhima, I; Ouanass, A

    2011-02-01

    Fahr's syndrome is characterized by the presence of intracerebral, bilateral and symmetrical non-arteriosclerotic calcifications, located in the central grey nuclei. One of its main etiologies is pseudohypoparathyroidism (PHP), due to a resistance to the action of parathormone (PTH) with essentially hypocalcaemia and a normal or a high rate of PTH. Mr B.A. is a 36-year-old man, admitted to hospital because of refractory psychotic symptoms associated with alcohol abuse and fits of convulsion, for diagnostic and therapeutic update. Mr B.A. had presented convulsions since the age of 10, without regular medical treatment. He showed a decrease in his school performances and started using alcohol. Since the age of 17, he began expressing delusions of persecution and of enchantment fed by the persistence of the convulsions. He was administered phenobarbital, and classic antipsychotics (haloperidol and levomepromazine) and developed serious extrapyramidal side effects, treated with an anticholinergic (trihexyphenidyl). Evolution was rather disadvantageous: more epileptic fits, exaggeration of tremors; abuse of alcohol and persistence of psychotic symptoms. On admission, psychiatric examination objectified paranoid delusions of being possessed and persecuted by others. Neurological examination revealed the presence of limb tremors, with a positive Froment's sign on the right, and dysarthria. Other than this, the patient was shorter in comparison with his siblings and exhibited bad dentition. A CT brain scan found bilateral, symmetric basal ganglia calcifications, confirmed by MRI, in favour of Fahr's syndrome. Phosphocalcic investigations revealed a low concentration of serum calcium (65 mg/l) and a hyperphosphataemia (60.1mg/l). The blood level of parathyroid hormone was in the upper limit of normal (66 ng/l), and levels of thyroid hormones and thyroid-stimulating hormone were normal. The diagnosis of Fahr's syndrome, revealing a pseudohypoparathyroidism was posed, and the

  5. Speeding Clouds May Reveal Invisible Black Holes

    Science.gov (United States)

    Kohler, Susanna

    2017-07-01

    Several small, speeding clouds have been discovered at the center of our galaxy. A new study suggests that these unusual objects may reveal the lurking presence of inactive black holes.Peculiar Cloudsa) Velocity-integrated intensity map showing the location of the two high-velocity compact clouds, HCN0.0090.044 and HCN0.0850.094, in the context of larger molecular clouds. b) and c) Latitude-velocity and longitude-velocity maps for HCN0.0090.044 and HCN0.0850.094, respectively. d) and e) spectra for the two compacts clouds, respectively. Click for a closer look. [Takekawa et al. 2017]Sgr A*, the supermassive black hole marking the center of our galaxy, is surrounded by a region roughly 650 light-years across known as the Central Molecular Zone. This area at the heart of our galaxy is filled with large amounts of warm, dense molecular gas that has a complex distribution and turbulent kinematics.Several peculiar gas clouds have been discovered within the Central Molecular Zone within the past two decades. These clouds, dubbed high-velocity compact clouds, are characterized by their compact sizes and extremely broad velocity widths.What created this mysterious population of energetic clouds? The recent discovery of two new high-velocity compact clouds, reported on in a paper led by Shunya Takekawa (Keio University, Japan), may help us to answer this question.Two More to the CountUsing the James Clerk Maxwell Telescope in Hawaii, Takekawa and collaborators detected the small clouds near the circumnuclear disk at the centermost part of our galaxy. These two clouds have velocity spreads of -80 to -20 km/s and -80 to 0 km/s and compact sizes of just over 1 light-year. The clouds similar appearances and physical properties suggest that they may both have been formed by the same process.Takekawa and collaborators explore and discard several possible origins for these clouds, such as outflows from massive protostars (no massive, luminous stars have been detected affiliated

  6. Anticipatory looks reveal expectations about discourse relations.

    Science.gov (United States)

    Rohde, Hannah; Horton, William S

    2014-12-01

    Previous research provides evidence for expectation-driven processing within sentences at phonological, lexical, and syntactic levels of linguistic structure. Less well-established is whether comprehenders also anticipate pragmatic relationships between sentences. To address this, we evaluate a unit of discourse structure that comprehenders must infer to hold between sentences in order for a discourse to make sense-the intersentential coherence relation. In a novel eyetracking paradigm, we trained participants to associate particular spatial locations with particular coherence relations. Experiment 1 shows that the subset of listeners who successfully acquired the location∼relation mappings during training subsequently looked to these locations during testing in response to a coherence-signaling intersentential connective. Experiment 2 finds that listeners' looks during sentences containing coherence-biasing verbs reveal expectations about upcoming sentence types. This work extends existing research on prediction beyond sentence-internal structure and provides a new methodology for examining the cues that comprehenders use to establish relationships at the discourse level. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. VISTA Reveals the Secret of the Unicorn

    Science.gov (United States)

    2010-10-01

    A new infrared image from ESO's VISTA survey telescope reveals an extraordinary landscape of glowing tendrils of gas, dark clouds and young stars within the constellation of Monoceros (the Unicorn). This star-forming region, known as Monoceros R2, is embedded within a huge dark cloud. The region is almost completely obscured by interstellar dust when viewed in visible light, but is spectacular in the infrared. An active stellar nursery lies hidden inside a massive dark cloud rich in molecules and dust in the constellation of Monoceros. Although it appears close in the sky to the more familiar Orion Nebula it is actually almost twice as far from Earth, at a distance of about 2700 light-years. In visible light a grouping of massive hot stars creates a beautiful collection of reflection nebulae where the bluish starlight is scattered from parts of the dark, foggy outer layers of the molecular cloud. However, most of the new-born massive stars remain hidden as the thick interstellar dust strongly absorbs their ultraviolet and visible light. In this gorgeous infrared image taken from ESO's Paranal Observatory in northern Chile, the Visible and Infrared Survey Telescope for Astronomy (VISTA [1], eso0949) penetrates the dark curtain of cosmic dust and reveals in astonishing detail the folds, loops and filaments sculpted from the dusty interstellar matter by intense particle winds and the radiation emitted by hot young stars. "When I first saw this image I just said 'Wow!' I was amazed to see all the dust streamers so clearly around the Monoceros R2 cluster, as well as the jets from highly embedded young stellar objects. There is such a great wealth of exciting detail revealed in these VISTA images," says Jim Emerson, of Queen Mary, University of London and leader of the VISTA consortium. With its huge field of view, large mirror and sensitive camera, VISTA is ideal for obtaining deep, high quality infrared images of large areas of the sky, such as the Monoceros R2 region

  8. [Polymyalgia rheumatica revealing a lung cancer].

    Science.gov (United States)

    Cocquempot, K; Defuentes, G; Duron-Martineau, S; Berets, O; Vaylet, F; Margery, J

    2013-01-01

    Polymyalgia rheumatica is an inflammatory condition belonging to the connective tissue diseases, which occurs quite frequently in the elderly. Previously, cases have been reported in association with malignant tumours, in a synchronous fashion or prior to the appearance of the cancer. In these cases, the polymyalgia rheumatica is considered to be a paraneoplastic syndrome. We report the cases of a 63-year-old woman and a 58-year-old man with severe proximal girdle pain associated to a high-level of systemic inflammatory markers and a diagnosis of polymyalgia rheumatica was made. In the face of a lack of ineffectiveness of analgesic and anti-inflammatory treatments, an intensive investigation was undertaken which in both cases revealed an adenocarcinoma of the lung. The rheumatic manifestations responded well to chemotherapy targeting the lung tumour. We present here a review of the literature to give prominence to the diagnostic pitfalls that can occur around paraneoplastic polymyalgia rheumatica. The presence of therapeutic resistance at the onset of treatment and other atypical features may suggest the presence of an occult malignancy. Copyright © 2012 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  9. Photoacoustic imaging reveals hidden underdrawings in paintings.

    Science.gov (United States)

    Tserevelakis, George J; Vrouvaki, Ilianna; Siozos, Panagiotis; Melessanaki, Krystallia; Hatzigiannakis, Kostas; Fotakis, Costas; Zacharakis, Giannis

    2017-04-07

    A novel, non-invasive, imaging methodology, based on the photoacoustic effect, is introduced in the context of artwork diagnostics with emphasis on the uncovering of hidden features such as underdrawings or original sketch lines in paintings. Photoacoustic microscopy, a rapidly growing imaging method widely employed in biomedical research, exploits the ultrasonic acoustic waves, generated by light from a pulsed or intensity modulated source interacting with a medium, to map the spatial distribution of absorbing components. Having over three orders of magnitude higher transmission through strongly scattering media, compared to light in the visible and near infrared, the photoacoustic signal offers substantially improved detection sensitivity and achieves excellent optical absorption contrast at high spatial resolution. Photoacoustic images, collected from miniature oil paintings on canvas, illuminated with a nanosecond pulsed Nd:YAG laser at 1064 nm on their reverse side, reveal clearly the presence of pencil sketch lines coated over by several paint layers, exceeding 0.5 mm in thickness. By adjusting the detection bandwidth of the optically induced ultrasonic waves, photoacoustic imaging can be used for looking into a broad variety of artefacts having diverse optical properties and geometrical profiles, such as manuscripts, glass objects, plastic modern art or even stone sculpture.

  10. Featured Image: Revealing Hidden Objects with Color

    Science.gov (United States)

    Kohler, Susanna

    2018-02-01

    Stunning color astronomical images can often be the motivation for astronomers to continue slogging through countless data files, calculations, and simulations as we seek to understand the mysteries of the universe. But sometimes the stunning images can, themselves, be the source of scientific discovery. This is the case with the below image of Lynds Dark Nebula 673, located in the Aquila constellation, that was captured with the Mayall 4-meter telescope at Kitt Peak National Observatory by a team of scientists led by Travis Rector (University of Alaska Anchorage). After creating the image with a novel color-composite imaging method that reveals faint H emission (visible in red in both images here), Rector and collaborators identified the presence of a dozen new Herbig-Haro objects small cloud patches that are caused when material is energetically flung out from newly born stars. The image adapted above shows three of the new objects, HH 118789, aligned with two previously known objects, HH 32 and 332 suggesting they are driven by the same source. For more beautiful images and insight into the authors discoveries, check out the article linked below!Full view of Lynds Dark Nebula 673. Click for the larger view this beautiful composite image deserves! [T.A. Rector (University of Alaska Anchorage) and H. Schweiker (WIYN and NOAO/AURA/NSF)]CitationT. A. Rector et al 2018 ApJ 852 13. doi:10.3847/1538-4357/aa9ce1

  11. Facial appearance reveals immunity in African men.

    Science.gov (United States)

    Phalane, Khutso G; Tribe, Catherine; Steel, Helen C; Cholo, Moloko C; Coetzee, Vinet

    2017-08-07

    Facial appearance is thought to indicate immunity in humans, but very few studies have tested this relationship directly. The aim of this study was to test the relationship between direct measures of immunity, perceived facial health and attractiveness, and facial cues in African men. We show that men with a stronger cytokine response are considered significantly more attractive and healthy. Men with more masculine, heavier facial features (i.e. muscular appearance) have a significantly higher cytokine response and appear significantly healthier and more attractive, while men with a yellower, lighter, "carotenoid" skin colour, have a marginally higher immune response and are also considered significantly more healthy and attractive. In contrast, more symmetrical, skinnier looking men appeared more attractive and healthier, but did not have a stronger cytokine response. These findings also shed new light on the "androgen-mediated" traits proposed by the immunocompetence handicap hypothesis (ICHH) and we propose that facial muscularity serves as a better estimate of an "androgen-mediated" trait than facial masculinity. Finally, we build on previous evidence to show that men's facial features do indeed reveal aspects of immunity, even better than more traditional measures of health, such as body mass index (BMI).

  12. Revealing the interface in polymer nanocomposites.

    Science.gov (United States)

    Zammarano, Mauro; Maupin, Paul H; Sung, Li-Piin; Gilman, Jeffrey W; McCarthy, Edward D; Kim, Yeon S; Fox, Douglas M

    2011-04-26

    The morphological characterization of polymer nanocomposites over multiple length scales is a fundamental challenge. Here, we report a technique for high-throughput monitoring of interface and dispersion in polymer nanocomposites based on Förster resonance energy transfer (FRET). Nanofibrillated cellulose (NFC), fluorescently labeled with 5-(4,6-dichlorotriazinyl)-aminofluorescein (FL) and dispersed into polyethylene (PE) doped with Coumarin 30 (C30), is used as a model system to assess the ability of FRET to evaluate the effect of processing on NFC dispersion in PE. The level of energy transfer and its standard deviation, measured by fluorescence spectroscopy and laser scanning confocal microscopy (LSCM), are exploited to monitor the extent of interface formation and composite homogeneity, respectively. FRET algorithms are used to generate color-coded images for a real-space observation of energy transfer efficiency. These images reveal interface formation at a nanoscale while probing a macroscale area that is large enough to be representative of the entire sample. The unique ability of this technique to simultaneously provide orientation/spatial information at a macroscale and nanoscale features, encoded in the FRET signal, provides a new powerful tool for structure-property-processing investigation in polymer nanocomposites.

  13. Myasthenia Revealed Following Laparotomy - A Case Report

    Directory of Open Access Journals (Sweden)

    Abdelilah GHANNAM

    2015-06-01

    Full Text Available Myasthenia (muscle weakness is a rare neuromuscular disease of which respiratory failure is the main complication. The accidental discovery of such disease in the perioperative period is rare and potentially serious.We report a case of a woman who underwent emergency operation for appendiceal peritonitis, and failed repeatedly at weaning from postoperative mechanical ventilation. The usual etiologies such as postoperative respiratory complications, ventilator-associated pneumonia, acute respiratory distress syndrome complicating the septic shock or having no impact on it, and neuromyopathy’s resuscitation were considered, researched, examined or eliminated.Faced with the diagnostic impasse and the obvious weaning failure, another interview revealed signs of muscle fatigue which led to the diagnosis of myasthenia gravis decompensated perioperatively. Once the diagnosis was confirmed by means of a neostigmine test, the specific treatment began, particularly through plasma exchange sessions, and the process of weaning resumed. The result was complete weaning. A three-month follow-up showed a stable patient with no significant muscular disability.

  14. ERYTHEMA NODOSUM REVEALING ACUTE MYELOID LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Chebbi Wafa

    2013-07-01

    Full Text Available Introduction: Erythema nodosum (EN is the most common type of panniculitis. It may be idiopathic or secondary to various etiologies. However, the occurrence of erythema nodosum in malignant hemopathy had rarely been reported. Case report: A 42 year-old woman presented with a four week history of recurrent multiple painful erythematous nodules developed on the lower limbs associated with arthralgia of the ankles and fever. The clinical features of skin lesions with contusiform color evolution allowed establishing the diagnosis of EN. No underlying cause was found. The skin lesions were improved with non-steroidal anti-inflammatory drugs and colchicine. Three months later, the patient consulted for recurrence of EN associated with fever, inflammatory polyarthralgia and hepatosplenomegaly. The peripheral blood count revealed pancytopenia. A bone marrow examination confirmed the diagnosis of acute myeloid leukemia type 2. Initiation of chemotherapy was followed by the complete disappearance of skin lesions of EN. Conclusion: Paraneoplastic erythema nodosum is a rare entity. In the literature, a few cases of association with leukemia have been reported. Exploration for solid neoplasms or hemopathy in case of recurrent EN or resistance to conventional treatment should be systematic

  15. Biosignatures as revealed by spectropolarimetry of Earthshine.

    Science.gov (United States)

    Sterzik, Michael F; Bagnulo, Stefano; Palle, Enric

    2012-02-29

    Low-resolution intensity spectra of Earth's atmosphere obtained from space reveal strong signatures of life ('biosignatures'), such as molecular oxygen and methane with abundances far from chemical equilibrium, as well as the presence of a 'red edge' (a sharp increase of albedo for wavelengths longer than 700 nm) caused by surface vegetation. Light passing through the atmosphere is strongly linearly polarized by scattering (from air molecules, aerosols and cloud particles) and by reflection (from oceans and land). Spectropolarimetric observations of local patches of Earth's sky light from the ground contain signatures of oxygen, ozone and water, and are used to characterize the properties of clouds and aerosols. When applied to exoplanets, ground-based spectropolarimetry can better constrain properties of atmospheres and surfaces than can standard intensity spectroscopy. Here we report disk-integrated linear polarization spectra of Earthshine, which is sunlight that has been first reflected by Earth and then reflected back to Earth by the Moon. The observations allow us to determine the fractional contribution of clouds and ocean surface, and are sensitive to visible areas of vegetation as small as 10 per cent. They represent a benchmark for the diagnostics of the atmospheric composition, mean cloud height and surfaces of exoplanets.

  16. NASA's Hyperwall Revealing the Big Picture

    Science.gov (United States)

    Sellers, Piers

    2011-01-01

    NASA:s hyperwall is a sophisticated visualization tool used to display large datasets. The hyperwall, or video wall, is capable of displaying multiple high-definition data visualizations and/or images simultaneously across an arrangement of screens. Functioning as a key component at many NASA exhibits, the hyperwall is used to help explain phenomena, ideas, or examples of world change. The traveling version of the hyperwall is typically comprised of nine 42-50" flat-screen monitors arranged in a 3x3 array (as depicted below). However, it is not limited to monitor size or number; screen sizes can be as large as 52" and the arrangement of screens can include more than nine monitors. Generally, NASA satellite and model data are used to highlight particular themes in atmospheric, land, and ocean science. Many of the existing hyperwall stories reveal change across space and time, while others display large-scale still-images accompanied by descriptive, story-telling captions. Hyperwall content on a variety of Earth Science topics already exists and is made available to the public at: eospso.gsfc.nasa.gov/hyperwall. Keynote and PowerPoint presentations as well as Summary of Story files are available for download on each existing topic. New hyperwall content and accompanying files will continue being developed to promote scientific literacy across a diverse group of audience members. NASA invites the use of content accessible through this website but requests the user to acknowledge any and all data sources referenced in the content being used.

  17. Combined Pharmacological and Genetic Manipulations Unlock Unprecedented Temporal Elasticity and Reveal Phase-Specific Modulation of the Molecular Circadian Clock of the Mouse Suprachiasmatic Nucleus

    OpenAIRE

    Patton, Andrew P.; Chesham, Johanna E.; Hastings, Michael H.

    2016-01-01

    The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional–translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuron...

  18. Microradiometers Reveal Ocean Health, Climate Change

    Science.gov (United States)

    2013-01-01

    When NASA researcher Stanford Hooker is in the field, he pays close attention to color. For Hooker, being in the field means being at sea. On one such research trip to the frigid waters of the Arctic, with a Coast Guard icebreaker looming nearby and the snow-crusted ice shelf a few feet away, Hooker leaned over the edge of his small boat and lowered a tethered device into the bright turquoise water, a new product devised by a NASA partner and enabled by a promising technology for oceanographers and atmospheric scientists alike. Color is a function of light. Pure water is clear, but the variation in color observed during a visit to the beach or a flight along a coastline depends on the water s depth and the constituents in it, how far down the light penetrates and how it is absorbed and scattered by dissolved and suspended material. Hooker cares about ocean color because of what it can reveal about the health of the ocean, and in turn, the health of our planet. "The main thing we are interested in is the productivity of the water," Hooker says. The seawater contains phytoplankton, microscopic plants, which are the food base for the ocean s ecosystems. Changes in the water s properties, whether due to natural seasonal effects or human influence, can lead to problems for delicate ecosystems such as coral reefs. Ocean color can inform researchers about the quantities and distribution of phytoplankton and other materials, providing clues as to how the world ocean is changing. NASA s Coastal Zone Color Scanner, launched in 1978, was the first ocean color instrument flown on a spacecraft. Since then, the Agency s ocean color research capabilities have become increasingly sophisticated with the launch of the SeaWiFS instrument in 1997 and the twin MODIS instruments carried into orbit on NASA s Terra (1999) and Aqua (2002) satellites. The technology provides sweeping, global information on ocean color on a scale unattainable by any other means. One issue that arises from

  19. Passive seismology reveals biannual calving periodicity

    Science.gov (United States)

    Bartholomaus, T. C.; Larsen, C. F.; West, M. E.; Oneel, S.

    2013-12-01

    Iceberg calving is a large and variable component of the total mass loss from marine-terminating glaciers worldwide. However, the processes that control the size and variability of calving fluxes are poorly understood. Even more basic descriptions of iceberg calving, such as its seasonality, are uncertain. Here, we present nearly two years of automatically-estimated calving fluxes at Yahtse Glacier, a tidewater glacier whose terminus flows at ~7 km/yr towards the Gulf of Alaska. At the terminus, ice losses to calving and submarine melt total approximately 1.5 km^3/yr. In order to identify temporal variability in this mean rate, we develop a statistical model of calving size based on characteristics of calving-generated icequakes. These characteristics include 4 amplitude-based variables and 5 variables related to the shape of the icequake envelope. We build our model by combining automatically-detected icequakes (O'Neel et al., 2007) located at the terminus of Yahtse Glacier (Jones et al., 2013) with a training set of 1400 icequakes produced by visually-observed calving events (Bartholomaus et al., 2012). In each of the models tested (regression trees, multinomial logistic regression and multiple linear regession), icequake duration emerges as the single best predictor of iceberg size, consistent with past studies (Qamar, 1988; O'Neel et al., 2007). Additional predictors, such as the mean icequake amplitude and the kurtosis of the icequake envelope improve the predictive capability of the model and reduce the mean squared error to well-within the error of the in-person classification. Once validated, we apply our model to ~ 400,000 icequakes produced by calving events at Yahtse Glacier between June 2009 and September 2011. These results reveal fluctuations in calving rate at a range of timescales, including twice per year. We suggest that the roughly 50%, biannual variation in calving rate is the result of the trade-off between two competing processes at the

  20. A spatially resolved network spike in model neuronal cultures reveals nucleation centers, circular traveling waves and drifting spiral waves

    Science.gov (United States)

    Paraskevov, A. V.; Zendrikov, D. K.

    2017-04-01

    We show that in model neuronal cultures, where the probability of interneuronal connection formation decreases exponentially with increasing distance between the neurons, there exists a small number of spatial nucleation centers of a network spike, from where the synchronous spiking activity starts propagating in the network typically in the form of circular traveling waves. The number of nucleation centers and their spatial locations are unique and unchanged for a given realization of neuronal network but are different for different networks. In contrast, if the probability of interneuronal connection formation is independent of the distance between neurons, then the nucleation centers do not arise and the synchronization of spiking activity during a network spike occurs spatially uniform throughout the network. Therefore one can conclude that spatial proximity of connections between neurons is important for the formation of nucleation centers. It is also shown that fluctuations of the spatial density of neurons at their random homogeneous distribution typical for the experiments in vitro do not determine the locations of the nucleation centers. The simulation results are qualitatively consistent with the experimental observations.

  1. What Facial Appearance Reveals Over Time: When Perceived Expressions in Neutral Faces Reveal Stable Emotion Dispositions.

    Science.gov (United States)

    Adams, Reginald B; Garrido, Carlos O; Albohn, Daniel N; Hess, Ursula; Kleck, Robert E

    2016-01-01

    It might seem a reasonable assumption that when we are not actively using our faces to express ourselves (i.e., when we display nonexpressive, or neutral faces), those around us will not be able to read our emotions. Herein, using a variety of expression-related ratings, we examined whether age-related changes in the face can accurately reveal one's innermost affective dispositions. In each study, we found that expressive ratings of neutral facial displays predicted self-reported positive/negative dispositional affect, but only for elderly women, and only for positive affect. These findings meaningfully replicate and extend earlier work examining age-related emotion cues in the face of elderly women (Malatesta et al., 1987a). We discuss these findings in light of evidence that women are expected to, and do, smile more than men, and that the quality of their smiles predicts their life satisfaction. Although ratings of old male faces did not significantly predict self-reported affective dispositions, the trend was similar to that found for old female faces. A plausible explanation for this gender difference is that in the process of attenuating emotional expressions over their lifetimes, old men reveal less evidence of their total emotional experiences in their faces than do old women.

  2. Facial cellulitis revealing choreo-acanthocytosis: A case report ...

    African Journals Online (AJOL)

    We report a 62 year-old-man with facial cellulitis revealing choreo-acanthocytosis (ChAc). He showed chorea that started 20 years ago. The orofacial dyskinisia with tongue and cheek biting resulted in facial cellulitis. The peripheral blood smear revealed acanthocytosis of 25%. The overall of chorea, orofacial dyskinetic ...

  3. Mitochondrial DNA analysis reveals a low nucleotide diversity of ...

    African Journals Online (AJOL)

    Mitochondrial DNA analysis reveals a low nucleotide diversity of Caligula japonica in China. ... Mitochondrial DNA analysis reveals a low nucleotide diversity of Caligula japonica in China. Y Li, B Yang, H Wang, R Xia, L Wang, Z Zhang, L Qin, Y Liu ...

  4. Diffusion tractography reveals pervasive asymmetry of cerebral white matter tracts in the bottlenose dolphin (Tursiops truncatus).

    Science.gov (United States)

    Wright, Alexandra K; Theilmann, Rebecca J; Ridgway, Sam H; Scadeng, Miriam

    2017-11-30

    Brain enlargement is associated with concomitant growth of interneuronal distance, increased conduction time, and reduced neuronal interconnectivity. Recognition of these functional constraints led to the hypothesis that large-brained mammals should exhibit greater structural and functional brain lateralization. As a taxon with the largest brains in the animal kingdom, Cetacea provides a unique opportunity to examine asymmetries of brain structure and function. In the present study, diffusion tensor imaging and tractography were used to investigate cerebral white matter asymmetry in the bottlenose dolphin (Tursiops truncatus). Widespread white matter asymmetries were observed with the preponderance of tracts exhibiting leftward structural asymmetries. Leftward lateralization may reflect differential processing and execution of behaviorally variant sensory and motor functions by the cerebral hemispheres. The arcuate fasciculus, an association tract linked to human language evolution, was isolated and exhibited rightward asymmetry suggesting a right hemisphere bias for conspecific communication unlike that of most mammals. This study represents the first examination of cetacean white matter asymmetry and constitutes an important step toward understanding potential drivers of structural asymmetry and its role in underpinning functional and behavioral lateralization in cetaceans.

  5. Facial cellulitis revealing choreo-acanthocytosis: a case report.

    Science.gov (United States)

    Samia, Younes; Yosra, Cherif; Foued, Bellazreg; Mouna, Aissi; Olfa, Berriche; Jihed, Souissi; Hammadi, Braham; Mahbouba, Frih-Ayed; Amel, Letaief; Habib, Sfar Mohamed

    2014-01-01

    We report a 62 year-old-man with facial cellulitis revealing choreo-acanthocytosis (ChAc). He showed chorea that started 20 years ago. The orofacial dyskinisia with tongue and cheek biting resulted in facial cellulitis. The peripheral blood smear revealed acanthocytosis of 25%. The overall of chorea, orofacial dyskinetic disorder, peripheral neuropathy, disturbed behavior, acanthocytosis and the atrophy of caudate nuclei was suggestive of a diagnosis of ChAc. To our knowledge no similar cases of facial cellulitis revealing choreo-acanthocytosis (ChAc) were found in a review of the literature.

  6. Neurogenic role of the depolarizing chloride gradient revealed by global overexpression of KCC2 from the onset of development.

    Science.gov (United States)

    Reynolds, Annie; Brustein, Edna; Liao, Meijiang; Mercado, Adriana; Babilonia, Elisa; Mount, David B; Drapeau, Pierre

    2008-02-13

    GABA- and glycine-induced depolarization is thought to provide important developmental signals, but the role of the underlying chloride gradient has not been examined from the onset of development. We therefore overexpressed globally the potassium-chloride cotransporter 2 (KCC2) in newly fertilized zebrafish embryos to reverse the chloride gradient. This rendered glycine hyperpolarizing in all neurons, tested at the time that motor behaviors (but not native KCC2) first appear. KCC2 overexpression resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity. We observed fewer motoneurons and interneurons, a reduction in the elaboration of axonal tracts, and smaller brains and spinal cords. However, we observed no increased apoptosis and a normal complement of sensory neurons, glia, and progenitors. These results suggest that chloride-mediated excitation plays a crucial role in promoting neurogenesis from the earliest stages of embryonic development.

  7. Revealing Slip Bands In A Metal-Matrix/Fiber Composite

    Science.gov (United States)

    Lerch, Bradley A.

    1995-01-01

    Experimental procedure includes heat treatments and metallographic techniques developed to facilitate studies of deformation of metal-matrix/fiber composite under stress. Reveals slip bands, indicative of plastic flow occurring in matrix during mechanical tests of specimens of composite.

  8. Gene Sequencing May Reveal Risks for Rare Diseases

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_166875.html Gene Sequencing May Reveal Risks for Rare Diseases But ... this study, the researchers analyzed nearly 5,000 genes associated with rare genetic conditions in 50 healthy ...

  9. Interaction proteomics reveals brain region-specific AMPA receptor complexes

    NARCIS (Netherlands)

    Chen, N.; Pandya, N.J.; Koopmans, F.T.W.; Castelo-Szekelv, V.; van der Schors, R.C.; Smit, A.B.; Li, K.W.

    2014-01-01

    Fast excitatory synaptic transmission in the brain is mediated by glutamate acting on postsynaptic AMPA receptors. Recent studies have revealed a substantial number of AMPA receptor auxiliary proteins, which potentially contribute to the regulation of AMPA receptor trafficking, subcellular receptor

  10. Genetic and biochemical evidences reveal novel insights into the ...

    Indian Academy of Sciences (India)

    Genetic and biochemical evidences reveal novel insights into the mechanism underlying Saccharomyces cerevisiae Sae2-mediated abrogation of DNA replication stress. Indrajeet Ghodke and K Muniyappa. Supplementary Material. Supplementary table 1. Plasmids used in this study ...

  11. 21 CFR 1.21 - Failure to reveal material facts.

    Science.gov (United States)

    2010-04-01

    ... possible product hazards) required in labeling for food, drugs, devices, or cosmetics under the act. (2...) Labeling of a food, drug, device, or cosmetic shall be deemed to be misleading if it fails to reveal facts...

  12. Activity screening of environmental metagenomic libraries reveals novel carboxylesterase families

    Science.gov (United States)

    Popovic, Ana; Hai, Tran; Tchigvintsev, Anatoly; Hajighasemi, Mahbod; Nocek, Boguslaw; Khusnutdinova, Anna N.; Brown, Greg; Glinos, Julia; Flick, Robert; Skarina, Tatiana; Chernikova, Tatyana N.; Yim, Veronica; Brüls, Thomas; Paslier, Denis Le; Yakimov, Michail M.; Joachimiak, Andrzej; Ferrer, Manuel; Golyshina, Olga V.; Savchenko, Alexei; Golyshin, Peter N.; Yakunin, Alexander F.

    2017-01-01

    Metagenomics has made accessible an enormous reserve of global biochemical diversity. To tap into this vast resource of novel enzymes, we have screened over one million clones from metagenome DNA libraries derived from sixteen different environments for carboxylesterase activity and identified 714 positive hits. We have validated the esterase activity of 80 selected genes, which belong to 17 different protein families including unknown and cyclase-like proteins. Three metagenomic enzymes exhibited lipase activity, and seven proteins showed polyester depolymerization activity against polylactic acid and polycaprolactone. Detailed biochemical characterization of four new enzymes revealed their substrate preference, whereas their catalytic residues were identified using site-directed mutagenesis. The crystal structure of the metal-ion dependent esterase MGS0169 from the amidohydrolase superfamily revealed a novel active site with a bound unknown ligand. Thus, activity-centered metagenomics has revealed diverse enzymes and novel families of microbial carboxylesterases, whose activity could not have been predicted using bioinformatics tools. PMID:28272521

  13. [Chronic vulvar lymphedema revealing Crohn disease in a teenage girl].

    Science.gov (United States)

    Aounallah, A; Ghariani Fetoui, N; Ksiaa, M; Boussofara, L; Saidi, W; Mokni, S; Sriha, B; Belajouza, C; Denguezli, M; Ghariani, N; Nouira, R

    2017-04-01

    Cutaneous Crohn disease is a rare cutaneous manifestation of Crohn disease in children. Herein is reported a case of persistent vulvar lymphedema revealing Crohn disease in a teenage girl. A 14-year-old girl presented with an 8-month history of persistent vulvar swelling associated with chronic macrocheilia. Dermatologic examination showed an inflammatory vulvar lymphedema, associated with perianal fissures and hypertrophic gingivitis. Vulvar skin biopsy revealed non-necrotizing granulomatous inflammation. Gastrointestinal endoscopy yielded no significant findings. The diagnosis of Crohn disease presenting as vulvar lymphedema was established. Oral metronidazole therapy resulted in partial improvement of cutaneous lesions beginning the 1st week. The originality of this case lies in the presentation of chronic macrocheilia with persistent vulvar lymphedema in a child, revealing Crohn disease without gastrointestinal involvement. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  14. Burned-out seminoma revealed by solitary rib bone metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Nishisho, Toshihiko; Miyagi, Ryo; Sairyo, Koichi [Tokushima University Graduate School, Department of Orthopedics, Institute of Biomedical Sciences, Tokushima-city, Tokushima (Japan); Sakaki, Mika [Saitama Medical University International Medical Center, Department of Pathology, Hidaka-city, Saitama (Japan); Takao, Shoichiro [Tokushima University Graduate School, Department of Radiology, Institute of Biomedical Sciences, Tokushima-city, Tokushima (Japan)

    2017-10-15

    Burned-out tumor is a rare phenomenon in which a testicular tumor regresses in the primary lesion and progresses in a metastatic lesion. We report the case of a 30-year-old male with burned-out seminoma revealed by open biopsy of solitary 10th rib bone metastasis. He underwent inguinal orchiectomy, which revealed hyalinization, indicating a spontaneously regressed testicular tumor. Chemotherapy for seminoma was administered in three cycles of bleomycin + etoposide + cisplatin therapy. The chemotherapy was effective, and wide resection of the rib was subsequently performed. No postoperative chemotherapy was performed, and there has been no evidence of recurrence for 3 years postoperatively. (orig.)

  15. Molecular variation in Cucumis melo as revealed by isoenzyme and ...

    African Journals Online (AJOL)

    Molecular variation in Cucumis melo as revealed by isoenzyme and RAPD markers. Tarek M Mohamed. Abstract. No Abstract. The Egyptian Journal of Biochemistry and Molecular Biology Vol. 23(2) 2005: 141-153. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT ...

  16. Sinai and Norfa chicken diversity revealed by microsatellite markers ...

    African Journals Online (AJOL)

    Sinai and Norfa chicken diversity revealed by microsatellite markers. M Soltan, S Farrag, A Enab, E Abou-Elewa, S El-Safty, A Abushady. Abstract. The present study aimed to outline the population differentiation of Sinai and Norfa chicken, native to Egypt, with microsatellite markers. Twenty microsatellite loci recommended ...

  17. On galaxy spiral arms' nature as revealed by rotation frequencies

    NARCIS (Netherlands)

    Roca-Fabrega, Santi; Valenzuela, Octavio; Figueras, Francesca; Romero-Gomez, Merce; Velazquez, Hector; Antoja Castelltort, Teresa; Pichardo, Barbara

    2013-01-01

    High-resolution N-body simulations using different codes and initial condition techniques reveal two different behaviours for the rotation frequency of transient spiral arms like structures. Whereas unbarred discs present spiral arms nearly corotating with disc particles, strong barred models

  18. In Reporting Lobbying Expenses, Some Institutions Do Not Reveal All.

    Science.gov (United States)

    Lederman, Douglas

    1998-01-01

    On a federal tax form, only 75 of 475 colleges and universities surveyed reported that they had spent money on lobbying, defined as direct contacts with legislators or executive-branch officials about specific bills. Guidelines concerning reporting are unclear and confusing, and some institutions reveal as little as possible. Data on 78…

  19. ID-check: Online concealed information test reveals true identity

    NARCIS (Netherlands)

    Verschuere, B.; Kleinberg, B.

    2016-01-01

    The Internet has already changed people's lives considerably and is likely to drastically change forensic research. We developed a web-based test to reveal concealed autobiographical information. Initial studies identified a number of conditions that affect diagnostic efficiency. By combining these

  20. UTV Expansion Pack: Special-Purpose Rank-Revealing Algorithms

    DEFF Research Database (Denmark)

    Fierro, Ricardo D.; Hansen, Per Christian

    2005-01-01

    -revealing VSV decompositions, we expand the algorithms for the ULLV decomposition of a matrix pair to handle interference-type problems with a rank-deficient covariance matrix, and we provide a robust and reliable Lanczos algorithm which - despite its simplicity - is able to capture all the dominant singular...

  1. SSR markers reveal genetic variation between improved cassava ...

    African Journals Online (AJOL)

    Five SSR primers that have PIC values between 0.50 and 0.67 were selected and further assessed using simple arithmetic progression combination method. The results obtained revealed a combination of these 5 primers from SSR primers collection at IITA that could readily distinguish the 36 cassava genotypes at 0.93 ...

  2. Genetic diversity of taraxacum germplasm revealed by sequence ...

    African Journals Online (AJOL)

    Genetic diversity of taraxacum germplasm revealed by sequence-related amplified polymorphism (SRAP) analysis. ... African Journal of Biotechnology ... The genetic relationships analyzed with un-weighed pairgroup method with arithmetic mean (UPMGA) showed that 11 population of taraxacum were grouped into three ...

  3. Cotranslational protein folding reveals the selective use of ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 93; Issue 3. Cotranslational protein folding reveals the selective use of synonymous codons along the coding sequence of a low expression gene. Suvendra Kumar Ray Vishwa Jyoti Baruah Siddhartha Sankar Satapathy Rajat Banerjee. Research Commentary Volume 93 Issue ...

  4. Heat islands over Mumbai as revealed by autorecorded ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Earth System Science; Volume 125; Issue 1. Heat islands over Mumbai as revealed by autorecorded thermograph data. A K Srivastava James Voogt ... One data point (Coloba, Mumbai) is in centre of the city and the other one (Santacruz, Mumbai) is at the airport. The study finds that there were ...

  5. Genetic relationships revealed by simple sequence repeat (SSR ...

    African Journals Online (AJOL)

    Genetic relationships revealed by simple sequence repeat (SSR) markers among Ghanaian cassava cultivars released by different research groups. ... Genetic diversity was observed within populations (HS = 0.552) and, therefore, suggesting a low rate of inter-population gene flow among the individuals constituting the ...

  6. MRI reveals reversible lesions resembling posterior reversible encephalopathy in porphyria

    Energy Technology Data Exchange (ETDEWEB)

    Celik, M. [Huesrev Gerede c, 128/4 Tesvikiye, 80690 Istanbul (Turkey); Department of Neurology, Sisli Etfal Education and Research Hospital, Sisli Etfal S., Sisli, Istanbul (Turkey); Forta, H.; Babacan, G. [Department of Neurology, Sisli Etfal Education and Research Hospital, Sisli Etfal S., Sisli, Istanbul (Turkey); Dalkilic, Tuerker [Department of Neurosurgery, Sisli Etfal Education and Research Hospital, Sisli Etfal S., Sisli, Istanbul (Turkey)

    2002-10-01

    We report a 20-year-old woman who had an attack of acute intermittent porphyria with seizures, hallucinations, autonomic and somatic neuropathy. T2-weighted MRI revealed multiple lesions which were no longer visible 3 months later. We suggest a similar mechanism to posterior reversible encephalopathy underlying cerebral symptoms in porphyria. (orig.)

  7. Genetic and biochemical evidences reveal novel insights into the ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 41; Issue 4. Genetic and biochemical evidences reveal novel insights into the mechanism underlying Saccharomyces cerevisiae Sae2-mediated abrogation of DNA replication stress. INDRAJEET GHODKE K MUNIYAPPA. ARTICLE Volume 41 Issue 4 December 2016 pp ...

  8. Whole exome sequencing reveals a MLL de novo mutation ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 94; Issue 4. Whole exome sequencing reveals a de novo mutation associated with mild developmental delay ... Keywords. Wiedemann–Steiner syndrome; whole exome sequencing; hairy elbows; hypertrichosis cubiti; gene; KMT2A; developmental delay; children.

  9. Natural Disasters that Reveal Cracks in Our Social Foundation

    Science.gov (United States)

    Langer, Nieli

    2004-01-01

    The recent deaths of more than 13,000 French elderly in the European heat wave of 2003 revealed cracks in the social foundation of urban communities, here and abroad. The breakdown occurred in community services, neighborhood networks, and governmental agencies that were responsible for warning of impending dangers to at-risk elderly. This paper…

  10. An acute adrenal insufficiency revealing pituitary metastases of lung ...

    African Journals Online (AJOL)

    The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases.

  11. Mitochondrial and nuclear DNA reveals a complete lineage sorti ng ...

    African Journals Online (AJOL)

    Glossogobius callidus exhibits broad salinity tolerance and is distributed in both estuarine and freshwater environments in southern Africa. Previous studies revealed substantial morphological and molecular variation among populations, suggesting they constitute a species complex. The present study utilised phylogenetic ...

  12. Puzzles in modern biology. I. Male sterility, failure reveals design

    OpenAIRE

    Frank, Steven A.

    2016-01-01

    Many human males produce dysfunctional sperm. Various plants frequently abort pollen. Hybrid matings often produce sterile males. Widespread male sterility is puzzling. Natural selection prunes reproductive failure. Puzzling failure implies something that we do not understand about how organisms are designed. Solving the puzzle reveals the hidden processes of design.

  13. Proteomic and transcriptomic analysis reveals evidence for the basis ...

    African Journals Online (AJOL)

    Proteomic and transcriptomic analysis reveals evidence for the basis of salt sensitivity in Thai jasmine rice ( Oryza sativa L. cv. ... African Journal of Biotechnology ... the posttranscriptional mechanisms controlling protein expression levels were not as efficient as in Pokkali, indicating targets for future genetic improvement.

  14. Whole-organism cellular gene-expression atlas reveals conserved cell types in the ventral nerve cord ofPlatynereis dumerilii.

    Science.gov (United States)

    Vergara, Hernando Martínez; Bertucci, Paola Yanina; Hantz, Peter; Tosches, Maria Antonietta; Achim, Kaia; Vopalensky, Pavel; Arendt, Detlev

    2017-06-06

    The comparative study of cell types is a powerful approach toward deciphering animal evolution. To avoid selection biases, however, comparisons ideally involve all cell types present in a multicellular organism. Here, we use image registration and a newly developed "Profiling by Signal Probability Mapping" algorithm to generate a cellular resolution 3D expression atlas for an entire animal. We investigate three-segmented young worms of the marine annelid Platynereis dumerilii , with a rich diversity of differentiated cells present in relatively low number. Starting from whole-mount expression images for close to 100 neural specification and differentiation genes, our atlas identifies and molecularly characterizes 605 bilateral pairs of neurons at specific locations in the ventral nerve cord. Among these pairs, we identify sets of neurons expressing similar combinations of transcription factors, located at spatially coherent anterior-posterior, dorsal-ventral, and medial-lateral coordinates that we interpret as cell types. Comparison with motor and interneuron types in the vertebrate neural tube indicates conserved combinations, for example, of cell types cospecified by Gata1/2/3 and Tal transcription factors. These include V2b interneurons and the central spinal fluid-contacting Kolmer-Agduhr cells in the vertebrates, and several neuron types in the intermediate ventral ganglionic mass in the annelid. We propose that Kolmer-Agduhr cell-like mechanosensory neurons formed part of the mucociliary sole in protostome-deuterostome ancestors and diversified independently into several neuron types in annelid and vertebrate descendants.

  15. Colored motifs reveal computational building blocks in the C. elegans brain.

    Directory of Open Access Journals (Sweden)

    Jifeng Qian

    Full Text Available BACKGROUND: Complex networks can often be decomposed into less complex sub-networks whose structures can give hints about the functional organization of the network as a whole. However, these structural motifs can only tell one part of the functional story because in this analysis each node and edge is treated on an equal footing. In real networks, two motifs that are topologically identical but whose nodes perform very different functions will play very different roles in the network. METHODOLOGY/PRINCIPAL FINDINGS: Here, we combine structural information derived from the topology of the neuronal network of the nematode C. elegans with information about the biological function of these nodes, thus coloring nodes by function. We discover that particular colorations of motifs are significantly more abundant in the worm brain than expected by chance, and have particular computational functions that emphasize the feed-forward structure of information processing in the network, while evading feedback loops. Interneurons are strongly over-represented among the common motifs, supporting the notion that these motifs process and transduce the information from the sensor neurons towards the muscles. Some of the most common motifs identified in the search for significant colored motifs play a crucial role in the system of neurons controlling the worm's locomotion. CONCLUSIONS/SIGNIFICANCE: The analysis of complex networks in terms of colored motifs combines two independent data sets to generate insight about these networks that cannot be obtained with either data set alone. The method is general and should allow a decomposition of any complex networks into its functional (rather than topological motifs as long as both wiring and functional information is available.

  16. Microbiota analysis to reveal temperature abuse of fresh pork

    DEFF Research Database (Denmark)

    Buschhardt, Tasja; Bahl, Martin Iain; Hansen, Tina Beck

    Violations of temperature regulations in the meat chain may affect meat safety. Methods are lacking to estimate whether meat has been subjected to temperature abuse. Exposure to too high temperatures may lead to systematic changes in the diverse bacterial communities of fresh meat. We investigated...... whether temperature induced changes in the community composition on fresh meat surfaces can reflect the temperature-history (combination of time and temperature). Sterile pieces of pork were inoculated with a carcass swab homogenate, to which Salmonella was added. Changes in the meat microbiota were...... was dominated by Pseudomonas only. We also showed that the initial community affects subsequent changes during storage. The results suggest that principal coordinate analysis of beta diversity could be a useful tool to reveal temperature abused meat. Sequence data and culturing data revealed a strong positive...

  17. Ascites and other incidental findings revealing undiagnosed systemic rheumatoid arthritis.

    Science.gov (United States)

    Szeto, Matthew Chak Hin; Disney, Benjamin; Perkins, Philip; Wood, Gordon

    2015-06-08

    We describe a case of a 43-year-old man presenting to the gastroenterology outpatient department with exudative ascites. Mediastinal lymphadenopathy, pericardial effusion and pleural effusion were detected on further imaging. Further clinical examination revealed subcutaneous nodules on the left arm, which were confirmed to be rheumatoid nodules on histology. Inflammatory markers were elevated with positive serology for rheumatoid factor and anticyclic citrullinated protein antibody. Our investigations excluded tuberculosis, pancreatitis and malignancy in the patient. Following review by a rheumatologist, a diagnosis of systemic rheumatoid arthritis (RA) was made. Pleuritis and pericarditis are well recognised as extra-articular manifestation of RA. Ascites, however, is rarely recognised as a manifestation of RA. Our literature search revealed two other cases of ascites due to RA disease activity, and both patients had long-standing known RA. This case adds to the discussion on whether ascites and peritonitis should be classified as extra-articular manifestations of RA. 2015 BMJ Publishing Group Ltd.

  18. Intracranial Hemorrhage Revealing Pseudohypoparathyroidism as a Cause of Fahr Syndrome

    Directory of Open Access Journals (Sweden)

    Abhijit Swami

    2011-01-01

    Full Text Available Pseudohypoparathyroidism is an infrequently encountered disease. It is one of the causes of Fahr syndrome which also is a rare clinical entity caused by multiple diseases. A 4-year-old man hospitalized for sudden onset left hemiparesis and hypertension was diagnosed to have right thalamic and midbrain hemorrhage on plain CT scan of the head which also revealed co-existent extensive intracranial calcifications involving the basal ganglia and cerebellum bilaterally. General physical examination revealed features of Albright hereditary osteodystrophy, goitre, hypertension, left hemiparesis, and signs of cerebellar dysfunction. Laboratory findings suggested hypocalcemia, hyperphosphatemia along with high TSH, low FT4, low FT3, and high anti-TPO antibody. Though bilateral intracranial calcifications are usually encountered as an incidental radiological finding in the CT scan of brain, in this case, the patient admitted for thalamic and midbrain hemorrhage was on investigation for associated intracranial calcification, and goitre was also found to have coexisting pseudohypoparathyroidism and autoimmune hypothyroidism.

  19. Maps of random walks on complex networks reveal community structure.

    Science.gov (United States)

    Rosvall, Martin; Bergstrom, Carl T

    2008-01-29

    To comprehend the multipartite organization of large-scale biological and social systems, we introduce an information theoretic approach that reveals community structure in weighted and directed networks. We use the probability flow of random walks on a network as a proxy for information flows in the real system and decompose the network into modules by compressing a description of the probability flow. The result is a map that both simplifies and highlights the regularities in the structure and their relationships. We illustrate the method by making a map of scientific communication as captured in the citation patterns of >6,000 journals. We discover a multicentric organization with fields that vary dramatically in size and degree of integration into the network of science. Along the backbone of the network-including physics, chemistry, molecular biology, and medicine-information flows bidirectionally, but the map reveals a directional pattern of citation from the applied fields to the basic sciences.

  20. Comparative Genomics Reveals High Genomic Diversity in the Genus Photobacterium

    DEFF Research Database (Denmark)

    Machado, Henrique; Gram, Lone

    2017-01-01

    Vibrionaceae is a large marine bacterial family, which can constitute up to 50% of the prokaryotic population in marine waters. Photobacterium is the second largest genus in the family and we used comparative genomics on 35 strains representing 16 of the 28 species described so far, to understand...... the genomic diversity present in the Photobacterium genus. Such understanding is important for ecophysiology studies of the genus. We used whole genome sequences to evaluate phylogenetic relationships using several analyses (16S rRNA, MLSA, fur, amino-acid usage, ANI), which allowed us to identify two...... misidentified strains. Genome analyses also revealed occurrence of higher and lower GC content clades, correlating with phylogenetic clusters. Pan-and core-genome analysis revealed the conservation of 25% of the genome throughout the genus, with a large and open pan-genome. The major source of genomic diversity...

  1. Sequencing of seven haloarchaeal genomes reveals patterns of genomic flux.

    Directory of Open Access Journals (Sweden)

    Erin A Lynch

    Full Text Available We report the sequencing of seven genomes from two haloarchaeal genera, Haloferax and Haloarcula. Ease of cultivation and the existence of well-developed genetic and biochemical tools for several diverse haloarchaeal species make haloarchaea a model group for the study of archaeal biology. The unique physiological properties of these organisms also make them good candidates for novel enzyme discovery for biotechnological applications. Seven genomes were sequenced to ∼20×coverage and assembled to an average of 50 contigs (range 5 scaffolds-168 contigs. Comparisons of protein-coding gene compliments revealed large-scale differences in COG functional group enrichment between these genera. Analysis of genes encoding machinery for DNA metabolism reveals genera-specific expansions of the general transcription factor TATA binding protein as well as a history of extensive duplication and horizontal transfer of the proliferating cell nuclear antigen. Insights gained from this study emphasize the importance of haloarchaea for investigation of archaeal biology.

  2. Expansion by regions: revealing potential and Glauber regions automatically

    Energy Technology Data Exchange (ETDEWEB)

    Jantzen, Bernd [RWTH Aachen University, Institut fuer Theoretische Teilchenphysik und Kosmologie, Aachen (Germany); Smirnov, Alexander V. [Moscow State University, Scientific Research Computing Center, Moscow (Russian Federation); KIT, Institut fuer Theoretische Teilchenphysik, Karlsruhe (Germany); Smirnov, Vladimir A. [Moscow State University, Skobeltsyn Institute of Nuclear Physics, Moscow (Russian Federation); KIT, Institut fuer Theoretische Teilchenphysik, Karlsruhe (Germany)

    2012-09-15

    When performing asymptotic expansions using the strategy of expansion by regions, it is a non-trivial task to find the relevant regions. The recently published Mathematica code asy.m automates this task, but it has not been able to detect potential regions in threshold expansions or Glauber regions. In this work we present an algorithm and its implementation in the update asy2.m which also reveals potential and Glauber regions automatically. (orig.)

  3. Digital tissue and what it may reveal about the brain.

    Science.gov (United States)

    Morgan, Josh L; Lichtman, Jeff W

    2017-10-30

    Imaging as a means of scientific data storage has evolved rapidly over the past century from hand drawings, to photography, to digital images. Only recently can sufficiently large datasets be acquired, stored, and processed such that tissue digitization can actually reveal more than direct observation of tissue. One field where this transformation is occurring is connectomics: the mapping of neural connections in large volumes of digitized brain tissue.

  4. Spontaneous chylothorax revealing a mediastinal and abdominal lymph node tuberculosis.

    Science.gov (United States)

    Amar, Jihen Ben; Zaibi, Haifa; Dahri, Besma; Aouina, Hichem

    2017-04-01

    Chylothorax is a rare manifestation of tuberculosis. We report a case of spontaneous chylothorax due to tuberculosis. A 62-year-old woman was admitted with fever, chest pain and dyspnea. Chest and abdominal computed tomography revealed a fluid collection with necrotic mediastinal and abdominal lymph nodes. Biopsy of lymph nodes by mediastinoscopy. The patient was treated with anti-tuberculosis medication. He is clinically improved and his pleural effusion also completely resolved. Copyright © 2016. Published by Elsevier B.V.

  5. King Lear Reveals the Tragic Pattern of Shakespeare

    OpenAIRE

    Salim Eflih Al-Ibia

    2017-01-01

    Rather than focusing on the obvious traditions of evaluating Shakespearean tragic heroes, this paper presents a groundbreaking approach to unfold the pattern William Shakespeare follows as he designed his unique characters. This pattern applies to most, if not all, Shakespearean tragic heroes. I argue that Shakespeare himself reveals a great portion of this pattern on the tongue of Lear as the latter disowns Goneril and Regan promising to have “such revenges on [them] both” in King Lear. Lear...

  6. Cavitary lung lesion suspicious for malignancy reveals Mycobacterium xenopi.

    Science.gov (United States)

    Fogla, Sumit; Pansare, Vaishali M; Camero, Luis G; Syeda, Uzma; Patil, Naveen; Chaudhury, Arun

    2018-01-01

    We report the case of a 68-year-old gentleman who presented with musculoskeletal chest pain which appeared suddenly when he bent over with his dog. The chest pain was localized to the left lower chest and increased with movement and deep breathing. The patient did not complain weight loss, night sweat, fever or chill. He complained of mild cough, with expectoration of whitish mucus. Imaging revealed cavitary chest lesion in the right upper lobe, which was initially suspected to be lung cancer. The patient had a 50-year-old history of smoking 2 packs per day. PET CT imaging did not reveal any specific activity. Needle biopsy and bronchoalveolar lavage, however, did not reveal any malignant cells. Rather, necrotic tissues were observed. A wedge resection of the lung mass was performed. No common organisms or fungi could be grown. However, acid fast bacilli were observed in clumps. The morphology hinted towards non-tuberculous mycobacterial organism(s). Molecular studies revealed infection with Mycobacterium xenopi. The patient was started on an anti-tuberculous regimen of INH, rifampicin, ethambutol and PZA, with pyridoxine. The patient is a Vietnam veteran and complained of exposure to dust from a bird's nest and asbestos exposure in childhood, but no specific exposure to tuberculosis. The patient had an uneventful recovery post-surgery. He complained of some nausea after initiation of the antituberculous medications, but his pain subsided with time. The patient had diabetes, though specific reasons of compromise of immune status could not be pinpointed as causative of his nontuberculous mycobacterial lung infection.

  7. Blue whale earplug reveals lifetime contaminant exposure and hormone profiles

    OpenAIRE

    Trumble, Stephen J.; Robinson, Eleanor M.; Berman-Kowalewski, Michelle; Potter, Charles W.; Usenko, Sascha

    2013-01-01

    Currently, obtaining lifetime chemical profiles (i.e., from birth to death) is extremely rare and difficult for most of Earth’s animals. We have developed a unique approach to quantify hormone and contaminant lifetime profiles for an individual blue whale with a 6-mo resolution using the wax earplug as a natural matrix capable of archiving and preserving these temporal profiles. Using a male blue whale earplug, chemical analysis reveals lifetime patterns of mercury and organic pollutant expos...

  8. Inheritance patterns in citation networks reveal scientific memes

    OpenAIRE

    Tobias Kuhn; Matjaž Perc; Dirk Helbing

    2014-01-01

    Memes are the cultural equivalent of genes that spread across human culture by means of imitation. What makes a meme and what distinguishes it from other forms of information, however, is still poorly understood. Our analysis of memes in the scientific literature reveals that they are governed by a surprisingly simple relationship between frequency of occurrence and the degree to which they propagate along the citation graph. We propose a simple formalization of this pattern and we validate i...

  9. Revealing the invisible: the paradox of picturing a phantom limb.

    Science.gov (United States)

    Schott, G D

    2014-03-01

    Illustrations of phantom limbs are intriguing as they depict an invisible perception. But such illustrations are also important: they provide a form of objectivity to phenomena, which particularly in the past, have often stretched credulity. Acknowledging the paradox of using images to reveal an absent though sensate body part, depictions of phantom limbs are discussed from the neurological perspective, starting with medieval pictures that showed the miraculous restoration of limbs, and which possibly represented pictorial metaphors for a phantom limb. Centuries later, phantom limbs-whether resulting from amputation or deafferentation-became illustrated, and some reasons for their illustration are considered. Although often depicted by others, the most precise and perhaps revealing illustrations of these phantoms have been those made when patients guide the artist, or draw the phantom themselves. In the case of phantom pains, the painful component too is sometimes illustrated, again, as with the miraculous, in metaphorical terms. More recently, depictions of phantoms have also been revealing in studies of some underlying mechanisms of phantom phenomena, notably in demonstrating novel patterns of referred sensations after amputation and attributable to cortical plasticity. Mention is made of photographs of phantom hands visualized using a mirror box, such visualization recalling full circle the miraculous restoration of limbs pictured in the past. The nature of the outline of the phantom is included in a discussion of demarcation of an invisible body part, before concluding that images of phantom limbs provide an invaluable background to understanding and studying these remarkable sensory phenomena.

  10. Transient light-induced intracellular oxidation revealed by redox biosensor

    Energy Technology Data Exchange (ETDEWEB)

    Kolossov, Vladimir L., E-mail: viadimer@illinois.edu [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Beaudoin, Jessica N. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Hanafin, William P. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); DiLiberto, Stephen J. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Kenis, Paul J.A. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801 (United States); Rex Gaskins, H. [Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801 (United States); Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801 (United States); Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801 (United States)

    2013-10-04

    Highlights: •Time-resolved live cell imaging revealed light-induced oxidation. •Only the roGFP probe fused with glutaredoxin reveals photooxidation. •The transient oxidation is rapidly reduced by the cytosolic antioxidant system. •Intracellular photooxidation is media-dependent. •Oxidation is triggered exclusively by exposure to short wavelength excitation. -- Abstract: We have implemented a ratiometric, genetically encoded redox-sensitive green fluorescent protein fused to human glutaredoxin (Grx1-roGFP2) to monitor real time intracellular glutathione redox potentials of mammalian cells. This probe enabled detection of media-dependent oxidation of the cytosol triggered by short wavelength excitation. The transient nature of light-induced oxidation was revealed by time-lapse live cell imaging when time intervals of less than 30 s were implemented. In contrast, transient ROS generation was not observed with the parental roGFP2 probe without Grx1, which exhibits slower thiol-disulfide exchange. These data demonstrate that the enhanced sensitivity of the Grx1-roGFP2 fusion protein enables the detection of short-lived ROS in living cells. The superior sensitivity of Grx1-roGFP2, however, also enhances responsiveness to environmental cues introducing a greater likelihood of false positive results during image acquisition.

  11. Active medulloblastoma enhancers reveal subgroup-specific cellular origins

    Science.gov (United States)

    Lin, Charles Y.; Erkek, Serap; Tong, Yiai; Yin, Linlin; Federation, Alexander J.; Zapatka, Marc; Haldipur, Parthiv; Kawauchi, Daisuke; Risch, Thomas; Warnatz, Hans-Jörg; Worst, Barbara C.; Ju, Bensheng; Orr, Brent A.; Zeid, Rhamy; Polaski, Donald R.; Segura-Wang, Maia; Waszak, Sebastian M.; Jones, David T.W.; Kool, Marcel; Hovestadt, Volker; Buchhalter, Ivo; Sieber, Laura; Johann, Pascal; Chavez, Lukas; Gröschel, Stefan; Ryzhova, Marina; Korshunov, Andrey; Chen, Wenbiao; Chizhikov, Victor V.; Millen, Kathleen J.; Amstislavskiy, Vyacheslav; Lehrach, Hans; Yaspo, Marie-Laure; Eils, Roland; Lichter, Peter; Korbel, Jan O.; Pfister, Stefan M.; Bradner, James E.; Northcott, Paul A.

    2016-01-01

    Summary Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-Seq, that are responsible for subgroup divergence and implicate candidate cells-of-origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins. PMID:26814967

  12. Genes but not genomes reveal bacterial domestication of Lactococcus lactis.

    Directory of Open Access Journals (Sweden)

    Delphine Passerini

    Full Text Available BACKGROUND: The population structure and diversity of Lactococcus lactis subsp. lactis, a major industrial bacterium involved in milk fermentation, was determined at both gene and genome level. Seventy-six lactococcal isolates of various origins were studied by different genotyping methods and thirty-six strains displaying unique macrorestriction fingerprints were analyzed by a new multilocus sequence typing (MLST scheme. This gene-based analysis was compared to genomic characteristics determined by pulsed-field gel electrophoresis (PFGE. METHODOLOGY/PRINCIPAL FINDINGS: The MLST analysis revealed that L. lactis subsp. lactis is essentially clonal with infrequent intra- and intergenic recombination; also, despite its taxonomical classification as a subspecies, it displays a genetic diversity as substantial as that within several other bacterial species. Genome-based analysis revealed a genome size variability of 20%, a value typical of bacteria inhabiting different ecological niches, and that suggests a large pan-genome for this subspecies. However, the genomic characteristics (macrorestriction pattern, genome or chromosome size, plasmid content did not correlate to the MLST-based phylogeny, with strains from the same sequence type (ST differing by up to 230 kb in genome size. CONCLUSION/SIGNIFICANCE: The gene-based phylogeny was not fully consistent with the traditional classification into dairy and non-dairy strains but supported a new classification based on ecological separation between "environmental" strains, the main contributors to the genetic diversity within the subspecies, and "domesticated" strains, subject to recent genetic bottlenecks. Comparison between gene- and genome-based analyses revealed little relationship between core and dispensable genome phylogenies, indicating that clonal diversification and phenotypic variability of the "domesticated" strains essentially arose through substantial genomic flux within the dispensable

  13. Revealed Comparative Advantage of Services in Cariforum Countries

    Directory of Open Access Journals (Sweden)

    Marie Freckleton

    2014-09-01

    Full Text Available A pesar de la importancia de las exportaciones de servicios a los países del CARIFORUM no hay muchos estudios sobre de la competitividad de las exportaciones. Este artículo examina la ventaja comparativa revelada de las exportaciones de servicios de los países del CARIFORUM. El análisis muestra que la mayoría de los países del CARIFORUM han puesto de manifiesto las ventajas comparativas en el turismo, pero también hay casos de ventaja comparativa revelada en otros servicios como transporte, seguros y servicios empresariales, servicios personales, culturales y recreativos. Los resultados sugieren que existe un potencial de CARIFORUM para diversificar las exportaciones de servicios con el fin de pro-mover el crecimiento económico y reducir la vulnerabilidad. Sin embargo, en la medida en que los países del CARIFORUM pueden tomar ventaja de las oportunidades existentes de acceso al Mercado de los servicios depende de su capacidad de mejorar la capacidad de oferta de servicios y promover la competitividad de los servicios. English: Despite the importance of services ex-ports to CARIFORUM countries there is limited research on the competitiveness of such exports. This article examines the revealed comparative advantage of services exports in CARIFORUM countries. The analysis shows that most CARIFORUM countries have revealed comparative advantage in tourism but there are also cases of revealed comparative advantage in other services including transport, insurance, business services and personal, cultural and recreational services. The results suggest that there is potential for CARIFORUM to diversify exports of services in order to promote economic growth and reduce vulnerability. However, the extent to which CARIFORUM countries can take advantage of existing market access opportunities for services depends on their ability to improve the capacity to supply services and to promote the competitiveness of services.

  14. The features of Drosophila core promoters revealed by statistical analysis

    Directory of Open Access Journals (Sweden)

    Trifonov Edward N

    2006-06-01

    Full Text Available Abstract Background Experimental investigation of transcription is still a very labor- and time-consuming process. Only a few transcription initiation scenarios have been studied in detail. The mechanism of interaction between basal machinery and promoter, in particular core promoter elements, is not known for the majority of identified promoters. In this study, we reveal various transcription initiation mechanisms by statistical analysis of 3393 nonredundant Drosophila promoters. Results Using Drosophila-specific position-weight matrices, we identified promoters containing TATA box, Initiator, Downstream Promoter Element (DPE, and Motif Ten Element (MTE, as well as core elements discovered in Human (TFIIB Recognition Element (BRE and Downstream Core Element (DCE. Promoters utilizing known synergetic combinations of two core elements (TATA_Inr, Inr_MTE, Inr_DPE, and DPE_MTE were identified. We also establish the existence of promoters with potentially novel synergetic combinations: TATA_DPE and TATA_MTE. Our analysis revealed several motifs with the features of promoter elements, including possible novel core promoter element(s. Comparison of Human and Drosophila showed consistent percentages of promoters with TATA, Inr, DPE, and synergetic combinations thereof, as well as most of the same functional and mutual positions of the core elements. No statistical evidence of MTE utilization in Human was found. Distinct nucleosome positioning in particular promoter classes was revealed. Conclusion We present lists of promoters that potentially utilize the aforementioned elements/combinations. The number of these promoters is two orders of magnitude larger than the number of promoters in which transcription initiation was experimentally studied. The sequences are ready to be experimentally tested or used for further statistical analysis. The developed approach may be utilized for other species.

  15. Genetics of aplasia cutis reveal novel regulators of skin morphogenesis.

    Science.gov (United States)

    Marneros, Alexander G

    2015-03-01

    The molecular mechanisms that control skin morphogenesis are complex and only incompletely understood. Aplasia cutis manifests with localized skin defects at birth and is a feature in various syndromes. Identifying the genes that cause these genetic skin conditions provides the opportunity to define novel regulators of skin morphogenesis. Recently, human genetic approaches have led to the identification of aplasia cutis-causing mutations in genes that have previously not been implicated to have an important role in skin biology. These findings reveal novel molecular mechanisms that are involved in skin formation during development.

  16. Dr. Oscar Costa Mandry: a life in the tropics revealed.

    Science.gov (United States)

    Christenson, Bernard

    2007-01-01

    Dr. Oscar Costa-Mandry, "The Father of Medical Technology in Puerto Rico"; his lifetime achievements in the tropics are revealed in the context of his influential role in the School of Tropical Medicine and his clear visionary perspective for the creation of the University of Puerto Rico School of Medicine. With his unique and diverse contributions for more than 40 years in the fields of clinical laboratory medicine, public health and medical education, and as an insightful historian, he dramatically influenced and reshaped the Puerto Rican medical and social landscape for future generations to come.

  17. Malar Bone Metastasis Revealing a Papillary Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Ihsen Slim

    2012-01-01

    Full Text Available Papillary thyroid carcinoma is the most common form of differentiated thyroid carcinoma. It is generally confined to the neck with or without spread to regional lymph nodes. Metastatic thyroid carcinomas are uncommon and mainly include lung and bone. Metastases involving oral and maxillofacial region are extremely rare. We described a case of malar metastasis revealing a follicular variant of papillary thyroid carcinoma, presenting with pain and swelling of the left cheek in a 67-years-old female patient with an unspecified histological left lobo-isthmectomy medical history. To our knowledge, this is the first recorded instance of a malar metastasis from a follicular variant of papillary thyroid carcinoma.

  18. Contrast-enhanced ultrasonography revealed active thoracic bleeding.

    Science.gov (United States)

    Sugihara, Takaaki; Koda, Masahiko; Tokunaga, Shiho; Matono, Tomomitsu; Nagahara, Takakazu; Ueki, Masaru; Murawaki, Yoshikazu; Kaminou, Toshio

    2010-07-01

    A 61-year-old woman with a hepatocellular carcinoma located in the subphrenic region was treated by radiofrequency ablation (RFA) under artificial pleural effusion. During RFA, B-mode ultrasonography showed a swirling high echoic lesion in the artificial pleural effusion. A real-time scan performed using contrast-enhanced ultrasonography (CEUS) revealed a jet-like extravasation of contrast medium and pooling of microbubbles in the pleural cavity, which were confirmed by angiography. CEUS successfully identified the site of bleeding and can be regarded an effective tool for detecting active bleeding in an emergency.

  19. Hepatobiliary Cystadenoma Revealed by a Jaundice: A Case Report

    Directory of Open Access Journals (Sweden)

    Taoufiq Harmouch

    2011-01-01

    Full Text Available Introduction. Hepatobiliary cystadenomas are rare benign cystic tumors and have a potential for recurrence and malignant transformation. The diagnosis may be very difficult because of absence of typical imaging feature in some cases. Case Presentation. In this paper, the authors discuss a 57-year-old woman who presented a jaundice related to hepatobiliary cystadenoma. Biological and radiological examinations have led to surgery, and the diagnosis is made after a histological examination of surgical specimens. Conclusion. This observation illustrates a hepatobiliary cystadenoma revealed by jaundice. Histology examination contributed to diagnosis. The authors discussed the mechanisms of biliary obstruction and differential diagnoses through a review of the literature.

  20. Linear stability analysis reveals exclusion zone for sliding bed transport

    Directory of Open Access Journals (Sweden)

    Talmon Arnold M.

    2015-06-01

    Full Text Available A bend or any another pipe component disturbs solids transport in pipes. Longitudinal pressure profiles downstream of such a component may show a stationary transient harmonic wave, as revealed by a recent settling slurry laboratory experiment. Therefore the fundamental transient response of the two-layer model for fully stratified flow is investigated as a first approach. A linear stability analysis of the sliding bed configuration is conducted. No stationary transient harmonic waves are found in this analysis, but adaptation lengths for exponential recovery are quantified. An example calculation is given for a 0.1 m diameter pipeline.

  1. Windows PowerShell desired state configuration revealed

    CERN Document Server

    Chaganti, Ravikanth

    2014-01-01

    Desired State Configuration (DSC) is a powerful new configuration management platform that makes it easier than ever to perform cross-platform configuration management of your infrastructure, whether on-premise or in the cloud. DSC provides the management platform and Application Programming Interface (API) that can be used with any programming language. Windows PowerShell Desired State Configuration Revealed will take you through this new technology from start to finish and demonstrates the DSC interfaces through Windows PowerShell. DSC allows you to manage target devices by simply declarin

  2. Seasonal succession in zooplankton feeding traits reveals trophic trait coupling

    DEFF Research Database (Denmark)

    Kenitz, Kasia; Visser, Andre; Mariani, Patrizio

    2017-01-01

    acquisition and photosynthesis, it also depends on grazing which couples feeding and motility traits across trophic guilds. Despite interannual variations in the species dominating the protist plankton community, the seasonal trait distribution reveals robust and repeatable seasonal patterns, changing between...... succession and shows how the physical environment controls the vertical structure of plankton communities, where ambush feeders exhibit a preference for greater depths during summer. We characterize the seasonal succession as trophic trait coupling and conjecture that this coupling leads to a trophic trait...... cascade where successive trophic levels alternate in their expression of activity traits further up in the food chain...

  3. The revealed competitiveness of U.S. exports

    OpenAIRE

    J. Gruber; B. Mandel; M. Del Gatto; di Mauro, F.

    2011-01-01

    We investigate the factors behind the recent decline in the U.S. share of world merchandise exports in an attempt to determine how big a role the changing productivity of U.S. firms has played. We do so against the backdrop of a measure of cost competitiveness which, insofar it is inferred from actual trade ows, we refer to as 'revealed marginal costs' (RMC). Although, in line with our purpose, we derive such measure as an implication of a trade model with (intra-industry) firm heterogeneity,...

  4. How the ``Blues'' reveals the intimacy of music and physics

    Science.gov (United States)

    Gibson, J. Murray

    2013-03-01

    Little do most people know when they hear blues piano - and you'll hear some live in this talk - that physics permeates the style, as it does all of music. Why should you care? By deconstructing blues piano the intimacy of physics, mathematics and music will be revealed in its glory.[1] The exercise says something about how the brains of the music composer and of the listener must be intimately linked to the physical principles of acoustics. And it provides a great vehicle to explain physical phenomena to non-scientists - everything from quantum mechanics to protein structure.

  5. Social Investment for Sustainability of Groundwater: A Revealed Preference Approach

    Directory of Open Access Journals (Sweden)

    Edna Tusak Loehman

    2014-08-01

    Full Text Available Groundwater is a form of natural capital that is valued for the goods it provides, including ecosystem health, water quality, and water consumption. Degradation of groundwater could be alleviated through social investment such as for water reuse and desalination to reduce the need for withdrawals from groundwater. This paper develops a participatory planning process—based on combining revealed preference with economic optimization—to choose a desired future for sustaining groundwater. Generation of potential groundwater futures is based on an optimal control model with investment and withdrawal from groundwater as control variables. In this model, groundwater stock and aquatic health are included as inter-temporal public goods. The social discount rate expressing time preference—an important parameter that drives optimization—is revealed through the participatory planning process. To implement the chosen future, a new method of inter-temporal pricing is presented to finance investment and supply costs. Furthermore, it is shown that the desired social outcome could be achieved by a form of privatization in which the pricing method, the appropriate discount rate, and the planning period are contractually specified.

  6. Using patients' narratives to reveal gender stereotypes among medical students.

    Science.gov (United States)

    Andersson, Jenny; Salander, Pär; Hamberg, Katarina

    2013-07-01

    Gender bias exists in patient treatment, and, like most people, health care providers harbor gender stereotypes. In this study, the authors examined the gender stereotypes that medical students hold about patients. In 2005, in Umeå, Sweden, the authors collected 81 narratives written by patients who had undergone cancer treatment; all information that might reveal the patients' gender was removed from the texts. Eighty-seven medical students read 40 or 41 narratives each, guessed the patient's gender, and explained their guess. The authors analyzed the students' explanations qualitatively and quantitatively to reveal the students' gender stereotypes and to determine whether those stereotypes had any predictive value for correctly guessing a patient's gender. The students' explanations contained 21 categories of justifications, 12 of which were significantly associated with the students guessing one gender or the other. Only three categories successfully predicted a correct identification of gender; two categories were more often associated with incorrect guesses. Medical students enter their training program with culturally shared stereotypes about male and female patients that could cause bias during their future careers as physicians. To prevent this, medical curricula must address gender stereotypes and their possible consequences. The impact of implicit stereotypes must be included in discussions about gender bias in health care.

  7. Ananke: temporal clustering reveals ecological dynamics of microbial communities

    Directory of Open Access Journals (Sweden)

    Michael W. Hall

    2017-09-01

    Full Text Available Taxonomic markers such as the 16S ribosomal RNA gene are widely used in microbial community analysis. A common first step in marker-gene analysis is grouping genes into clusters to reduce data sets to a more manageable size and potentially mitigate the effects of sequencing error. Instead of clustering based on sequence identity, marker-gene data sets collected over time can be clustered based on temporal correlation to reveal ecologically meaningful associations. We present Ananke, a free and open-source algorithm and software package that complements existing sequence-identity-based clustering approaches by clustering marker-gene data based on time-series profiles and provides interactive visualization of clusters, including highlighting of internal OTU inconsistencies. Ananke is able to cluster distinct temporal patterns from simulations of multiple ecological patterns, such as periodic seasonal dynamics and organism appearances/disappearances. We apply our algorithm to two longitudinal marker gene data sets: faecal communities from the human gut of an individual sampled over one year, and communities from a freshwater lake sampled over eleven years. Within the gut, the segregation of the bacterial community around a food-poisoning event was immediately clear. In the freshwater lake, we found that high sequence identity between marker genes does not guarantee similar temporal dynamics, and Ananke time-series clusters revealed patterns obscured by clustering based on sequence identity or taxonomy. Ananke is free and open-source software available at https://github.com/beiko-lab/ananke.

  8. [Apparent worsening of psoriasis lesions revealing methotrexate overdosage].

    Science.gov (United States)

    Haber, R; Baroudjian, B; Battistella, M; Bagot, M; Petit, A

    2017-09-13

    Methotrexate (MTX) is an antimetabolite drug used in the treatment of cancers and autoimmune diseases and frequently in dermatology for cutaneous and/or arthritic psoriasis. Toxicities due to MTX overdosage are mainly cutaneous, hepatic and hematologic. Herein, we report a case of MTX overdosage presenting as an erosive and an inflammatory flare of preexisting psoriatic plaques and with new palmar lesions. A 51-year-old male with a 6-year history of plaque psoriasis resistant to topical corticosteroids was started for the first time on MTX 20mg weekly. One week later, he presented with fever, general weakness and mucocutaneous ulcerations. Physical examination revealed inflammatory, erythematous and partially erosive annular plaques strictly confined to preexisting psoriatic lesions, along with keratotic psoriatic palmar plaques. Further questioning indicated that the patient was taking MTX 20mg daily. Investigations revealed neutropenia (1040/mm3) and skin histology showed prominent dystrophic keratinocytes and confirmed the diagnosis of methotrexate toxicity. Clinical and biological improvements were observed after cessation of MTX and treatment with folinic acid, IV hydration and urine alkalization. Skin lesions due to acute MTX toxicity are rare, but they herald later-onset pancytopenia. Identification of these cutaneous lesions might enable earlier treatment initiation. The predilection of MTX toxicity for preexisting lesions or the de novo appearance of palmoplantar pustules should not lead to the erroneous diagnosis of psoriasis flare. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. Elastic network normal mode dynamics reveal the GPCR activation mechanism.

    Science.gov (United States)

    Kolan, Dikla; Fonar, Gennadiy; Samson, Abraham O

    2014-04-01

    G-protein-coupled receptors (GPCR) are a family of membrane-embedded metabotropic receptors which translate extracellular ligand binding into an intracellular response. Here, we calculate the motion of several GPCR family members such as the M2 and M3 muscarinic acetylcholine receptors, the A2A adenosine receptor, the β2 -adrenergic receptor, and the CXCR4 chemokine receptor using elastic network normal modes. The normal modes reveal a dilation and a contraction of the GPCR vestibule associated with ligand passage, and activation, respectively. Contraction of the vestibule on the extracellular side is correlated with cavity formation of the G-protein binding pocket on the intracellular side, which initiates intracellular signaling. Interestingly, the normal modes of rhodopsin do not correlate well with the motion of other GPCR family members. Electrostatic potential calculation of the GPCRs reveal a negatively charged field around the ligand binding site acting as a siphon to draw-in positively charged ligands on the membrane surface. Altogether, these results expose the GPCR activation mechanism and show how conformational changes on the cell surface side of the receptor are allosterically translated into structural changes on the inside. Copyright © 2013 Wiley Periodicals, Inc.

  10. Aberrant activity in degenerated retinas revealed by electrical imaging

    Directory of Open Access Journals (Sweden)

    Günther eZeck

    2016-02-01

    Full Text Available In this review I present and discuss the current understanding of aberrant electrical activity found in the ganglion cell layer (GCL of rod-degenerated (rd mouse retinas. The reported electrophysiological properties revealed by electrical imaging using high-density microelectrode arrays can be subdivided between spiking activity originating from retinal ganglion cells (RGCs and local field potentials reflecting strong trans-membrane currents within the GCL. RGCs in rod-degenerated retinas show increased and rhythmic spiking compared to age-matched wild-type retinas. Fundamental spiking frequencies range from 5 to 15 Hz in various mouse models. The rhythmic RGC spiking is driven by a presynaptic network comprising AII amacrine and bipolar cells. In the healthy retina this rhythm-generating circuit is inhibited by photoreceptor input. A unique physiological feature of rd retinas is rhythmic local field potentials (LFP manifested as spatially-restricted low-frequency (5–15 Hz voltage changes. Their spatiotemporal characterization revealed propagation and correlation with RGC spiking. LFPs rely on gap-junctional coupling and are shaped by glycinergic and by GABAergic transmission. The aberrant RGC spiking and LFPs provide a simple readout of the functionality of the remaining retinal circuitry which can be used in the development of improved vision restoration strategies.

  11. Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

    Science.gov (United States)

    Shaffer, John R; Li, Jinxi; Lee, Myoung Keun; Roosenboom, Jasmien; Orlova, Ekaterina; Adhikari, Kaustabh; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; González-José, Rolando; Pfeffer, Paige E; Wollenschlaeger, Christopher A; Hecht, Jacqueline T; Wehby, George L; Moreno, Lina M; Ding, Anan; Jin, Li; Yang, Yajun; Carlson, Jenna C; Leslie, Elizabeth J; Feingold, Eleanor; Marazita, Mary L; Hinds, David A; Cox, Timothy C; Wang, Sijia; Ruiz-Linares, Andrés; Weinberg, Seth M

    2017-12-07

    The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. King Lear Reveals the Tragic Pattern of Shakespeare

    Directory of Open Access Journals (Sweden)

    Salim Eflih Al-Ibia

    2017-04-01

    Full Text Available Rather than focusing on the obvious traditions of evaluating Shakespearean tragic heroes, this paper presents a groundbreaking approach to unfold the pattern William Shakespeare follows as he designed his unique characters. This pattern applies to most, if not all, Shakespearean tragic heroes. I argue that Shakespeare himself reveals a great portion of this pattern on the tongue of Lear as the latter disowns Goneril and Regan promising to have “such revenges on [them] both” in King Lear. Lear’s threats bestow four unique aspects that apply not only to his character but they also apply to Shakespearean tragic heroes. Lear’s speech tells us that he is determined to have an awful type of revenge on his daughters. However, the very same speech tells us that he seems uncertain about the method through which he should carry out this revenge. Lear does not express any type of remorse as he pursues his vengeful plans nor should he aim at amnesty. He also admits his own madness as he closes his revealing speech. This research develops these facts about Lear to unfold the unique pattern Shakespeare follows as he portrayed his major tragic figures. This pattern is examined, described and analyzed in King Lear, Othello, and Hamlet. We will find out that the pattern suggested in this study helps us better understand Shakespeare’s tragedies and enables us to provide better explanations for some controversial scenes in the tragedies discussed.

  13. Membrane Protein Properties Revealed through Data-Rich Electrostatics Calculations.

    Science.gov (United States)

    Marcoline, Frank V; Bethel, Neville; Guerriero, Christopher J; Brodsky, Jeffrey L; Grabe, Michael

    2015-08-04

    The electrostatic properties of membrane proteins often reveal many of their key biophysical characteristics, such as ion channel selectivity and the stability of charged membrane-spanning segments. The Poisson-Boltzmann (PB) equation is the gold standard for calculating protein electrostatics, and the software APBSmem enables the solution of the PB equation in the presence of a membrane. Here, we describe significant advances to APBSmem, including full automation of system setup, per-residue energy decomposition, incorporation of PDB2PQR, calculation of membrane-induced pKa shifts, calculation of non-polar energies, and command-line scripting for large-scale calculations. We highlight these new features with calculations carried out on a number of membrane proteins, including the recently solved structure of the ion channel TRPV1 and a large survey of 1,614 membrane proteins of known structure. This survey provides a comprehensive list of residues with large electrostatic penalties for being embedded in the membrane, potentially revealing interesting functional information. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Economic choices reveal probability distortion in macaque monkeys.

    Science.gov (United States)

    Stauffer, William R; Lak, Armin; Bossaerts, Peter; Schultz, Wolfram

    2015-02-18

    Economic choices are largely determined by two principal elements, reward value (utility) and probability. Although nonlinear utility functions have been acknowledged for centuries, nonlinear probability weighting (probability distortion) was only recently recognized as a ubiquitous aspect of real-world choice behavior. Even when outcome probabilities are known and acknowledged, human decision makers often overweight low probability outcomes and underweight high probability outcomes. Whereas recent studies measured utility functions and their corresponding neural correlates in monkeys, it is not known whether monkeys distort probability in a manner similar to humans. Therefore, we investigated economic choices in macaque monkeys for evidence of probability distortion. We trained two monkeys to predict reward from probabilistic gambles with constant outcome values (0.5 ml or nothing). The probability of winning was conveyed using explicit visual cues (sector stimuli). Choices between the gambles revealed that the monkeys used the explicit probability information to make meaningful decisions. Using these cues, we measured probability distortion from choices between the gambles and safe rewards. Parametric modeling of the choices revealed classic probability weighting functions with inverted-S shape. Therefore, the animals overweighted low probability rewards and underweighted high probability rewards. Empirical investigation of the behavior verified that the choices were best explained by a combination of nonlinear value and nonlinear probability distortion. Together, these results suggest that probability distortion may reflect evolutionarily preserved neuronal processing. Copyright © 2015 Stauffer et al.

  15. The new galaxy evolution paradigm revealed by the Herschel surveys

    Science.gov (United States)

    Eales, Stephen; Smith, Dan; Bourne, Nathan; Loveday, Jon; Rowlands, Kate; van der Werf, Paul; Driver, Simon; Dunne, Loretta; Dye, Simon; Furlanetto, Cristina; Ivison, R. J.; Maddox, Steve; Robotham, Aaron; Smith, Matthew W. L.; Taylor, Edward N.; Valiante, Elisabetta; Wright, Angus; Cigan, Philip; De Zotti, Gianfranco; Jarvis, Matt J.; Marchetti, Lucia; Michałowski, Michał J.; Phillipps, Steven; Viaene, Sebastien; Vlahakis, Catherine

    2018-01-01

    The Herschel Space Observatory has revealed a very different galaxyscape from that shown by optical surveys which presents a challenge for galaxy-evolution models. The Herschel surveys reveal (1) that there was rapid galaxy evolution in the very recent past and (2) that galaxies lie on a single Galaxy Sequence (GS) rather than a star-forming 'main sequence' and a separate region of 'passive' or 'red-and-dead' galaxies. The form of the GS is now clearer because far-infrared surveys such as the Herschel ATLAS pick up a population of optically red star-forming galaxies that would have been classified as passive using most optical criteria. The space-density of this population is at least as high as the traditional star-forming population. By stacking spectra of H-ATLAS galaxies over the redshift range 0.001 < z < 0.4, we show that the galaxies responsible for the rapid low-redshift evolution have high stellar masses, high star-formation rates but, even several billion years in the past, old stellar populations - they are thus likely to be relatively recent ancestors of early-type galaxies in the Universe today. The form of the GS is inconsistent with rapid quenching models and neither the analytic bathtub model nor the hydrodynamical EAGLE simulation can reproduce the rapid cosmic evolution. We propose a new gentler model of galaxy evolution that can explain the new Herschel results and other key properties of the galaxy population.

  16. Gaussian graphical modeling reveals specific lipid correlations in glioblastoma cells

    Science.gov (United States)

    Mueller, Nikola S.; Krumsiek, Jan; Theis, Fabian J.; Böhm, Christian; Meyer-Bäse, Anke

    2011-06-01

    Advances in high-throughput measurements of biological specimens necessitate the development of biologically driven computational techniques. To understand the molecular level of many human diseases, such as cancer, lipid quantifications have been shown to offer an excellent opportunity to reveal disease-specific regulations. The data analysis of the cell lipidome, however, remains a challenging task and cannot be accomplished solely based on intuitive reasoning. We have developed a method to identify a lipid correlation network which is entirely disease-specific. A powerful method to correlate experimentally measured lipid levels across the various samples is a Gaussian Graphical Model (GGM), which is based on partial correlation coefficients. In contrast to regular Pearson correlations, partial correlations aim to identify only direct correlations while eliminating indirect associations. Conventional GGM calculations on the entire dataset can, however, not provide information on whether a correlation is truly disease-specific with respect to the disease samples and not a correlation of control samples. Thus, we implemented a novel differential GGM approach unraveling only the disease-specific correlations, and applied it to the lipidome of immortal Glioblastoma tumor cells. A large set of lipid species were measured by mass spectrometry in order to evaluate lipid remodeling as a result to a combination of perturbation of cells inducing programmed cell death, while the other perturbations served solely as biological controls. With the differential GGM, we were able to reveal Glioblastoma-specific lipid correlations to advance biomedical research on novel gene therapies.

  17. Drastic changes in Pluto atmosphere revealed by stellar occultations

    Science.gov (United States)

    Sicardy, B.; Widemann, T.; Lellouch, T.; Colas, F.; Roques, F.; Veillet, C.; Cuillandre, J.-C.

    Pluto's tenuous nitrogen atmosphere was first detected by stellar occultations from Israel in 1985, and more extensively studied during a second event from Australia in June 1988. This atmosphere is poorly known, however, due to the rarity of these events. We report here the first Pluto occultation observations in 2002 (July 20 and august 21), after a lapse of fourteen years. The July data were gathered from northern Chile with a portable telescope, in the frame of a large campaign in South America, while the August event was observed from Hawaii (CFHT). Results of our analysis reveal drastic changes undergone by the atmosphere since 1988, namely a two-fold pressure increase, revealing the effect of seasonal changes on Pluto over this fourteen year interval. This provides insights into surface-atmosphere interactions and temporal variability on distant icy bodies of the solar system. Spikes observed in the CFHT lightcurve betrays the presence of a dynamical activity, either associated with shear instabilities caused by strong winds, or with a hypothetical troposphere near the surface of the planet.

  18. Blue whale earplug reveals lifetime contaminant exposure and hormone profiles

    Science.gov (United States)

    Trumble, Stephen J.; Robinson, Eleanor M.; Berman-Kowalewski, Michelle; Potter, Charles W.; Usenko, Sascha

    2013-01-01

    Lifetime contaminant and hormonal profiles have been reconstructed for an individual male blue whale (Balaenoptera musculus, Linnaeus 1758) using the earplug as a natural aging matrix that is also capable of archiving and preserving lipophilic compounds. These unprecedented lifetime profiles (i.e., birth to death) were reconstructed with a 6-mo resolution for a wide range of analytes including cortisol (stress hormone), testosterone (developmental hormone), organic contaminants (e.g., pesticides and flame retardants), and mercury. Cortisol lifetime profiles revealed a doubling of cortisol levels over baseline. Testosterone profiles suggest this male blue whale reached sexual maturity at approximately 10 y of age, which corresponds well with and improves on previous estimates. Early periods of the reconstructed contaminant profiles for pesticides (such as dichlorodiphenyltrichloroethanes and chlordanes), polychlorinated biphenyls, and polybrominated diphenyl ethers demonstrate significant maternal transfer occurred at 0–12 mo. The total lifetime organic contaminant burden measured between the earplug (sum of contaminants in laminae layers) and blubber samples from the same organism were similar. Total mercury profiles revealed reduced maternal transfer and two distinct pulse events compared with organic contaminants. The use of a whale earplug to reconstruct lifetime chemical profiles will allow for a more comprehensive examination of stress, development, and contaminant exposure, as well as improve the assessment of contaminant use/emission, environmental noise, ship traffic, and climate change on these important marine sentinels. PMID:24043814

  19. The microbiome of Brazilian mangrove sediments as revealed by metagenomics.

    Directory of Open Access Journals (Sweden)

    Fernando Dini Andreote

    Full Text Available Here we embark in a deep metagenomic survey that revealed the taxonomic and potential metabolic pathways aspects of mangrove sediment microbiology. The extraction of DNA from sediment samples and the direct application of pyrosequencing resulted in approximately 215 Mb of data from four distinct mangrove areas (BrMgv01 to 04 in Brazil. The taxonomic approaches applied revealed the dominance of Deltaproteobacteria and Gammaproteobacteria in the samples. Paired statistical analysis showed higher proportions of specific taxonomic groups in each dataset. The metabolic reconstruction indicated the possible occurrence of processes modulated by the prevailing conditions found in mangrove sediments. In terms of carbon cycling, the sequences indicated the prevalence of genes involved in the metabolism of methane, formaldehyde, and carbon dioxide. With respect to the nitrogen cycle, evidence for sequences associated with dissimilatory reduction of nitrate, nitrogen immobilization, and denitrification was detected. Sequences related to the production of adenylsulfate, sulfite, and H(2S were relevant to the sulphur cycle. These data indicate that the microbial core involved in methane, nitrogen, and sulphur metabolism consists mainly of Burkholderiaceae, Planctomycetaceae, Rhodobacteraceae, and Desulfobacteraceae. Comparison of our data to datasets from soil and sea samples resulted in the allotment of the mangrove sediments between those samples. The results of this study add valuable data about the composition of microbial communities in mangroves and also shed light on possible transformations promoted by microbial organisms in mangrove sediments.

  20. Molecular conformation changes along the malignancy revealed by optical nanosensors

    Science.gov (United States)

    Cinta Pinzaru, Simona; Falamas, Alexandra; Dehelean, Cristina Adriana

    2013-01-01

    An interdisciplinary approach employing functionalized nanoparticles and ultrasensitive spectroscopic techniques is reported here to track the molecular changes in early stage of malignancy. Melanoma tissue tracking at molecular level using both labelled and unlabelled silver and gold nanoparticles has been achieved using surface enhanced Raman scattering (SERS) technique. We used skin tissue from ex vivo mice with induced melanoma. Raman and SERS molecular characterization of melanoma tissue is proposed here for the first time. Optical nanosensors based on Ag and Au nanoparticles with chemisorbed cresyl violet molecular species as labels revealed sensitive capability to tissues tagging and local molecular characterization. Sensitive information originating from surrounding native biological molecules is provided by the tissue SERS spectra obtained either with visible or NIR laser line. Labelled nanoparticles introduced systematic differences in tissue response compared with unlabelled ones, suggesting that the label functional groups tag specific tissue components revealed by proteins or nucleic acids bands. Vibrational data collected from tissue are presented in conjunction with the immunohistochemical analysis. The results obtained here open perspectives in applied plasmonic nanoparticles and SERS for the early cancer diagnostic based on the appropriate spectral databank. PMID:23301881

  1. A systems biology approach reveals common metastatic pathways in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Flores Ricardo J

    2012-05-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models. Results mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a “shortest-path” algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including “Cytoskeleton remodeling/TGF/WNT”, “Cytoskeleton remodeling/Cytoskeleton remodeling”, and “Cell adhesion/Chemokines and adhesion”. Of these, the “Cytoskeleton remodeling/TGF/WNT” was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the “Cytoskeleton remodeling/TGF/WNT” pathway in the Sa

  2. A Survey of Electronic Serials Managers Reveals Diversity in Practice

    Directory of Open Access Journals (Sweden)

    Laura Costello

    2014-09-01

    Full Text Available A Review of: Branscome, B. A. (2013. Management of electronic serials in academic libraries: The results of an online survey. Serials Review, 39(4, 216-226. http://dx.doi.org/10.1016/j.serrev.2013.10.004 Abstract Objective – To examine industry standards for the management of electronic serials and measure the adoption of electronic serials over print. Design – Survey questionnaire. Setting – Email lists aimed at academic librarians working in serials management. Subjects – 195 self-selected subscribers to serials email lists. Methods – The author created a 20 question survey that consisted primarily of closed-ended questions pertaining to the collection demographics, staff, budget, and tools of serials management groups in academic libraries. The survey was conducted via Survey Monkey and examined using the analytical features of the tool. Participants remained anonymous and the survey questions did not ask them to reveal identifiable information about their libraries. Main Results – Collection demographics questions revealed that 78% of surveyed librarians estimated that print-only collections represented 40% or fewer of their serials holdings. The author observed diversity in the factors that influence print to digital transitions in academic libraries. However 71.5% of participants indicated that publisher technology support like IP authentication was required before adopting digital subscriptions. A lack of standardization also marked serials workflows, department responsibilities, and department titles. The author did not find a correlation between serials budget and the enrollment size of the institution. Participants reported that they used tools from popular serials management vendors like Serials Solutions, Innovative Interfaces, EBSCO, and Ex Libris, but most indicated that they used more than one tool for serials management. Participants specified 52 unique serials management products used in their libraries. Conclusion

  3. An Addison disease revealed with a serious hyponatremia.

    Science.gov (United States)

    Maguet, Hadrien; Carreau, Agnès; Hautefeuille, Serge; Bonnin, Pierre; Beaune, Gaspard

    2017-02-01

    We present the case of an Addison's disease revealed by a serious hyponatremia. The serum concentration of ACTH and 21-hydroxylase antibodies were increased and lead to the diagnosis. The cortisol blood level was lowered but required to take into account the stress induced by the hospitalisation of the patient. Addison's disease is characterized by the destruction of the adrenal cortex. Autoimmune adrenalitis is the main cause of adrenal insufficiency. Treatment involves normalisation of sodium concentration and corticosteroids replacement. With a good patient compliance, the survival rate of Addisonian patient is similar to that of the normal population. Management of patient requires vigilance because of the occurrence of others autoimmunes diseases during patient life.

  4. Deciphering CAPTCHAs: what a Turing test reveals about human cognition.

    Directory of Open Access Journals (Sweden)

    Thomas Hannagan

    Full Text Available Turning Turing's logic on its head, we used widespread letter-based Turing Tests found on the internet (CAPTCHAs to shed light on human cognition. We examined the basis of the human ability to solve CAPTCHAs, where machines fail. We asked whether this is due to our use of slow-acting inferential processes that would not be available to machines, or whether fast-acting automatic orthographic processing in humans has superior robustness to shape variations. A masked priming lexical decision experiment revealed efficient processing of CAPTCHA words in conditions that rule out the use of slow inferential processing. This shows that the human superiority in solving CAPTCHAs builds on a high degree of invariance to location and continuous transforms, which is achieved during the very early stages of visual word recognition in skilled readers.

  5. Bibliometric Analyses Reveal Patterns of Collaboration between ASMS Members

    Science.gov (United States)

    Palmblad, Magnus; van Eck, Nees Jan

    2018-01-01

    We have explored the collaborative network of the current American Society for Mass Spectrometry (ASMS) membership using bibliometric methods. The analysis shows that 4249 members are connected in a single, large, co-authorship graph, including the majority of the most published authors in the field of mass spectrometry. The map reveals topographical differences between university groups and national laboratories, and that the co-authors with the strongest links have long worked together at the same location. We have collected and summarized information on the geographical distribution of members, showing a high coverage of active researchers in North America and Western Europe. Looking at research fields, we could also identify a number of new or `hot' topics among ASMS members. Interactive versions of the maps are available on-line at https://goo.gl/UBNFMQ (collaborative network) and https://goo.gl/WV25vm (research topics).

  6. Sequencing of 50 human exomes reveals adaptation to high altitude

    DEFF Research Database (Denmark)

    Yi, Xin; Liang, Yu; Huerta-Sanchez, Emilia

    2010-01-01

    represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency......Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which...... difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus...

  7. Metabolomics reveals metabolic biomarkers of Crohn's disease

    Energy Technology Data Exchange (ETDEWEB)

    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  8. Spring-block model reveals region-like structures.

    Directory of Open Access Journals (Sweden)

    Gabriell Máté

    Full Text Available A mechanical spring-block model is used for realizing an objective space partition of settlements from a geographic territory in region-like structures. The method is based on the relaxation-dynamics of the spring-block system and reveals in a hierarchical manner region-like entities at different spatial scales. It takes into account in an elegant manner both the spatiality of the elements and the connectivity relations among them. Spatiality is taken into account by using the geographic coordinates of the settlements, and by detecting the neighbors with the help of a Delaunay triangulation. Connectivity between neighboring settlements are quantified using a Pearson-like correlation for the relative variation of a relevant socio-economic parameter (population size, GDP, tax payed per inhabitant, etc.. The method is implemented in an interactive JAVA application and it is applied with success for an artificially generated society and for the case of USA, Hungary and Transylvania.

  9. Airborne observations reveal elevational gradient in tropical forest isoprene emissions

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Dasa; Guenther, Alex B.; Shilling, John E.; Yu, Haofei; Huang, Maoyi; Zhao, Chun; Yang, Qing; Martin, Scot T.; Artaxo, Paulo; Kim, Saewung; Seco, Roger; Stavrakou, Trissevgeni; Longo, Karla M.; Tóta, Julio; de Souza, Rodrigo Augusto Ferreira; Vega, Oscar; Liu, Ying; Shrivastava, Manish; Alves, Eliane G.; Santos, Fernando C.; Leng, Guoyong; Hu, Zhiyuan

    2017-05-23

    Isoprene dominates global non-methane volatile organic compound emissions, and impacts tropospheric chemistry by influencing oxidants and aerosols. Isoprene emission rates vary over several orders of magnitude for different plants, and characterizing this immense biological chemodiversity is a challenge for estimating isoprene emission from tropical forests. Here we present the isoprene emission estimates from aircraft eddy covariance measurements over the Amazonian forest. We report isoprene emission rates that are three times higher than satellite top-down estimates and 35% higher than model predictions. The results reveal strong correlations between observed isoprene emission rates and terrain elevations, which are confirmed by similar correlations between satellite-derived isoprene emissions and terrain elevations. We propose that the elevational gradient in the Amazonian forest isoprene emission capacity is determined by plant species distributions and can substantially explain isoprene emission variability in tropical forests, and use a model to demonstrate the resulting impacts on regional air quality.

  10. Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium

    Science.gov (United States)

    Ma, Li-Jun; van der Does, H. Charlotte; Borkovich, Katherine A.; Coleman, Jeffrey J.; Daboussi, Marie-Josée; Di Pietro, Antonio; Dufresne, Marie; Freitag, Michael; Grabherr, Manfred; Henrissat, Bernard; Houterman, Petra M.; Kang, Seogchan; Shim, Won-Bo; Woloshuk, Charles; Xie, Xiaohui; Xu, Jin-Rong; Antoniw, John; Baker, Scott E.; Bluhm, Burton H.; Breakspear, Andrew; Brown, Daren W.; Butchko, Robert A. E.; Chapman, Sinead; Coulson, Richard; Coutinho, Pedro M.; Danchin, Etienne G. J.; Diener, Andrew; Gale, Liane R.; Gardiner, Donald M.; Goff, Stephen; Hammond-Kosack, Kim E.; Hilburn, Karen; Hua-Van, Aurélie; Jonkers, Wilfried; Kazan, Kemal; Kodira, Chinnappa D.; Koehrsen, Michael; Kumar, Lokesh; Lee, Yong-Hwan; Li, Liande; Manners, John M.; Miranda-Saavedra, Diego; Mukherjee, Mala; Park, Gyungsoon; Park, Jongsun; Park, Sook-Young; Proctor, Robert H.; Regev, Aviv; Ruiz-Roldan, M. Carmen; Sain, Divya; Sakthikumar, Sharadha; Sykes, Sean; Schwartz, David C.; Turgeon, B. Gillian; Wapinski, Ilan; Yoder, Olen; Young, Sarah; Zeng, Qiandong; Zhou, Shiguo; Galagan, James; Cuomo, Christina A.; Kistler, H. Corby; Rep, Martijn

    2011-01-01

    Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective. PMID:20237561

  11. Transcriptomic variation in a coral reveals pathways of clonal organisation

    DEFF Research Database (Denmark)

    K Bay, Line; Nielsen, Henrik Bjørn; Jarmer, Hanne Østergaard

    2009-01-01

    A microarray study was undertaken to examine the potential for clonal gene expression variation in a branching reef building coral, Acropora millepora. The role of small-scale gradients in light and water flow was examined by comparing gene expression levels between branch elevation (tip and base......) and position (centre and edge) of replicate coral colonies (n=3). Analyses of variance revealed that almost 60% of variation in gene expression was present between colonies and 34 genes were considered differentially expressed between colonies (minimum P=6.5 x 10(-4)). These genes are associated with energy...... of corymbose-like branching coral colonies such as A. millepora. Four genes were differentially expressed between the tip and base of branches (P=3.239 x 10(-4)) and were associated with lysosome lipase activity and fluorescence, suggesting that branch tips may encounter higher pathogen loads or levels...

  12. Physical Principles of Skeletal Minerals Revealed with Spectromicroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Gilbert, Pupa [U of Wisconsin-Madison

    2009-08-05

    Skeletal elements of marine and terrestrial organisms have the most fascinating nano-to-macro-structures, attracting the attention of physicists, biologists, chemists, and materials scientists. Using X-PEEM spectromicroscopy we revealed some of the fundamental mechanisms leading to the formation of these biominerals. Specifically, we addressed the following questions and provided the answers: 1Q) How do teeth, bones, and echinoderm and mollusk shells acquire their unusual, curved and complex morphology, if they are composed of single crystals? 1A) Via amorphous precursor phases; 2Q) How does crystallinity propagate through the amorophous precursor phases in sea urchin spicules and teeth? 2A) By secondary nucleation, following random walk patterns; 3Q) How does iridescent mother-of-pearl become ordered? 3A) Gradually, through a kinetic mechanisms in which fastest growing single-crystals win the competition for space, thus end up being approximately co-oriented.

  13. Comparative genomics reveals insights into avian genome evolution and adaptation

    Science.gov (United States)

    Zhang, Guojie; Li, Cai; Li, Qiye; Li, Bo; Larkin, Denis M.; Lee, Chul; Storz, Jay F.; Antunes, Agostinho; Greenwold, Matthew J.; Meredith, Robert W.; Ödeen, Anders; Cui, Jie; Zhou, Qi; Xu, Luohao; Pan, Hailin; Wang, Zongji; Jin, Lijun; Zhang, Pei; Hu, Haofu; Yang, Wei; Hu, Jiang; Xiao, Jin; Yang, Zhikai; Liu, Yang; Xie, Qiaolin; Yu, Hao; Lian, Jinmin; Wen, Ping; Zhang, Fang; Li, Hui; Zeng, Yongli; Xiong, Zijun; Liu, Shiping; Zhou, Long; Huang, Zhiyong; An, Na; Wang, Jie; Zheng, Qiumei; Xiong, Yingqi; Wang, Guangbiao; Wang, Bo; Wang, Jingjing; Fan, Yu; da Fonseca, Rute R.; Alfaro-Núñez, Alonzo; Schubert, Mikkel; Orlando, Ludovic; Mourier, Tobias; Howard, Jason T.; Ganapathy, Ganeshkumar; Pfenning, Andreas; Whitney, Osceola; Rivas, Miriam V.; Hara, Erina; Smith, Julia; Farré, Marta; Narayan, Jitendra; Slavov, Gancho; Romanov, Michael N; Borges, Rui; Machado, João Paulo; Khan, Imran; Springer, Mark S.; Gatesy, John; Hoffmann, Federico G.; Opazo, Juan C.; Håstad, Olle; Sawyer, Roger H.; Kim, Heebal; Kim, Kyu-Won; Kim, Hyeon Jeong; Cho, Seoae; Li, Ning; Huang, Yinhua; Bruford, Michael W.; Zhan, Xiangjiang; Dixon, Andrew; Bertelsen, Mads F.; Derryberry, Elizabeth; Warren, Wesley; Wilson, Richard K; Li, Shengbin; Ray, David A.; Green, Richard E.; O’Brien, Stephen J.; Griffin, Darren; Johnson, Warren E.; Haussler, David; Ryder, Oliver A.; Willerslev, Eske; Graves, Gary R.; Alström, Per; Fjeldså, Jon; Mindell, David P.; Edwards, Scott V.; Braun, Edward L.; Rahbek, Carsten; Burt, David W.; Houde, Peter; Zhang, Yong; Yang, Huanming; Wang, Jian; Jarvis, Erich D.; Gilbert, M. Thomas P.; Wang, Jun

    2015-01-01

    Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits. PMID:25504712

  14. Revealing Tripartite Quantum Discord with Tripartite Information Diagram

    Science.gov (United States)

    Lee, Wei-Ting; Li, Che-Ming

    2017-11-01

    A new measure based on the tripartite information diagram is proposed for identifying quantum discord in tripartite systems. The proposed measure generalizes the mutual information underlying discord from bipartite to tripartite systems, and utilizes both one-particle and two-particle projective measurements to reveal the characteristics of the tripartite quantum discord. The feasibility of the proposed measure is demonstrated by evaluating the tripartite quantum discord for systems with states close to Greenberger-Horne-Zeilinger, W, and biseparable states. In addition, the connections between tripartite quantum discord and two other quantum correlations---namely genuine tripartite entanglement and genuine tripartite Einstein-Podolsky-Rosen steering---are briefly discussed. The present study considers the case of quantum discord in tripartite systems. However, the proposed framework can be readily extended to general N-partite systems.

  15. Airborne observations reveal elevational gradient in tropical forest isoprene emissions

    Science.gov (United States)

    Gu, Dasa; Guenther, Alex B.; Shilling, John E.; Yu, Haofei; Huang, Maoyi; Zhao, Chun; Yang, Qing; Martin, Scot T.; Artaxo, Paulo; Kim, Saewung; Seco, Roger; Stavrakou, Trissevgeni; Longo, Karla M.; Tóta, Julio; de Souza, Rodrigo Augusto Ferreira; Vega, Oscar; Liu, Ying; Shrivastava, Manish; Alves, Eliane G.; Santos, Fernando C.; Leng, Guoyong; Hu, Zhiyuan

    2017-05-01

    Isoprene dominates global non-methane volatile organic compound emissions, and impacts tropospheric chemistry by influencing oxidants and aerosols. Isoprene emission rates vary over several orders of magnitude for different plants, and characterizing this immense biological chemodiversity is a challenge for estimating isoprene emission from tropical forests. Here we present the isoprene emission estimates from aircraft eddy covariance measurements over the Amazonian forest. We report isoprene emission rates that are three times higher than satellite top-down estimates and 35% higher than model predictions. The results reveal strong correlations between observed isoprene emission rates and terrain elevations, which are confirmed by similar correlations between satellite-derived isoprene emissions and terrain elevations. We propose that the elevational gradient in the Amazonian forest isoprene emission capacity is determined by plant species distributions and can substantially explain isoprene emission variability in tropical forests, and use a model to demonstrate the resulting impacts on regional air quality.

  16. Drought-Responsive Mechanisms in Plant Leaves Revealed by Proteomics.

    Science.gov (United States)

    Wang, Xiaoli; Cai, Xiaofeng; Xu, Chenxi; Wang, Quanhua; Dai, Shaojun

    2016-10-18

    Plant drought tolerance is a complex trait that requires a global view to understand its underlying mechanism. The proteomic aspects of plant drought response have been extensively investigated in model plants, crops and wood plants. In this review, we summarize recent proteomic studies on drought response in leaves to reveal the common and specialized drought-responsive mechanisms in different plants. Although drought-responsive proteins exhibit various patterns depending on plant species, genotypes and stress intensity, proteomic analyses show that dominant changes occurred in sensing and signal transduction, reactive oxygen species scavenging, osmotic regulation, gene expression, protein synthesis/turnover, cell structure modulation, as well as carbohydrate and energy metabolism. In combination with physiological and molecular results, proteomic studies in leaves have helped to discover some potential proteins and/or metabolic pathways for drought tolerance. These findings provide new clues for understanding the molecular basis of plant drought tolerance.

  17. Diffusion Tensor Tractography Reveals Disrupted Structural Connectivity during Brain Aging

    Science.gov (United States)

    Lin, Lan; Tian, Miao; Wang, Qi; Wu, Shuicai

    2017-10-01

    Brain aging is one of the most crucial biological processes that entail many physical, biological, chemical, and psychological changes, and also a major risk factor for most common neurodegenerative diseases. To improve the quality of life for the elderly, it is important to understand how the brain is changed during the normal aging process. We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 75 healthy old subjects by using graph theory metrics to describe the anatomical networks and connectivity patterns, and network-based statistic (NBS) analysis was used to identify pairs of regions with altered structural connectivity. The NBS analysis revealed a significant network comprising nine distinct fiber bundles linking 10 different brain regions showed altered white matter structures in young-old group compare with middle-aged group (p < .05, family-wise error-corrected). Our results might guide future studies and help to gain a better understanding of brain aging.

  18. Tyrannosauroid integument reveals conflicting patterns of gigantism and feather evolution.

    Science.gov (United States)

    Bell, Phil R; Campione, Nicolás E; Persons, W Scott; Currie, Philip J; Larson, Peter L; Tanke, Darren H; Bakker, Robert T

    2017-06-01

    Recent evidence for feathers in theropods has led to speculations that the largest tyrannosaurids, including Tyrannosaurus rex, were extensively feathered. We describe fossil integument from Tyrannosaurus and other tyrannosaurids (Albertosaurus, Daspletosaurus, Gorgosaurus and Tarbosaurus), confirming that these large-bodied forms possessed scaly, reptilian-like skin. Body size evolution in tyrannosauroids reveals two independent occurrences of gigantism; specifically, the large sizes in Yutyrannus and tyrannosaurids were independently derived. These new findings demonstrate that extensive feather coverings observed in some early tyrannosauroids were lost by the Albian, basal to Tyrannosauridae. This loss is unrelated to palaeoclimate but possibly tied to the evolution of gigantism, although other mechanisms exist. © 2017 The Author(s).

  19. Dramatic changes in electronic structure revealed by fractionally charged nuclei

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, Aron J. [Department of Chemistry, Lensfield Rd., University of Cambridge, Cambridge CB2 1EW (United Kingdom); Mori-Sánchez, Paula, E-mail: paula.mori@uam.es [Departamento de Química, Universidad Autónoma de Madrid, 28049 Madrid (Spain)

    2014-01-28

    Discontinuous changes in the electronic structure upon infinitesimal changes to the Hamiltonian are demonstrated. These are revealed in one and two electron molecular systems by full configuration interaction (FCI) calculations when the realm of the nuclear charge is extended to be fractional. FCI electron densities in these systems show dramatic changes in real space and illustrate the transfer, hopping, and removal of electrons. This is due to the particle nature of electrons seen in stretched systems and is a manifestation of an energy derivative discontinuity at constant number of electrons. Dramatic errors of density functional theory densities are seen in real space as this physics is missing from currently used approximations. The movements of electrons in these simple systems encapsulate those in real physical processes, from chemical reactions to electron transport and pose a great challenge for the development of new electronic structure methods.

  20. Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Nepal, Chirag; O'Rourke, Colm J; Oliveira, Douglas Vnp

    2018-01-01

    -exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients, and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, 'undetermined'). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, co...... all 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier...... genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) that influence pharmacologic response in drug repositioning protocols. This genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity...

  1. [Thoracic aortic dissection revealed by systemic cholesterol embolism].

    Science.gov (United States)

    Braem, L; Paule, P; Héno, P; Morand, J J; Mafart, B; La Folie, T; Varlet, P; Mioulet, D; Fourcade, L

    2006-10-01

    Systemic cholesterol embolism is a rare complication of atherosclerosis, and has various presentations. Arterial catheterisms are a common cause. However, the association with an aortic dissection has been exceptionally reported. We report the observation of a 70 year-old man, with coronary artery disease, hypertension, diabetes and dyslipidemia. Six months before hospitalization, a coronary angioplasty was performed due to recurrent angina. The association of purpuric lesions on the feet, with acute renal failure confirmed cholesterol embolism syndrome. Transoesophageal echocardiography showed a dissection of the descending thoracic aorta associated with complex atheroma. The evolution was marked by the pulpar necrosis of a toe and by a worsening of the renal failure, requiring definitive hemodialysis. Further echographic control highlighted the rupture of the intimal veil of the dissection. Cholesterol embolism syndrome may reveal an aortic dissection in patients without thoracic symptoms. In such cases, transoesophageal echocardiography is a useful and non-invasive examination.

  2. Structure of mega-hemocyanin reveals protein origami in snails.

    Science.gov (United States)

    Gatsogiannis, Christos; Hofnagel, Oliver; Markl, Jürgen; Raunser, Stefan

    2015-01-06

    Mega-hemocyanin is a 13.5 MDa oxygen transporter found in the hemolymph of some snails. Similar to typical gastropod hemocyanins, it is composed of 400 kDa building blocks but has additional 550 kDa subunits. Together, they form a large, completely filled cylinder. The structural basis for this highly complex protein packing is not known so far. Here, we report the electron cryomicroscopy (cryo-EM) structure of mega-hemocyanin complexes from two different snail species. The structures reveal that mega-hemocyanin is composed of flexible building blocks that differ in their conformation, but not in their primary structure. Like a protein origami, these flexible blocks are optimally packed, implementing different local symmetries and pseudosymmetries. A comparison between the two structures suggests a surprisingly simple evolutionary mechanism leading to these large oxygen transporters. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Adipsic diabetes insipidus revealing a bifocal intracranial germinoma.

    Science.gov (United States)

    Kreutz, Julie; Potorac, Iulia; Lutteri, Laurence; Gennigens, Christine; Martin, Didier; Daly, Adrian F; Bonneville, Jean-Francois; Tshibanda, Luaba; Beckers, Albert

    2017-07-01

    Adipsic diabetes insipidus is a rare complication of intracranial tumors in which impaired antidiuretic hormone secretion is associated with the loss of thirst sensation. Here, we present the case of a patient with bifocal intracranial germinoma, diagnosed due to symptoms mainly caused by adipsic diabetes insipidus. This is, to our knowledge, the first case of adipsic diabetes insipidus revealing an intracranial germinoma reported in the literature. We describe the diagnostic procedures and the three-year follow-up of this patient. Management of intracranial germ-cell tumors is made complex by the wide range of histological features. Although germinomas have a generally better prognosis than most nongerminomatous tumors, they can have severe or even life-threatening presentations. Adipsic diabetes insipidus is one such severe presentation and its rarity can make it difficult to recognize and manage. Awareness of this potential entity is therefore important for clinical practice. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Mathematical Analysis of Biomolecular Network Reveals Connections Between Diseases

    Science.gov (United States)

    Wang, Guanyu

    2012-02-01

    Connections between cancer and metabolic diseases may consist in the complex network of interactions among a common set of biomolecules. By applying singularity and bifurcation analysis, the phenotypes constrained by the AKT signaling pathway are identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties (sensitivity, robustness and adaptivity) the AKT pathway must possess in order to efficiently sense growth factors and nutrients, the region of normal responses is located. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions (cell growth, survival, proliferation and metabolism) and how their deregulation may lead to the development of diseases. The analytical expressions summarize the synergistic interactions among many molecules, which provides valuable insights into therapeutic interventions.

  5. High-frequency microrheology reveals cytoskeleton dynamics in living cells

    Science.gov (United States)

    Rigato, Annafrancesca; Miyagi, Atsushi; Scheuring, Simon; Rico, Felix

    2017-08-01

    Living cells are viscoelastic materials, dominated by an elastic response on timescales longer than a millisecond. On shorter timescales, the dynamics of individual cytoskeleton filaments are expected to emerge, but active microrheology measurements on cells accessing this regime are scarce. Here, we develop high-frequency microrheology experiments to probe the viscoelastic response of living cells from 1 Hz to 100 kHz. We report the viscoelasticity of different cell types under cytoskeletal drug treatments. On previously inaccessible short timescales, cells exhibit rich viscoelastic responses that depend on the state of the cytoskeleton. Benign and malignant cancer cells revealed remarkably different scaling laws at high frequencies, providing a unique mechanical fingerprint. Microrheology over a wide dynamic range--up to the frequency characterizing the molecular components--provides a mechanistic understanding of cell mechanics.

  6. Multicentric Castleman's Disease in a Child Revealed by Chronic Diarrhea.

    Science.gov (United States)

    Benmiloud, Sarra; Chaouki, Sana; Atmani, Samir; Hida, Moustapha

    2015-01-01

    Multicentric Castleman's disease is a rare benign and unexplained lymphoproliferative disorder that is extremely uncommon in children. It presents with fever, systemic symptoms, generalized lymphadenopathy, and laboratory markers of inflammation. Its treatment is not standardized and its prognosis is poor. We report a novel case of multicentric Castleman's disease in a 13-year-old girl who had presented with chronic diarrhea as the only initial presenting symptom. The diagnosis of celiac or inflammatory bowel diseases was suspected, but two and a half years later, the diagnosis of multicentric Castleman's disease was brought following the appearance of abdominal mass whose biopsy revealed Castleman's disease in the plasma cell form. The outcome was favorable after treatment by corticosteroid, chemotherapy, and surgery. The occurrence of diarrhea as the initial symptom of multicentric Castleman's disease without lymph node involvement is very rare. This case report underlines the diagnostic difficulties and the long interval between onset and diagnosis when diarrhea occurs first.

  7. Electron tomography reveals unbranched networks of actin filaments in lamellipodia.

    Science.gov (United States)

    Urban, Edit; Jacob, Sonja; Nemethova, Maria; Resch, Guenter P; Small, J Victor

    2010-05-01

    Eukaryotic cells can initiate movement using the forces exerted by polymerizing actin filaments to extend lamellipodial and filopodial protrusions. In the current model, actin filaments in lamellipodia are organized in a branched, dendritic network. We applied electron tomography to vitreously frozen 'live' cells, fixed cells and cytoskeletons, embedded in vitreous ice or in deep-negative stain. In lamellipodia from four cell types, including rapidly migrating fish keratocytes, we found that actin filaments are almost exclusively unbranched. The vast majority of apparent filament junctions proved to be overlapping filaments, rather than branched end-to-side junctions. Analysis of the tomograms revealed that actin filaments terminate at the membrane interface within a zone several hundred nanometres wide at the lamellipodium front, and yielded the first direct measurements of filament densities. Actin filament pairs were also identified as lamellipodium components and bundle precursors. These data provide a new structural basis for understanding actin-driven protrusion during cell migration.

  8. Offenders' crime narratives as revealed by the Narrative Roles Questionnaire.

    Science.gov (United States)

    Youngs, Donna; Canter, David V

    2013-03-01

    The study of narrative processes as part of the immediate factors that shape criminal action is limited by the lack of a methodology for differentiating the narrative themes that characterise specific crime events. The current study explores how the roles offenders see themselves as playing during an offence encapsulate their underlying crime narratives and thus provide the basis for a quantitative methodology. To test this possibility, a 33-item Narrative Roles Questionnaire (NRQ) was developed from intensive interviews with offenders about their experience of committing a recent offence. A multidimensional analysis of the NRQ completed by 71 convicted offenders revealed life narrative themes similar to those identified in fiction by Frye and with noncriminals by McAdams, labelled The Professional, Victim, Hero, and Revenger offence roles. The NRQ thus is a first step in opening up the possibility of empirical studies of the narrative aetiological perspective in criminology.

  9. Treated-skin temperature regularities revealed by IR thermography

    Science.gov (United States)

    Vainer, Boris G.

    2001-03-01

    Experimental results disclosing temperature change of human skin affected by various unnatural factors are presented in detail. Thermograms are obtained with the IR thermograph containing high performance InAs CID FPA-based photosensitive unit. Using logarithmic scale of time, evolution of skin temperature after moistening, spirit sponging, and olive oil lubrication is investigated. A comparative analysis of the resulting effects of treatments including alpha-hydroxy acid, cosmetic regenerating cream, spirit, and water, is made. Quantitative distinctions between skin regions characterized by ordinary, and depleted blood supply, including areas located directly above surface main vessels, are revealed. Strongly logarithmic time- dependence of a skin temperature is discovered when the skin is cooled down after its preliminary heating with a hot wax. Non-monotonic change of a local temperature during electrically active procedure is described. Low level light therapy equipment is also applied. A special role of the temperature of nose is discussed.

  10. [Metastatic cervical fasciitis revealing invasive lobular breast carcinoma].

    Science.gov (United States)

    Munoz, J; Garcia, C; Joujoux, J-M; Dandurand, M; Meunier, L; Stoebner, P-E

    2015-02-01

    We describe the case of a 71-year-old woman presenting cervical metastatic fasciitis with invasive lobular carcinoma (ILC) of the breast. The patient consulted for a deep and painless skin infiltration of the neck associated with dysphagia and restricted cervical mobility. Skin and muscle biopsies were normal. Muscle fascia biopsy showed a linear infiltration of metastatic cells in "single file", revealing ILC of the right breast. ILCs have a particular metastatic pattern. They can permeate through tissue planes, infiltrate solid organs and spread on serous membranes in an insidious fashion. Our case shows that ILC can metastasise into muscular fascia, causing "fasciitis-like" symptoms. Dermatologists should be aware of this particular pattern of dissemination. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  11. Experience and Interpretation: Emotion as Revealed in Narration

    Directory of Open Access Journals (Sweden)

    Annikki Kaivola-Bregenhøj

    2008-12-01

    Full Text Available I discuss in this article some key narratives of women I interviewed in Ingria 1992–1993. The narratives of those women were about dramatic stages of their lives during the World War II. The main themes of the life stories were forced transfers and deportation suffered by the Ingrian Finns. I examine with some examples how various paralinguistic devices, such as speech tempo, emotional outbursts or silence, were tied in with the verbalisation of experiences. The three factors I discuss here are woven into the narratives of the women I interviewed. The first factor is “impassioned narrating”, which shows how a narrator reveals how she is reliving the event, she told about. The second factor is weeping and we may ask how the tears affect the narrator. The third factor is silence and reticence. In retrospect I have thought about the therapeutic effect of speaking, forgetting and remaining silent.

  12. Proteomic analyses reveal divergent ubiquitylation site patterns in murinetissues

    DEFF Research Database (Denmark)

    Wagner, Sebastian A; Beli, Petra; Weinert, Brian T

    2012-01-01

    including proteasomal degradation of proteins, DNA damage repair and innateimmune responses. Here we combine high-resolution mass spectrometry with single-stepimmunoenrichment of di-glycine modified peptides for mapping of endogenous putativeubiquitylation sites in murine tissues. We identify more than 20......Posttranslational modifications of proteins increase the complexity of the cellular proteome andenable rapid regulation of protein functions in response to environmental changes. Proteinubiquitylation is a central regulatory posttranslational modification that controls numerousbiological processes......,000 unique ubiquitylation sites onproteins involved in diverse biological processes. Our data reveals that ubiquitylation regulates coresignaling pathways common for each of the studied tissues. In addition, we discover thatubiquitylation regulates tissue-specific signaling networks. Many tissue...

  13. Inheritance Patterns in Citation Networks Reveal Scientific Memes

    Directory of Open Access Journals (Sweden)

    Tobias Kuhn

    2014-11-01

    Full Text Available Memes are the cultural equivalent of genes that spread across human culture by means of imitation. What makes a meme and what distinguishes it from other forms of information, however, is still poorly understood. Our analysis of memes in the scientific literature reveals that they are governed by a surprisingly simple relationship between frequency of occurrence and the degree to which they propagate along the citation graph. We propose a simple formalization of this pattern and validate it with data from close to 50 million publication records from the Web of Science, PubMed Central, and the American Physical Society. Evaluations relying on human annotators, citation network randomizations, and comparisons with several alternative approaches confirm that our formula is accurate and effective, without a dependence on linguistic or ontological knowledge and without the application of arbitrary thresholds or filters.

  14. Inheritance Patterns in Citation Networks Reveal Scientific Memes

    Science.gov (United States)

    Kuhn, Tobias; Perc, Matjaž; Helbing, Dirk

    2014-10-01

    Memes are the cultural equivalent of genes that spread across human culture by means of imitation. What makes a meme and what distinguishes it from other forms of information, however, is still poorly understood. Our analysis of memes in the scientific literature reveals that they are governed by a surprisingly simple relationship between frequency of occurrence and the degree to which they propagate along the citation graph. We propose a simple formalization of this pattern and validate it with data from close to 50 million publication records from the Web of Science, PubMed Central, and the American Physical Society. Evaluations relying on human annotators, citation network randomizations, and comparisons with several alternative approaches confirm that our formula is accurate and effective, without a dependence on linguistic or ontological knowledge and without the application of arbitrary thresholds or filters.

  15. Bibliometric Analyses Reveal Patterns of Collaboration between ASMS Members.

    Science.gov (United States)

    Palmblad, Magnus; van Eck, Nees Jan

    2018-01-05

    We have explored the collaborative network of the current American Society for Mass Spectrometry (ASMS) membership using bibliometric methods. The analysis shows that 4249 members are connected in a single, large, co-authorship graph, including the majority of the most published authors in the field of mass spectrometry. The map reveals topographical differences between university groups and national laboratories, and that the co-authors with the strongest links have long worked together at the same location. We have collected and summarized information on the geographical distribution of members, showing a high coverage of active researchers in North America and Western Europe. Looking at research fields, we could also identify a number of new or 'hot' topics among ASMS members. Interactive versions of the maps are available on-line at https://goo.gl/UBNFMQ (collaborative network) and https://goo.gl/WV25vm (research topics). Graphical Abstract ᅟ.

  16. The genome of Tetranychus urticae reveals herbivorous pest adaptations

    Science.gov (United States)

    Grbić, Miodrag; Van Leeuwen, Thomas; Clark, Richard M.; Rombauts, Stephane; Rouzé, Pierre; Grbić, Vojislava; Osborne, Edward J.; Dermauw, Wannes; Ngoc, Phuong Cao Thi; Ortego, Félix; Hernández-Crespo, Pedro; Diaz, Isabel; Martinez, Manuel; Navajas, Maria; Sucena, Élio; Magalhães, Sara; Nagy, Lisa; Pace, Ryan M.; Djuranović, Sergej; Smagghe, Guy; Iga, Masatoshi; Christiaens, Olivier; Veenstra, Jan A.; Ewer, John; Villalobos, Rodrigo Mancilla; Hutter, Jeffrey L.; Hudson, Stephen D.; Velez, Marisela; Yi, Soojin V.; Zeng, Jia; Pires-daSilva, Andre; Roch, Fernando; Cazaux, Marc; Navarro, Marie; Zhurov, Vladimir; Acevedo, Gustavo; Bjelica, Anica; Fawcett, Jeffrey A.; Bonnet, Eric; Martens, Cindy; Baele, Guy; Wissler, Lothar; Sanchez-Rodriguez, Aminael; Tirry, Luc; Blais, Catherine; Demeestere, Kristof; Henz, Stefan R.; Gregory, T. Ryan; Mathieu, Johannes; Verdon, Lou; Farinelli, Laurent; Schmutz, Jeremy; Lindquist, Erika; Feyereisen, René; Van de Peer, Yves

    2016-01-01

    The spider mite Tetranychus urticae is a cosmopolitan agricultural pest with an extensive host plant range and an extreme record of pesticide resistance. Here we present the completely sequenced and annotated spider mite genome, representing the first complete chelicerate genome. At 90 megabases T. urticae has the smallest sequenced arthropod genome. Compared with other arthropods, the spider mite genome shows unique changes in the hormonal environment and organization of the Hox complex, and also reveals evolutionary innovation of silk production. We find strong signatures of polyphagy and detoxification in gene families associated with feeding on different hosts and in new gene families acquired by lateral gene transfer. Deep transcriptome analysis of mites feeding on different plants shows how this pest responds to a changing host environment. The T. urticae genome thus offers new insights into arthropod evolution and plant–herbivore interactions, and provides unique opportunities for developing novel plant protection strategies. PMID:22113690

  17. Probing protein flexibility reveals a mechanism for selective promiscuity.

    Science.gov (United States)

    Pabon, Nicolas A; Camacho, Carlos J

    2017-04-22

    Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anticancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets.

  18. The ecological origins of snakes as revealed by skull evolution.

    Science.gov (United States)

    Da Silva, Filipe O; Fabre, Anne-Claire; Savriama, Yoland; Ollonen, Joni; Mahlow, Kristin; Herrel, Anthony; Müller, Johannes; Di-Poï, Nicolas

    2018-01-25

    The ecological origin of snakes remains amongst the most controversial topics in evolution, with three competing hypotheses: fossorial; marine; or terrestrial. Here we use a geometric morphometric approach integrating ecological, phylogenetic, paleontological, and developmental data for building models of skull shape and size evolution and developmental rate changes in squamates. Our large-scale data reveal that whereas the most recent common ancestor of crown snakes had a small skull with a shape undeniably adapted for fossoriality, all snakes plus their sister group derive from a surface-terrestrial form with non-fossorial behavior, thus redirecting the debate toward an underexplored evolutionary scenario. Our comprehensive heterochrony analyses further indicate that snakes later evolved novel craniofacial specializations through global acceleration of skull development. These results highlight the importance of the interplay between natural selection and developmental processes in snake origin and diversification, leading first to invasion of a new habitat and then to subsequent ecological radiations.

  19. Dynamical Processes within an Anticyclonic Eddy Revealed from Argo Floats

    Science.gov (United States)

    Zhang, W. Z.; Xue, H.; Chai, F.; Ni, Q.

    2016-02-01

    Mesoscale eddies play a significant role in supplying the nutrients required for phytoplankton blooms and redistributing biomass in the ocean. However, how anticyclonic eddies influence nutrient flux and biomass distribution remains unclear and controversial. Here we reveal two important dynamical processes (radial displacement and vertical fluctuations) within an anticyclonic eddy using observations from Argo floats. Particles in the eddy were displaced toward the eddy edge due to the imbalance of radial momentum. Vertical fluctuations below the mixed layer resulted in alternating upwelling and downwelling in the inner and outer parts of the eddy. High salinity deep water was uplifted tens of meters by the upwelling and further extended to the surface with the aid of wind effects and submesoscale effects. Vertical motions associated with the fluctuations penetrated into the layer of several hundred meters deep. These processes exhibit crucial dynamical mechanisms for the motion of particles in mature anticyclonic eddies.

  20. A Network Based Methodology to Reveal Patterns in Knowledge Transfer

    Directory of Open Access Journals (Sweden)

    Orlando López-Cruz

    2015-12-01

    Full Text Available This paper motivates, presents and demonstrates in use a methodology based in complex network analysis to support research aimed at identification of sources in the process of knowledge transfer at the interorganizational level. The importance of this methodology is that it states a unified model to reveal knowledge sharing patterns and to compare results from multiple researches on data from different periods of time and different sectors of the economy. This methodology does not address the underlying statistical processes. To do this, national statistics departments (NSD provide documents and tools at their websites. But this proposal provides a guide to model information inferences gathered from data processing revealing links between sources and recipients of knowledge being transferred and that the recipient detects as main source to new knowledge creation. Some national statistics departments set as objective for these surveys the characterization of innovation dynamics in firms and to analyze the use of public support instruments. From this characterization scholars conduct different researches. Measures of dimensions of the network composed by manufacturing firms and other organizations conform the base to inquiry the structure that emerges from taking ideas from other organizations to incept innovations. These two sets of data are actors of a two- mode-network. The link between two actors (network nodes, one acting as the source of the idea. The second one acting as the destination comes from organizations or events organized by organizations that “provide” ideas to other group of firms. The resulting demonstrated design satisfies the objective of being a methodological model to identify sources in knowledge transfer of knowledge effectively used in innovation.

  1. Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions

    Directory of Open Access Journals (Sweden)

    Marin de Mas Igor

    2011-10-01

    Full Text Available Abstract Background Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution. Results The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate. The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells. Conclusions The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose

  2. Eye movement monitoring reveals differential influences of emotion on memory

    Directory of Open Access Journals (Sweden)

    Lily Riggs

    2010-11-01

    Full Text Available Research shows that memory for emotional aspects of an event may be enhanced at the cost of impaired memory for surrounding peripheral details. However, this has only been assessed directly via verbal reports which reveal the outcome of a long stream of processing but cannot shed light on how/when emotion may affect the retrieval process. In the present experiment, eye movement monitoring was used as an indirect measure of memory as it can reveal aspects of online memory processing. For example, do emotions modulate the nature of memory representations or the speed with which such memories can be accessed? Participants viewed central negative and neutral scenes surrounded by three neutral objects and after a brief delay, memory was assessed indirectly via eye movement monitoring and then directly via verbal reports. Consistent with the previous literature, emotion enhanced central and impaired peripheral memory as indexed by eye movement scanning and verbal reports. This suggests that eye movement scanning may contribute and/or is related to conscious access of memory. However, the central/peripheral tradeoff effect was not observed in an early measure of eye movement behavior, i.e. participants were faster to orient to a critical region of change in the periphery irrespective of whether it was previously studied in a negative or neutral context. These findings demonstrate emotion’s differential influences on different aspects of retrieval. In particular, emotion appears to affect the detail within, and/or the evaluation of, stored memory representations, but it may not affect the initial access to those representations.

  3. Vibrio cholerae classical biotype strains reveal distinct signatures in Mexico.

    Science.gov (United States)

    Alam, Munirul; Islam, M Tarequl; Rashed, Shah Manzur; Johura, Fatema-tuz; Bhuiyan, Nurul A; Delgado, Gabriela; Morales, Rosario; Mendez, Jose Luis; Navarro, Armando; Watanabe, Haruo; Hasan, Nur-A; Colwell, Rita R; Cravioto, Alejandro

    2012-07-01

    Vibrio cholerae O1 classical (CL) biotype caused the fifth and sixth pandemics, and probably the earlier cholera pandemics, before the El Tor (ET) biotype initiated the seventh pandemic in Asia in the 1970s by completely displacing the CL biotype. Although the CL biotype was thought to be extinct in Asia and although it had never been reported from Latin America, V. cholerae CL and ET biotypes, including a hybrid ET, were found associated with areas of cholera endemicity in Mexico between 1991 and 1997. In this study, CL biotype strains isolated from areas of cholera endemicity in Mexico between 1983 and 1997 were characterized in terms of major phenotypic and genetic traits and compared with CL biotype strains isolated in Bangladesh between 1962 and 1989. According to sero- and biotyping data, all V. cholerae strains tested had the major phenotypic and genotypic characteristics specific for the CL biotype. Antibiograms revealed the majority of the Bangladeshi strains to be resistant to trimethoprim-sulfamethoxazole, furazolidone, ampicillin, and gentamicin, while the Mexican strains were sensitive to all of these drugs, as well as to ciprofloxacin, erythromycin, and tetracycline. Pulsed-field gel electrophoresis (PFGE) of NotI-digested genomic DNA revealed characteristic banding patterns for all of the CL biotype strains although the Mexican strains differed from the Bangladeshi strains in 1 to 2 DNA bands. The difference was subtle but consistent, as confirmed by the subclustering patterns in the PFGE-based dendrogram, and can serve as a regional signature, suggesting the pre-1991 existence and evolution of the CL biotype strains in the Americas, independent from Asia.

  4. Architecture of cognitive flexibility revealed by lesion mapping

    Science.gov (United States)

    Barbey, Aron K.; Colom, Roberto; Grafman, Jordan

    2013-01-01

    Neuroscience has made remarkable progress in understanding the architecture of human intelligence, identifying a distributed network of brain structures that support goal-directed, intelligent behavior. However, the neural foundations of cognitive flexibility and adaptive aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n = 149) that investigates the neural bases of key competencies of cognitive flexibility (i.e., mental flexibility and the fluent generation of new ideas) and systematically examine their contributions to a broad spectrum of cognitive and social processes, including psychometric intelligence (Wechsler Adult Intelligence Scale), emotional intelligence (Mayer, Salovey, Caruso Emotional Intelligence Test), and personality (Neuroticism–Extraversion–Openness Personality Inventory). Latent variable modeling was applied to obtain error-free indices of each factor, followed by voxel-based lesion-symptom mapping to elucidate their neural substrates. Regression analyses revealed that latent scores for psychometric intelligence reliably predict latent scores for cognitive flexibility (adjusted R2 = 0.94). Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal, and parietal regions, including white matter association tracts, which bind these areas into an integrated system. A targeted analysis of the unique variance explained by cognitive flexibility further revealed selective damage within the right superior temporal gyrus, a region known to support insight and the recognition of novel semantic relations. The observed findings motivate an integrative framework for understanding the neural foundations of adaptive behavior, suggesting that core elements of cognitive flexibility emerge from a distributed network of brain regions that support specific competencies for human intelligence. PMID:23721727

  5. Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge.

    Science.gov (United States)

    Turner, Mandy E; White, Christine A; Hopman, Wilma M; Ward, Emilie C; Jeronimo, Paul S; Adams, Michael A; Holden, Rachel M

    2018-01-01

    Elevated serum phosphate is consistently linked with cardiovascular disease (CVD) events and mortality in the setting of normal and impaired kidney function. However, serum phosphate does not often exceed the upper limit of normal until glomerular filtration rate (GFR) falls below 30 mL/min/m2 . It was hypothesized that the response to an oral, bioavailable phosphate load will unmask impaired phosphate tolerance, a maladaptation not revealed by baseline serum phosphate concentrations. In this study, rats with varying kidney function as well as normo-phosphatemic human subjects, with inulin-measured GFR (13.2 to 128.3mL/min), received an oral phosphate load. Hormonal and urinary responses were evaluated over 2 hours. Results revealed that the more rapid elevation of serum phosphate was associated with subjects and rats with higher levels of kidney function, greater responsiveness to acute changes in parathyroid hormone (PTH), and significantly more urinary phosphate at 2 hours. In humans, increases in urinary phosphate to creatinine ratio did not correlate with baseline serum phosphate concentrations but did correlate strongly to early increase of serum phosphate. The blunted rise in serum phosphate in rats with CKD was not the result of altered absorption. This result suggests acute tissue deposition may be altered in the setting of kidney function impairment. Early recognition of impaired phosphate tolerance could translate to important interventions, such as dietary phosphate restriction or phosphate binders, being initiated at much higher levels of kidney function than is current practice. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

  6. Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions.

    Science.gov (United States)

    de Mas, Igor Marin; Selivanov, Vitaly A; Marin, Silvia; Roca, Josep; Orešič, Matej; Agius, Loranne; Cascante, Marta

    2011-10-28

    Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution. The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells. The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution

  7. [Latent-disseminated tuberculosis revealed by atypical skin ulcerations].

    Science.gov (United States)

    Ferrati-Fidelin, G; Pham-Ledard, A; Fauconneau, A; Chauvel, A; Houard, C; Doutre, M-S; Beylot-Barry, M

    2016-10-01

    Cutaneous tuberculosis (CT) is rare in industrialized countries. Given the clinicopathological polymorphism and the difficulty of isolating the pathogen, diagnosis can be difficult. The condition may be associated with other known locations of the disease or in rare cases, it may be a tell-tale sign, as in our case, in which leg ulcers revealed paucisymptomatic disseminated tuberculosis. A 67-year-old man was referred for rapidly extensive ulcers of the right leg contiguous to debilitating arthritis of the knee of unknown aetiology for 18 months. Earlier investigations revealed thymoma and a pulmonary nodule considered to be sarcoidosis. A skin biopsy showed a granulomatous eosinophilic-rich infiltrate and vasculitis of the small vessels. Screening of the skin sample and gastric aspirate for Koch Bacillus (BK) was negative. A diagnosis of sarcoidosis was made. A positive QuantiFERON test eventually led to the correct diagnosis. On further testing of bronchoalveolar fluid and a synovial biopsy, culture for Mycobacterium tuberculosis (MT) was positive. The PET scan showed high metabolism in the prostate, bone, spleen, liver, nodes and heart. The quad- and then dual-antibiotic antitubercular therapies produced a rapid improvement but treatment was continued over 12 months, given the persistence of high metabolism on PET-CT scan and the low blood rifampicin concentration. A CT should be considered in the presence of giant-cell granulomas, even in the absence of caseous necrosis, and where both direct examination and culture for the skin are negative. Our case also underlines the importance of an extensive workup to rule out disseminated disease even if the patient is not symptomatic. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Architecture of cognitive flexibility revealed by lesion mapping.

    Science.gov (United States)

    Barbey, Aron K; Colom, Roberto; Grafman, Jordan

    2013-11-15

    Neuroscience has made remarkable progress in understanding the architecture of human intelligence, identifying a distributed network of brain structures that support goal-directed, intelligent behavior. However, the neural foundations of cognitive flexibility and adaptive aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n=149) that investigates the neural bases of key competencies of cognitive flexibility (i.e., mental flexibility and the fluent generation of new ideas) and systematically examine their contributions to a broad spectrum of cognitive and social processes, including psychometric intelligence (Wechsler Adult Intelligence Scale), emotional intelligence (Mayer, Salovey, Caruso Emotional Intelligence Test), and personality (Neuroticism-Extraversion-Openness Personality Inventory). Latent variable modeling was applied to obtain error-free indices of each factor, followed by voxel-based lesion-symptom mapping to elucidate their neural substrates. Regression analyses revealed that latent scores for psychometric intelligence reliably predict latent scores for cognitive flexibility (adjusted R(2)=0.94). Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal, and parietal regions, including white matter association tracts, which bind these areas into an integrated system. A targeted analysis of the unique variance explained by cognitive flexibility further revealed selective damage within the right superior temporal gyrus, a region known to support insight and the recognition of novel semantic relations. The observed findings motivate an integrative framework for understanding the neural foundations of adaptive behavior, suggesting that core elements of cognitive flexibility emerge from a distributed network of brain regions that support specific competencies for human intelligence. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Astronomers Reveal Extinct Extra-Terrestrial Fusion Reactor

    Science.gov (United States)

    2004-06-01

    An international team of astronomers, studying the left-over remnants of stars like our own Sun, have found a remarkable object where the nuclear reactor that once powered it has only just shut down. This star, the hottest known white dwarf, H1504+65, seems to have been stripped of its entire outer regions during its death throes leaving behind the core that formed its power plant. Scientists from the United Kingdom, Germany and the USA focused two of NASA's space telescopes, the Chandra X-ray Observatory and the Far Ultraviolet Spectroscopic Explorer (FUSE), onto H1504+65 to probe its composition and measure its temperature. The data revealed that the stellar surface is extremely hot, 200,000 degrees, and is virtually free of hydrogen and helium, something never before observed in any star. Instead, the surface is composed mainly of carbon and oxygen, the 'ashes' of the fusion of helium in a nuclear reactor. An important question we must answer is why has this unique star lost the hydrogen and helium, which usually hide the stellar interior from our view? Professor Martin Barstow (University of Leicester) said. 'Studying the nature of the ashes of dead stars give us important clues as to how stars like the Sun live their lives and eventually die. The nuclear waste of carbon and oxygen produced in the process are essential elements for life and are eventually recycled into interstellar space to form new stars, planets and, possibly, living beings.' Professor Klaus Werner (University of Tübingen) said. 'We realized that this star has, on astronomical time scales, only very recently shut down nuclear fusion (about a hundred years ago). We clearly see the bare, now extinct reactor that once powered a bright giant star.' Dr Jeffrey Kruk (Johns Hopkins University) said: 'Astronomers have long predicted that many stars would have carbon-oxygen cores near the end of their lives, but I never expected we would actually be able to see one. This is a wonderful opportunity to

  10. Acoustic telemetry reveals cryptic residency of whale sharks.

    Science.gov (United States)

    Cagua, E Fernando; Cochran, Jesse E M; Rohner, Christoph A; Prebble, Clare E M; Sinclair-Taylor, Tane H; Pierce, Simon J; Berumen, Michael L

    2015-04-01

    Although whale sharks (Rhincodon typus) have been documented to move thousands of kilometres, they are most frequently observed at a few predictable seasonal aggregation sites. The absence of sharks at the surface during visual surveys has led to the assumption that sharks disperse to places unknown during the long 'off-seasons' at most of these locations. Here we compare 2 years of R. typus visual sighting records from Mafia Island in Tanzania to concurrent acoustic telemetry of tagged individuals. Sightings revealed a clear seasonal pattern with a peak between October and February and no sharks observed at other times. By contrast, acoustic telemetry demonstrated year-round residency of R. typus. The sharks use a different habitat in the off-season, swimming deeper and further away from shore, presumably in response to prey distributions. This behavioural change reduces the sharks' visibility, giving the false impression that they have left the area. We demonstrate, for the first time to our knowledge, year-round residency of unprovisioned, individual R. typus at an aggregation site, and highlight the importance of using multiple techniques to study the movement ecology of marine megafauna. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  11. Metabolomics reveals insect metabolic responses associated with fungal infection.

    Science.gov (United States)

    Xu, Yong-Jiang; Luo, Feifei; Gao, Qiang; Shang, Yanfang; Wang, Chengshu

    2015-06-01

    The interactions between insects and pathogenic fungi are complex. We employed metabolomic techniques to profile insect metabolic dynamics upon infection by the pathogenic fungus Beauveria bassiana. Silkworm larvae were infected with fungal spores and microscopic observations demonstrated that the exhaustion of insect hemocytes was coupled with fungal propagation in the insect body cavity. Metabolomic analyses revealed that fungal infection could significantly alter insect energy and nutrient metabolisms as well as the immune defense responses, including the upregulation of carbohydrates, amino acids, fatty acids, and lipids, but the downregulation of eicosanoids and amines. The insect antifeedant effect of the fungal infection was evident with the reduced level of maclurin (a component of mulberry leaves) in infected insects but elevated accumulations in control insects. Insecticidal and cytotoxic mycotoxins like oosporein and beauveriolides were also detected in insects at the later stages of infection. Taken together, the metabolomics data suggest that insect immune responses are energy-cost reactions and the strategies of nutrient deprivation, inhibition of host immune responses, and toxin production would be jointly employed by the fungus to kill insects. The data obtained in this study will facilitate future functional studies of genes and pathways associated with insect-fungus interactions.

  12. Effective connectivity reveals strategy differences in an expert calculator.

    Directory of Open Access Journals (Sweden)

    Ludovico Minati

    Full Text Available Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of "cortical hubs" supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material.

  13. Acoustic telemetry reveals cryptic residency of whale sharks

    KAUST Repository

    Cagua, Edgar F.

    2015-04-01

    Althoughwhale sharks (Rhincodon typus) have beendocumentedtomove thousands of kilometres, they are most frequently observed at a few predictable seasonal aggregation sites. The absence of sharks at the surface during visual surveys has led to the assumption that sharks disperse to places unknown during the long \\'off-seasons\\' at most of these locations. Here we compare 2 years of R. typus visual sighting records from Mafia Island in Tanzania to concurrent acoustic telemetry of tagged individuals. Sightings revealed a clear seasonal pattern with a peak between October and February and no sharks observed at other times. By contrast, acoustic telemetry demonstrated yearround residency of R. typus. The sharks use a different habitat in the offseason, swimming deeper and further away from shore, presumably in response to prey distributions. This behavioural change reduces the sharks\\' visibility, giving the false impression that they have left the area.We demonstrate, for the first timeto our knowledge, year-roundresidencyofunprovisioned, individual R. typus at an aggregation site, and highlight the importance of using multiple techniques to study the movement ecology of marine megafauna. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  14. Symbolic joint entropy reveals the coupling of various brain regions

    Science.gov (United States)

    Ma, Xiaofei; Huang, Xiaolin; Du, Sidan; Liu, Hongxing; Ning, Xinbao

    2018-01-01

    The convergence and divergence of oscillatory behavior of different brain regions are very important for the procedure of information processing. Measurements of coupling or correlation are very useful to study the difference of brain activities. In this study, EEG signals were collected from ten subjects under two conditions, i.e. eyes closed state and idle with eyes open. We propose a nonlinear algorithm, symbolic joint entropy, to compare the coupling strength among the frontal, temporal, parietal and occipital lobes and between two different states. Instead of decomposing the EEG into different frequency bands (theta, alpha, beta, gamma etc.), the novel algorithm is to investigate the coupling from the entire spectrum of brain wave activities above 4Hz. The coupling coefficients in two states with different time delay steps are compared and the group statistics are presented as well. We find that the coupling coefficient of eyes open state with delay consistently lower than that of eyes close state across the group except for one subject, whereas the results without delay are not consistent. The differences between two brain states with non-zero delay can reveal the intrinsic inter-region coupling better. We also use the well-known Hénon map data to validate the algorithm proposed in this paper. The result shows that the method is robust and has a great potential for other physiologic time series.

  15. Visual features underlying perceived brightness as revealed by classification images.

    Directory of Open Access Journals (Sweden)

    Ilmari Kurki

    Full Text Available Along with physical luminance, the perceived brightness is known to depend on the spatial structure of the stimulus. Often it is assumed that neural computation of the brightness is based on the analysis of luminance borders of the stimulus. However, this has not been tested directly. We introduce a new variant of the psychophysical reverse-correlation or classification image method to estimate and localize the physical features of the stimuli which correlate with the perceived brightness, using a brightness-matching task. We derive classification images for the illusory Craik-O'Brien-Cornsweet stimulus and a "real" uniform step stimulus. For both stimuli, classification images reveal a positive peak at the stimulus border, along with a negative peak at the background, but are flat at the center of the stimulus, suggesting that brightness is determined solely by the border information. Features in the perceptually completed area in the Craik-O'Brien-Cornsweet do not contribute to its brightness, nor could we see low-frequency boosting, which has been offered as an explanation for the illusion. Tuning of the classification image profiles changes remarkably little with stimulus size. This supports the idea that only certain spatial scales are used for computing the brightness of a surface.

  16. Spatial congruity effects reveal metaphorical thinking, not polarity correspondence

    Directory of Open Access Journals (Sweden)

    Sarah eDolscheid

    2015-11-01

    Full Text Available Spatial congruity effects have often been interpreted as evidence for metaphorical thinking, but an alternative account based on polarity correspondence (a.k.a. markedness has challenged this view. Here we compared metaphor- and polarity-correspondence-based explanations for spatial congruity effects, using musical pitch as a testbed. In one experiment, English speakers classified high- and low-frequency pitches as high and low, or as front and back, to determine whether space-pitch congruity effects could be elicited by any marked spatial continuum. Although both pairs of terms describe bipolar spatial continuums, we found congruity effects only for high/low judgments, indicating that markedness is not sufficient to produce space-pitch congruity effects. A second experiment confirmed that there were no space-pitch congruity effects for another pair of terms that have clear markedness (big/small, but which do not denote spatial height. By contrast, this experiment showed congruity effects for words that cued an appropriate vertical spatial schema (tall/short, even though these words are not used conventionally in English to describe pitches, ruling out explanations for the observed pattern of results based on verbal polysemy. Together, results suggest that space-pitch congruity effects reveal metaphorical uses of spatial schemas, not polarity correspondence effects.

  17. Spatial Congruity Effects Reveal Metaphorical Thinking, not Polarity Correspondence.

    Science.gov (United States)

    Dolscheid, Sarah; Casasanto, Daniel

    2015-01-01

    Spatial congruity effects have often been interpreted as evidence for metaphorical thinking, but an alternative account based on polarity correspondence (a.k.a. markedness) has challenged this view. Here we compared metaphor- and polarity-correspondence-based explanations for spatial congruity effects, using musical pitch as a testbed. In one experiment, English speakers classified high- and low-frequency pitches as "high" and "low," or as "front" and "back," to determine whether space-pitch congruity effects could be elicited by any marked spatial continuum. Although both pairs of terms describe bipolar spatial continuums, we found congruity effects only for high/low judgments, indicating that markedness is not sufficient to produce space-pitch congruity effects. A second experiment confirmed that there were no space-pitch congruity effects for another pair of terms that have clear markedness (big/small), but which do not denote spatial height. By contrast, this experiment showed congruity effects for words that cued an appropriate vertical spatial schema (tall/short), even though these words are not used conventionally in English to describe pitches, ruling out explanations for the observed pattern of results based on verbal polysemy. Together, results suggest that space-pitch congruity effects reveal metaphorical uses of spatial schemas, not polarity correspondence effects.

  18. Statistical universals reveal the structures and functions of human music.

    Science.gov (United States)

    Savage, Patrick E; Brown, Steven; Sakai, Emi; Currie, Thomas E

    2015-07-21

    Music has been called "the universal language of mankind." Although contemporary theories of music evolution often invoke various musical universals, the existence of such universals has been disputed for decades and has never been empirically demonstrated. Here we combine a music-classification scheme with statistical analyses, including phylogenetic comparative methods, to examine a well-sampled global set of 304 music recordings. Our analyses reveal no absolute universals but strong support for many statistical universals that are consistent across all nine geographic regions sampled. These universals include 18 musical features that are common individually as well as a network of 10 features that are commonly associated with one another. They span not only features related to pitch and rhythm that are often cited as putative universals but also rarely cited domains including performance style and social context. These cross-cultural structural regularities of human music may relate to roles in facilitating group coordination and cohesion, as exemplified by the universal tendency to sing, play percussion instruments, and dance to simple, repetitive music in groups. Our findings highlight the need for scientists studying music evolution to expand the range of musical cultures and musical features under consideration. The statistical universals we identified represent important candidates for future investigation.

  19. Pyrosequencing Reveals Fungal Communities in the Rhizosphere of Xinjiang Jujube

    Directory of Open Access Journals (Sweden)

    Peng Liu

    2015-01-01

    Full Text Available Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research.

  20. Distributed neural system for emotional intelligence revealed by lesion mapping.

    Science.gov (United States)

    Barbey, Aron K; Colom, Roberto; Grafman, Jordan

    2014-03-01

    Cognitive neuroscience has made considerable progress in understanding the neural architecture of human intelligence, identifying a broadly distributed network of frontal and parietal regions that support goal-directed, intelligent behavior. However, the contributions of this network to social and emotional aspects of intellectual function remain to be well characterized. Here we investigated the neural basis of emotional intelligence in 152 patients with focal brain injuries using voxel-based lesion-symptom mapping. Latent variable modeling was applied to obtain measures of emotional intelligence, general intelligence and personality from the Mayer, Salovey, Caruso Emotional Intelligence Test (MSCEIT), the Wechsler Adult Intelligence Scale and the Neuroticism-Extroversion-Openness Inventory, respectively. Regression analyses revealed that latent scores for measures of general intelligence and personality reliably predicted latent scores for emotional intelligence. Lesion mapping results further indicated that these convergent processes depend on a shared network of frontal, temporal and parietal brain regions. The results support an integrative framework for understanding the architecture of executive, social and emotional processes and make specific recommendations for the interpretation and application of the MSCEIT to the study of emotional intelligence in health and disease.

  1. Pyrosequencing reveals fungal communities in the rhizosphere of Xinjiang Jujube.

    Science.gov (United States)

    Liu, Peng; Wang, Xiao-Hui; Li, Jian-Gui; Qin, Wei; Xiao, Cheng-Ze; Zhao, Xu; Jiang, Hong-Xia; Sui, Jun-Kang; Sa, Rong-Bo; Wang, Wei-Yan; Liu, Xun-Li

    2015-01-01

    Fungi are important soil components as both decomposers and plant symbionts and play a major role in ecological and biogeochemical processes. However, little is known about the richness and structure of fungal communities. DNA sequencing technologies allow for the direct estimation of microbial community diversity, avoiding culture-based biases. We therefore used 454 pyrosequencing to investigate the fungal communities in the rhizosphere of Xinjiang jujube. We obtained no less than 40,488 internal transcribed spacer (ITS) rDNA reads, the number of each sample was 6943, 6647, 6584, 6550, 6860, and 6904, and we used bioinformatics and multivariate statistics to analyze the results. The index of diversity showed greater richness in the rhizosphere fungal community of a 3-year-old jujube than in that of an 8-year-old jujube. Most operational taxonomic units belonged to Ascomycota, and taxonomic analyses identified Hypocreales as the dominant fungal order. Our results demonstrated that the fungal orders are present in different proportions in different sampling areas. Redundancy analysis (RDA) revealed a significant correlation between soil properties and the abundance of fungal phyla. Our results indicated lower fungal diversity in the rhizosphere of Xinjiang jujube than that reported in other studies, and we hope our findings provide a reference for future research.

  2. Can strong correlations be experimentally revealed for Ҡ -mesons?

    Directory of Open Access Journals (Sweden)

    Hiesmayr Beatrix C.

    2014-01-01

    Full Text Available In 1964 the physicists John St. Bell working at CERN took the 1935-idea of Einstein-Podolsky-Rosen seriously and found that all theories based on local realism have to satisfy a certain inequality, nowadays dubbed Bell’s inequality. Experiments with ordinary matter systems or light show violations of Bell’s inequality favouring the quantum theory though a loophole free experiment has not yet been performed. This contribution presents an experimentally feasible Bell inequality for systems at higher energy scales, i.e. entangled neutral Ҡ -meson pairs that are typically produced in Φ -mesons decays or proton-antiproton annihilation processes. Strong requirements have to be overcome in order to achieve a conclusive tests, such a proposal was recently published. Surprisingly, this new Bell inequality reveals new features for weakly decaying particles, in particular, a strong sensitivity to the combined charge-conjugation-parity (CP symmetry. Here-with, a puzzling relation between a symmetry breaking for mesons and Bell’s inequality—which is a necessary and sufficient condition for the security of quantum cryptography protocols— is established. This becomes the more important since CP symmetry is related to the cosmological question why the antimatter disappeared after the Big Bang.

  3. Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

    Directory of Open Access Journals (Sweden)

    Yongsheng Li

    2017-10-01

    Full Text Available It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

  4. Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell.

    Science.gov (United States)

    Hoggatt, Jonathan; Singh, Pratibha; Tate, Tiffany A; Chou, Bin-Kuan; Datari, Shruti R; Fukuda, Seiji; Liu, Liqiong; Kharchenko, Peter V; Schajnovitz, Amir; Baryawno, Ninib; Mercier, Francois E; Boyer, Joseph; Gardner, Jason; Morrow, Dwight M; Scadden, David T; Pelus, Louis M

    2018-01-11

    Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Beyond Contagion: Reality Mining Reveals Complex Patterns of Social Influence.

    Science.gov (United States)

    Alshamsi, Aamena; Pianesi, Fabio; Lepri, Bruno; Pentland, Alex; Rahwan, Iyad

    2015-01-01

    Contagion, a concept from epidemiology, has long been used to characterize social influence on people's behavior and affective (emotional) states. While it has revealed many useful insights, it is not clear whether the contagion metaphor is sufficient to fully characterize the complex dynamics of psychological states in a social context. Using wearable sensors that capture daily face-to-face interaction, combined with three daily experience sampling surveys, we collected the most comprehensive data set of personality and emotion dynamics of an entire community of work. From this high-resolution data about actual (rather than self-reported) face-to-face interaction, a complex picture emerges where contagion (that can be seen as adaptation of behavioral responses to the behavior of other people) cannot fully capture the dynamics of transitory states. We found that social influence has two opposing effects on states: adaptation effects that go beyond mere contagion, and complementarity effects whereby individuals' behaviors tend to complement the behaviors of others. Surprisingly, these effects can exhibit completely different directions depending on the stable personality or emotional dispositions (stable traits) of target individuals. Our findings provide a foundation for richer models of social dynamics, and have implications on organizational engineering and workplace well-being.

  6. Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Li Jun; van der Does, H. C.; Borkovich, Katherine A.; Coleman, Jeffrey J.; Daboussi, Marie-Jose; Di Pietro, Antonio; Dufresne, Marie; Freitag, Michael; Grabherr, Manfred; Henrissat, Bernard; Houterman, Petra M.; Kang, Seogchan; Shim, Won-Bo; Wolochuk, Charles; Xie, Xiaohui; Xu, Jin Rong; Antoniw, John; Baker, Scott E.; Bluhm, Burton H.; Breakspear, Andrew; Brown, Daren W.; Butchko, Robert A.; Chapman, Sinead; Coulson, Richard; Coutinho, Pedro M.; Danchin, Etienne G.; Diener, Andrew; Gale, Liane R.; Gardiner, Donald; Goff, Steven; Hammond-Kossack, Kim; Hilburn, Karen; Hua-Van, Aurelie; Jonkers, Wilfried; Kazan, Kemal; Kodira, Chinnappa D.; Koehrsen, Michael; Kumar, Lokesh; Lee, Yong Hwan; Li, Liande; Manners, John M.; Miranda-Saavedra, Diego; Mukherjee, Mala; Park, Gyungsoon; Park, Jongsun; Park, Sook Young; Proctor, Robert H.; Regev, Aviv; Ruiz-Roldan, M. C.; Sain, Divya; Sakthikumar, Sharadha; Sykes, Sean; Schwartz, David C.; Turgeon, Barbara G.; Wapinski, Ilan; Yoder, Olen; Young, Sarah; Zeng, Qiandong; Zhou, Shiguo; Galagan, James; Cuomo, Christina A.; Kistler, H. Corby; Rep, Martijn

    2010-03-18

    Fusarium species are among the most important phytopathogenic and toxigenic fungi, having significant impact on crop production and animal health. Distinctively, members of the F. oxysporum species complex exhibit wide host range but discontinuously distributed host specificity, reflecting remarkable genetic adaptability. To understand the molecular underpinnings of diverse phenotypic traits and their evolution in Fusarium, we compared the genomes of three economically important and phylogenetically related, yet phenotypically diverse plant-pathogenic species, F. graminearum, F. verticillioides and F. oxysporum f. sp. lycopersici. Our analysis revealed greatly expanded lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes, accounting for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity. Experimentally, we demonstrate for the first time the transfer of two LS chromosomes between strains of F. oxysporum, resulting in the conversion of a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in the F. oxysporum species complex, putting the evolution of fungal pathogenicity into a new perspective.

  7. Beyond Contagion: Reality Mining Reveals Complex Patterns of Social Influence.

    Directory of Open Access Journals (Sweden)

    Aamena Alshamsi

    Full Text Available Contagion, a concept from epidemiology, has long been used to characterize social influence on people's behavior and affective (emotional states. While it has revealed many useful insights, it is not clear whether the contagion metaphor is sufficient to fully characterize the complex dynamics of psychological states in a social context. Using wearable sensors that capture daily face-to-face interaction, combined with three daily experience sampling surveys, we collected the most comprehensive data set of personality and emotion dynamics of an entire community of work. From this high-resolution data about actual (rather than self-reported face-to-face interaction, a complex picture emerges where contagion (that can be seen as adaptation of behavioral responses to the behavior of other people cannot fully capture the dynamics of transitory states. We found that social influence has two opposing effects on states: adaptation effects that go beyond mere contagion, and complementarity effects whereby individuals' behaviors tend to complement the behaviors of others. Surprisingly, these effects can exhibit completely different directions depending on the stable personality or emotional dispositions (stable traits of target individuals. Our findings provide a foundation for richer models of social dynamics, and have implications on organizational engineering and workplace well-being.

  8. Nicotinamide riboside kinase structures reveal new pathways to NAD+.

    Directory of Open Access Journals (Sweden)

    Wolfram Tempel

    2007-10-01

    Full Text Available The eukaryotic nicotinamide riboside kinase (Nrk pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+ by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.

  9. Nicotinamide riboside kinase structures reveal new pathways to NAD+.

    Science.gov (United States)

    Tempel, Wolfram; Rabeh, Wael M; Bogan, Katrina L; Belenky, Peter; Wojcik, Marzena; Seidle, Heather F; Nedyalkova, Lyudmila; Yang, Tianle; Sauve, Anthony A; Park, Hee-Won; Brenner, Charles

    2007-10-02

    The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.

  10. Molecular Mechanisms Regulating Hepcidin Revealed by Hepcidin Disorders

    Directory of Open Access Journals (Sweden)

    Clara Camaschella

    2011-01-01

    Full Text Available Iron is essential for human life, but toxic if present in excess. To avoid iron overload and maintain iron homeostasis, all cells are able to regulate their iron content through the post-transcriptional control of iron genes operated by the cytosolic iron regulatory proteins that interact with iron responsive elements on iron gene mRNA. At the systemic level, iron homeostasis is regulated by the liver peptide hepcidin. Disruption of these regulatory loops leads to genetic diseases characterized by iron deficiency (iron-refractory iron-deficiency anemia or iron overload (hemochromatosis. Alterations of the same systems are also found in acquired disorders, such as iron-loading anemias characterized by ineffective erythropoiesis and anemia of chronic diseases (ACD associated with common inflammatory conditions. In ACD, iron is present in the body, but maldistributed, being deficient for erythropoiesis, but sequestered in macrophages. Studies of the hepcidin regulation by iron and inflammatory cytokines are revealing new pathways that might become targets of new therapeutic intervention in iron disorders.

  11. Individual olfactory perception reveals meaningful nonolfactory genetic information.

    Science.gov (United States)

    Secundo, Lavi; Snitz, Kobi; Weissler, Kineret; Pinchover, Liron; Shoenfeld, Yehuda; Loewenthal, Ron; Agmon-Levin, Nancy; Frumin, Idan; Bar-Zvi, Dana; Shushan, Sagit; Sobel, Noam

    2015-07-14

    Each person expresses a potentially unique subset of ∼ 400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the "olfactory fingerprint." Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10(-4)), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10(-6)). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information.