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Sample records for presynaptic sensory neuron

  1. Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals.

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    Diego J Rodriguez-Gil

    Full Text Available Olfactory sensory neurons (OSNs project their axons from the olfactory epithelium toward the olfactory bulb (OB in a heterogeneous and unsorted arrangement. However, as the axons approach the glomerular layer of the OB, axons from OSNs expressing the same odorant receptor (OR sort and converge to form molecularly homogeneous glomeruli. Axon guidance cues, cell adhesion molecules, and OR induced activity have been implicated in the final targeting of OSN axons to specific glomeruli. Less understood, and often controversial, are the mechanisms used by OSN axons to initially navigate from the OE toward the OB. We previously demonstrated a role for Wnt and Frizzled (Fz molecules in OSN axon extension and organization within the olfactory nerve. Building on that we now turned our attention to the downstream signaling cascades from Wnt-Fz interactions. Dishevelled (Dvl is a key molecule downstream of Fz receptors. Three isoforms of Dvl with specific as well as overlapping functions are found in mammals. Here, we show that Dvl-1 expression is restricted to OSNs in the dorsal recess of the nasal cavity, and labels a unique subpopulation of glomeruli. Dvl-2 and Dvl-3 have a widespread distribution in both the OE and OB. Both Dvl-1 and Dvl-2 are associated with intra-glomerular pre-synaptic OSN terminals, suggesting a role in synapse formation/stabilization. Moreover, because Dvl proteins were observed in all OSN axons, we hypothesize that they are important determinants of OSN cell differentiation and axon extension.

  2. Shaping Neuronal Network Activity by Presynaptic Mechanisms.

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    Ayal Lavi

    2015-09-01

    Full Text Available Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level.

  3. Sensory transduction channel subunits, tax-4 and tax-2, modify presynaptic molecular architecture in C. elegans.

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    Hellman, Andrew B; Shen, Kang

    2011-01-01

    During development, neural activity is important for forming proper connections in neural networks. The effect of activity on the gross morphology and synaptic strength of neurons has been well documented, but little is known about how activity affects different molecular components during development. Here, we examine the localization of four fluorescently-tagged presynaptic proteins, RAB-3, SNG-1/synaptogyrin, SYD-2/Liprin-α, and SAD-1/SAD kinase, in the C. elegans thermosensory neuron AFD. We show that tax-4 and tax-2, two genes that encode the cyclic nucleotide-gated channel necessary for sensory transduction in AFD, disrupt the localization of all four proteins. In wild-type animals, the synaptic vesicle (SV) markers RAB-3 and SNG-1 and the active zone markers SYD-2 and SAD-1 localize in a stereotyped, punctate pattern in the AFD axon. In tax-4 and tax-2 mutants, SV and SYD-2 puncta are more numerous and less intense. Interestingly, SAD-1 puncta are also less intense but do not increase in number. The change in puncta number can be rescued cell-autonomously in AFD. These results suggest that sensory transduction genes tax-4 and tax-2 are necessary for the proper assembly of presynapses.

  4. Sensory transduction channel subunits, tax-4 and tax-2, modify presynaptic molecular architecture in C. elegans.

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    Andrew B Hellman

    Full Text Available During development, neural activity is important for forming proper connections in neural networks. The effect of activity on the gross morphology and synaptic strength of neurons has been well documented, but little is known about how activity affects different molecular components during development. Here, we examine the localization of four fluorescently-tagged presynaptic proteins, RAB-3, SNG-1/synaptogyrin, SYD-2/Liprin-α, and SAD-1/SAD kinase, in the C. elegans thermosensory neuron AFD. We show that tax-4 and tax-2, two genes that encode the cyclic nucleotide-gated channel necessary for sensory transduction in AFD, disrupt the localization of all four proteins. In wild-type animals, the synaptic vesicle (SV markers RAB-3 and SNG-1 and the active zone markers SYD-2 and SAD-1 localize in a stereotyped, punctate pattern in the AFD axon. In tax-4 and tax-2 mutants, SV and SYD-2 puncta are more numerous and less intense. Interestingly, SAD-1 puncta are also less intense but do not increase in number. The change in puncta number can be rescued cell-autonomously in AFD. These results suggest that sensory transduction genes tax-4 and tax-2 are necessary for the proper assembly of presynapses.

  5. Identifying local and descending inputs for primary sensory neurons.

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    Zhang, Yi; Zhao, Shengli; Rodriguez, Erica; Takatoh, Jun; Han, Bao-Xia; Zhou, Xiang; Wang, Fan

    2015-10-01

    Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived inputs for primary neurons have not been systematically identified. Using a monosynaptic rabies viruses-based transneuronal tracing method combined with sensory-specific Cre-drivers, we found that sensory neurons receive intraganglion, intraspinal, and supraspinal inputs, the latter of which are mainly derived from the rostroventral medulla (RVM). The viral-traced central neurons were largely inhibitory but also consisted of some glutamatergic neurons in the spinal cord and serotonergic neurons in the RVM. The majority of RVM-derived descending inputs were dual GABAergic and enkephalinergic (opioidergic). These inputs projected through the dorsolateral funiculus and primarily innervated layers I, II, and V of the dorsal horn, where pain-sensory afferents terminate. Silencing or activation of the dual GABA/enkephalinergic RVM neurons in adult animals substantially increased or decreased behavioral sensitivity, respectively, to heat and mechanical stimuli. These results are consistent with the fact that both GABA and enkephalin can exert presynaptic inhibition of the sensory afferents. Taken together, this work provides a systematic view of and a set of tools for examining peri- and extrasynaptic regulations of pain-afferent transmission.

  6. Kappe neurons, a novel population of olfactory sensory neurons

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    Ahuja, Gaurav; Nia, Shahrzad Bozorg; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I.

    2014-01-01

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons ar...

  7. Effects of propofol and pentobarbital on calcium concentration in presynaptic boutons on a rat hippocampal neuron.

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    Ito, Shinichi; Sugiyama, Hitomi; Kitahara, Seiko; Ikemoto, Yoshimi; Yokoyama, Takeshi

    2011-10-01

    Numerous reports suggest that intravenously administered (IV) anesthetics affect postsynaptic events in the central nervous system. However, there is little evidence about how general anesthetics influence the presynaptic processes. The level of presynaptic calcium (Ca(2+)) concentration ([Ca(2+)](pre)) regulates neurotransmitter release. In this study, we investigated the effects of anesthetic propofol IV and the barbiturate pentobarbital on neurotransmitter release by measuring [Ca(2+)](pre) in the presynaptic nerve terminals (boutons) on a dissociated single hippocampal rat neuron. Sprague-Dawley rats 10-14 days old were decapitated under pentobarbital anesthesia, and brain slices were prepared. The hippocampal CA1 area was touched with a fire-polished glass pipette, which vibrated horizontally, and neurons were dissociated, along with the attached presynaptic boutons. The presynaptic boutons were visualized under a confocal laser-scanning microscope after staining with FM1-43 dye, and [Ca(2+)](pre) was measured with acetoxymethyl ester of fluo-3 (fluo-3 AM). High potassium (K(+)) (15-90 mM) increased the [Ca(2+)](pre) in the Ca(2+)-containing solution in a concentration-dependent manner. Whereas propofol (10 μM) and pentobarbital (300 μM) suppressed the high K(+) (60 mM)-induced increase in [Ca(2+)](pre) in the boutons attached to the dendrite, they did not affect [Ca(2+)](pre) in the boutons attached to the soma or dendrite base. As a large majority of excitatory synapses are located on dendritic spines, these agents may affect Ca(2+) mobilization in the excitatory presynaptic boutons. Propofol and pentobarbital may affect neurotransmitter release from the excitatory presynaptic nerve terminals due to inhibition of increase in [Ca(2+)](pre).

  8. Axonal and presynaptic protein synthesis: new insights into the biology of the neuron.

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    Giuditta, Antonio; Kaplan, Barry B; van Minnen, Jan; Alvarez, Jaime; Koenig, Edward

    2002-08-01

    The presence of a local mRNA translation system in axons and terminals was proposed almost 40 years ago. Over the ensuing period, an impressive body of evidence has grown to support this proposal -- yet the nerve cell body is still considered to be the only source of axonal and presynaptic proteins. To dispel this lingering neglect, we now present the wealth of recent observations bearing on this central idea, and consider their impact on our understanding of the biology of the neuron. We demonstrate that extrasomatic translation sites, which are now well recognized in dendrites, are also present in axonal and presynaptic compartments.

  9. Presynaptic Glycine Receptors Increase GABAergic Neurotransmission in Rat Periaqueductal Gray Neurons

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    Kwi-Hyung Choi

    2013-01-01

    Full Text Available The periaqueductal gray (PAG is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+ channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.

  10. Protein synthesizing units in presynaptic and postsynaptic domains of squid neurons.

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    Martin, R; Vaida, B; Bleher, R; Crispino, M; Giuditta, A

    1998-11-01

    Putative protein synthesizing domains, called plaques, are characterized in the squid giant synapse and axon and in terminals of squid photoreceptor neurons. Plaques are oval-shaped formations of about 1 microm in size, which (1) generate signals that have spectroscopic electron energy loss characteristics of ribosomes, (2) exhibit ribonuclease-sensitive binding of YOYO-1, a fluorescent RNA/DNA dye, and (3) in part hybridize with a poly(dT) oligonucleotide. In the giant synapse plaques are abundant in the postsynaptic area, but are absent in the presynaptic terminal. In the cortical layer of the optic lobes, plaques are localized in the large carrot-shaped presynaptic terminals of photoreceptor neurons, where they are surrounded by synaptic vesicles and mitochondria. Biochemical and autoradiographic data have documented that the protein synthetic activity of squid optic lobe synaptosomes is largely due to the presynaptic terminals of the photoreceptor neurons. The identification of ribosomes and poly(A+)-mRNA in the plaques indicates that these structures are sites of local protein synthesis in synaptic domains.

  11. Kappe neurons, a novel population of olfactory sensory neurons.

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    Ahuja, Gaurav; Bozorg Nia, Shahrzad; Zapilko, Veronika; Shiriagin, Vladimir; Kowatschew, Daniel; Oka, Yuichiro; Korsching, Sigrun I

    2014-02-10

    Perception of olfactory stimuli is mediated by distinct populations of olfactory sensory neurons, each with a characteristic set of morphological as well as functional parameters. Beyond two large populations of ciliated and microvillous neurons, a third population, crypt neurons, has been identified in teleost and cartilaginous fishes. We report here a novel, fourth olfactory sensory neuron population in zebrafish, which we named kappe neurons for their characteristic shape. Kappe neurons are identified by their Go-like immunoreactivity, and show a distinct spatial distribution within the olfactory epithelium, similar to, but significantly different from that of crypt neurons. Furthermore, kappe neurons project to a single identified target glomerulus within the olfactory bulb, mdg5 of the mediodorsal cluster, whereas crypt neurons are known to project exclusively to the mdg2 glomerulus. Kappe neurons are negative for established markers of ciliated, microvillous and crypt neurons, but appear to have microvilli. Kappe neurons constitute the fourth type of olfactory sensory neurons reported in teleost fishes and their existence suggests that encoding of olfactory stimuli may require a higher complexity than hitherto assumed already in the peripheral olfactory system.

  12. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

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    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  13. Presynaptic Inputs to Any CNS Projection Neuron Identified by Dual Recombinant Virus Infection.

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    Bráz, João M; Wang, Fan; Basbaum, Allan I

    2015-01-01

    Although neuroanatomical tracing studies have defined the origin and targets of major projection neurons (PN) of the central nervous system (CNS), there is much less information about the circuits that influence these neurons. Recently, genetic approaches that use Cre recombinase-dependent viral vectors have greatly facilitated such circuit analysis, but these tracing approaches are limited by the availability of Cre-expressing mouse lines and the difficulty in restricting Cre expression to discrete regions of the CNS. Here, we illustrate an alternative approach to drive Cre expression specifically in defined subsets of CNS projection neurons, so as to map both direct and indirect presynaptic inputs to these cells. The method involves a combination of Cre-dependent transneuronal viral tracers that can be used in the adult and that does not require genetically modified mice. To trigger Cre-expression we inject a Cre-expressing adenovirus that is retrogradely transported to the projection neurons of interest. The region containing the retrogradely labeled projection neurons is next injected with Cre-dependent pseudorabies or rabies vectors, which results in labeling of poly- and monosynaptic neuronal inputs, respectively. In proof-of-concept experiments, we used this novel tracing system to study the circuits that engage projection neurons of the superficial dorsal horn of the spinal cord and trigeminal nucleus caudalis, neurons of the parabrachial nucleus of the dorsolateral pons that project to the amygdala and cortically-projecting neurons of the lateral geniculate nucleus. Importantly, because this dual viral tracing method does not require genetically derived Cre-expressing mouse lines, inputs to almost any projection system can be studied and the analysis can be performed in larger animals, such as the rat.

  14. Presynaptic Inputs to Any CNS Projection Neuron Identified by Dual Recombinant Virus Infection.

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    João M Bráz

    Full Text Available Although neuroanatomical tracing studies have defined the origin and targets of major projection neurons (PN of the central nervous system (CNS, there is much less information about the circuits that influence these neurons. Recently, genetic approaches that use Cre recombinase-dependent viral vectors have greatly facilitated such circuit analysis, but these tracing approaches are limited by the availability of Cre-expressing mouse lines and the difficulty in restricting Cre expression to discrete regions of the CNS. Here, we illustrate an alternative approach to drive Cre expression specifically in defined subsets of CNS projection neurons, so as to map both direct and indirect presynaptic inputs to these cells. The method involves a combination of Cre-dependent transneuronal viral tracers that can be used in the adult and that does not require genetically modified mice. To trigger Cre-expression we inject a Cre-expressing adenovirus that is retrogradely transported to the projection neurons of interest. The region containing the retrogradely labeled projection neurons is next injected with Cre-dependent pseudorabies or rabies vectors, which results in labeling of poly- and monosynaptic neuronal inputs, respectively. In proof-of-concept experiments, we used this novel tracing system to study the circuits that engage projection neurons of the superficial dorsal horn of the spinal cord and trigeminal nucleus caudalis, neurons of the parabrachial nucleus of the dorsolateral pons that project to the amygdala and cortically-projecting neurons of the lateral geniculate nucleus. Importantly, because this dual viral tracing method does not require genetically derived Cre-expressing mouse lines, inputs to almost any projection system can be studied and the analysis can be performed in larger animals, such as the rat.

  15. Deformation of attractor landscape via cholinergic presynaptic modulations: a computational study using a phase neuron model.

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    Takashi Kanamaru

    Full Text Available Corticopetal acetylcholine (ACh is released transiently from the nucleus basalis of Meynert (NBM into the cortical layers and is associated with top-down attention. Recent experimental data suggest that this release of ACh disinhibits layer 2/3 pyramidal neurons (PYRs via muscarinic presynaptic effects on inhibitory synapses. Together with other possible presynaptic cholinergic effects on excitatory synapses, this may result in dynamic and temporal modifications of synapses associated with top-down attention. However, the system-level consequences and cognitive relevance of such disinhibitions are poorly understood. Herein, we propose a theoretical possibility that such transient modifications of connectivity associated with ACh release, in addition to top-down glutamatergic input, may provide a neural mechanism for the temporal reactivation of attractors as neural correlates of memories. With baseline levels of ACh, the brain returns to quasi-attractor states, exhibiting transitive dynamics between several intrinsic internal states. This suggests that top-down attention may cause the attention-induced deformations between two types of attractor landscapes: the quasi-attractor landscape (Q-landscape, present under low-ACh, non-attentional conditions and the attractor landscape (A-landscape, present under high-ACh, top-down attentional conditions. We present a conceptual computational model based on experimental knowledge of the structure of PYRs and interneurons (INs in cortical layers 1 and 2/3 and discuss the possible physiological implications of our results.

  16. Electrical receptive fields of retinal ganglion cells: Influence of presynaptic neurons.

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    Maturana, Matias I; Apollo, Nicholas V; Garrett, David J; Kameneva, Tatiana; Cloherty, Shaun L; Grayden, David B; Burkitt, Anthony N; Ibbotson, Michael R; Meffin, Hamish

    2018-02-01

    Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON-OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell's spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one-dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear.

  17. Super-resolution microscopy reveals presynaptic localization of the ALS / FTD related protein FUS in hippocampal neurons

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    Michael eSchoen

    2016-01-01

    Full Text Available Fused in Sarcoma (FUS is a multifunctional RNA- / DNA-binding protein, which is involved in the pathogenesis of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD. A common hallmark of these disorders is the abnormal accumulation of mutated FUS protein in the cytoplasm. Under normal conditions FUS is confined to the nuclear compartment, in neurons however, additional somatodendritic localization can be observed. In this study, we carefully analyzed the subcellular localization of endogenous FUS at synaptic sites of hippocampal neurons which are among the most affected cell types in frontotemporal dementia with FUS pathology. We could confirm a strong nuclear localization of FUS as well as its prominent and widespread neuronal expression throughout the adult and developing rat brain, particularly in the hippocampus, the cerebellum and the outer layers of the cortex. Intriguingly, FUS was also consistently observed at synaptic sites as detected by neuronal subcellular fractionation as well as by immunolabeling. To define a pre- and / or postsynaptic localization of FUS, we employed super-resolution fluorescence localization microscopy. FUS was found to be localized within the axon terminal in close proximity to the presynaptic vesicle protein Synaptophysin1 and adjacent to the active zone protein Bassoon, but well separated from the postsynaptic protein PSD-95. Having shown the presynaptic localization of FUS in the nervous system, a novel extranuclear role of FUS at neuronal contact sites has to be considered. Since there is growing evidence that local presynaptic translation might also be an important mechanism for plasticity, FUS - like the fragile X mental retardation protein FMRP - might act as one of the presynaptic RNA-binding proteins regulating this machinery. Our observation of presynaptic FUS should foster further investigations to determine its role in neurodegenerative diseases such as

  18. Integration of Plasticity Mechanisms within a Single Sensory Neuron of C. elegans Actuates a Memory.

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    Hawk, Josh D; Calvo, Ana C; Liu, Ping; Almoril-Porras, Agustin; Aljobeh, Ahmad; Torruella-Suárez, María Luisa; Ren, Ivy; Cook, Nathan; Greenwood, Joel; Luo, Linjiao; Wang, Zhao-Wen; Samuel, Aravinthan D T; Colón-Ramos, Daniel A

    2018-01-17

    Neural plasticity, the ability of neurons to change their properties in response to experiences, underpins the nervous system's capacity to form memories and actuate behaviors. How different plasticity mechanisms act together in vivo and at a cellular level to transform sensory information into behavior is not well understood. We show that in Caenorhabditis elegans two plasticity mechanisms-sensory adaptation and presynaptic plasticity-act within a single cell to encode thermosensory information and actuate a temperature preference memory. Sensory adaptation adjusts the temperature range of the sensory neuron (called AFD) to optimize detection of temperature fluctuations associated with migration. Presynaptic plasticity in AFD is regulated by the conserved kinase nPKCε and transforms thermosensory information into a behavioral preference. Bypassing AFD presynaptic plasticity predictably changes learned behavioral preferences without affecting sensory responses. Our findings indicate that two distinct neuroplasticity mechanisms function together through a single-cell logic system to enact thermotactic behavior. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence.

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    Lai, N Y; Mills, K; Chiu, I M

    2017-07-01

    Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  20. Presynaptic pH and vesicle fusion in Drosophila larvae neurones.

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    Caldwell, Lesley; Harries, Peter; Sydlik, Sebastian; Schwiening, Christof J

    2013-11-01

    Both intracellular pH (pHi) and synaptic cleft pH change during neuronal activity yet little is known about how these pH shifts might affect synaptic transmission by influencing vesicle fusion. To address this we imaged pH- and Ca(2+) -sensitive fluorescent indicators (HPTS, Oregon green) in boutons at neuromuscular junctions. Electrical stimulation of motor nerves evoked presynaptic Ca(2+) i rises and pHi falls (∼0.1 pH units) followed by recovery of both Ca(2+) i and pHi. The plasma-membrane calcium ATPase (PMCA) inhibitor, 5(6)-carboxyeosin diacetate, slowed both the calcium recovery and the acidification. To investigate a possible calcium-independent role for the pHi shifts in modulating vesicle fusion we recorded post-synaptic miniature end-plate potential (mEPP) and current (mEPC) frequency in Ca(2+) -free solution. Acidification by propionate superfusion, NH(4)(+) withdrawal, or the inhibition of acid extrusion on the Na(+)/H(+) exchanger (NHE) induced a rise in miniature frequency. Furthermore, the inhibition of acid extrusion enhanced the rise induced by propionate addition and NH(4)(+) removal. In the presence of NH(4)(+), 10 out of 23 cells showed, after a delay, one or more rises in miniature frequency. These findings suggest that Ca(2+) -dependent pHi shifts, caused by the PMCA and regulated by NHE, may stimulate vesicle release. Furthermore, in the presence of membrane permeant buffers, exocytosed acid or its equivalents may enhance release through positive feedback. This hitherto neglected pH signalling, and the potential feedback role of vesicular acid, could explain some important neuronal excitability changes associated with altered pH and its buffering. Copyright © 2013 Wiley Periodicals, Inc.

  1. Postnatal maturation of GABAergic modulation of sensory inputs onto lateral amygdala principal neurons.

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    Bosch, Daniel; Ehrlich, Ingrid

    2015-10-01

    Throughout life, fear learning is indispensable for survival and neural plasticity in the lateral amygdala underlies this learning and storage of fear memories. During development, properties of fear learning continue to change into adulthood, but currently little is known about changes in amygdala circuits that enable these behavioural transitions. In recordings from neurons in lateral amygdala brain slices from infant up to adult mice, we show that spontaneous and evoked excitatory and inhibitory synaptic transmissions mature into adolescence. At this time, increased inhibitory activity and signalling has the ability to restrict the function of excitation by presynaptic modulation, and may thus enable precise stimulus associations to limit fear generalization from adolescence onward. Our results provide a basis for addressing plasticity mechanisms that underlie altered fear behaviour in young animals. Convergent evidence suggests that plasticity in the lateral amygdala (LA) participates in acquisition and storage of fear memory. Sensory inputs from thalamic and cortical areas activate principal neurons and local GABAergic interneurons, which provide feed-forward inhibition that tightly controls LA activity and plasticity via pre- and postsynaptic GABAA and GABAB receptors. GABAergic control is also critical during fear expression, generalization and extinction in adult animals. During rodent development, properties of fear and extinction learning continue to change into early adulthood. Currently, few studies have assessed physiological changes in amygdala circuits that may enable these behavioural transitions. To obtain first insights, we investigated changes in spontaneous and sensory input-evoked inhibition onto LA principal neurons and then focused on GABAB receptor-mediated modulation of excitatory sensory inputs in infant, juvenile, adolescent and young adult mice. We found that spontaneous and sensory-evoked inhibition increased during development

  2. System identification of Drosophila olfactory sensory neurons.

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    Kim, Anmo J; Lazar, Aurel A; Slutskiy, Yevgeniy B

    2011-02-01

    The lack of a deeper understanding of how olfactory sensory neurons (OSNs) encode odors has hindered the progress in understanding the olfactory signal processing in higher brain centers. Here we employ methods of system identification to investigate the encoding of time-varying odor stimuli and their representation for further processing in the spike domain by Drosophila OSNs. In order to apply system identification techniques, we built a novel low-turbulence odor delivery system that allowed us to deliver airborne stimuli in a precise and reproducible fashion. The system provides a 1% tolerance in stimulus reproducibility and an exact control of odor concentration and concentration gradient on a millisecond time scale. Using this novel setup, we recorded and analyzed the in-vivo response of OSNs to a wide range of time-varying odor waveforms. We report for the first time that across trials the response of OR59b OSNs is very precise and reproducible. Further, we empirically show that the response of an OSN depends not only on the concentration, but also on the rate of change of the odor concentration. Moreover, we demonstrate that a two-dimensional (2D) Encoding Manifold in a concentration-concentration gradient space provides a quantitative description of the neuron's response. We then use the white noise system identification methodology to construct one-dimensional (1D) and two-dimensional (2D) Linear-Nonlinear-Poisson (LNP) cascade models of the sensory neuron for a fixed mean odor concentration and fixed contrast. We show that in terms of predicting the intensity rate of the spike train, the 2D LNP model performs on par with the 1D LNP model, with a root mean-square error (RMSE) increase of about 5 to 10%. Surprisingly, we find that for a fixed contrast of the white noise odor waveforms, the nonlinear block of each of the two models changes with the mean input concentration. The shape of the nonlinearities of both the 1D and the 2D LNP model appears to be

  3. Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia

    Science.gov (United States)

    Zhou, Chunyi; Luo, Z. David

    2015-01-01

    Background Upregulation of voltage-gated-calcium-channel α2δ1 subunit post spinal nerve ligation injury (SNL) or in α2δ1-overexpressing transgenic (Tg) mice correlates with tactile allodynia, a pain state mediated mainly by Aβ sensory fibers forming synaptic connections with deep dorsal horn neurons. It is not clear however whether dysregulated α2δ1 alters deep dorsal horn synaptic neurotransmission that underlies tactile allodynia development post nerve injury. Methods Tactile allodynia was tested in the SNL and α2δ1 Tg models. Miniature excitatory/inhibitory postsynaptic currents were recorded in deep dorsal horn (DDH) neurons from these animal models using whole cell patch clamp slice recording techniques.. Results There was a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSC) in DDH neurons that correlated with tactile allodynia in SNL and α2δ1 Tg mice. Gabapentin, an α2δ1 ligand that is known to block tactile allodynia in these models, also normalized mEPSC frequency dose-dependently in DDH neurons from SNL and α2δ1 Tg mice. In contrast, neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSC) was altered in DDH neurons from SNL and α2δ1 Tg mice. Conclusion Our data suggest that α2δ1 dysregulation is highly likely contributing to tactile allodynia through a pre-synaptic mechanism involving facilitation of excitatory synaptic neurotransmission in deep dorsal horn of spinal cord. PMID:25691360

  4. Complete functional characterization of sensory neurons by system identification.

    Science.gov (United States)

    Wu, Michael C-K; David, Stephen V; Gallant, Jack L

    2006-01-01

    System identification is a growing approach to sensory neurophysiology that facilitates the development of quantitative functional models of sensory processing. This approach provides a clear set of guidelines for combining experimental data with other knowledge about sensory function to obtain a description that optimally predicts the way that neurons process sensory information. This prediction paradigm provides an objective method for evaluating and comparing computational models. In this chapter we review many of the system identification algorithms that have been used in sensory neurophysiology, and we show how they can be viewed as variants of a single statistical inference problem. We then review many of the practical issues that arise when applying these methods to neurophysiological experiments: stimulus selection, behavioral control, model visualization, and validation. Finally we discuss several problems to which system identification has been applied recently, including one important long-term goal of sensory neuroscience: developing models of sensory systems that accurately predict neuronal responses under completely natural conditions.

  5. Axonal and presynaptic protein synthesis: new insights into the biology of the neuron

    NARCIS (Netherlands)

    Giuditta, A.; Kaplan, B.B.; van Minnen, J.; Alvarez, J.; Koenig, E.

    2002-01-01

    The presence of a local mRNA translation system in axons and terminals was proposed almost 40 years ago. Over the ensuing period, an impressive body of evidence has grown to support this proposal - yet the nerve cell body is still considered to be the only source of axonal and presynaptic proteins.

  6. Protective Effects of Testosterone on Presynaptic Terminals against Oligomeric β-Amyloid Peptide in Primary Culture of Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Chi-Fai Lau

    2014-01-01

    Full Text Available Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer’s disease (AD, there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ, but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomeric Aβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD.

  7. Nuclear architecture and gene silencing in olfactory sensory neurons.

    Science.gov (United States)

    Armelin-Correa, Lucia M; Nagai, Maíra H; Leme Silva, Artur G; Malnic, Bettina

    2014-01-01

    Odorants are discriminated by hundreds of odorant receptor (OR) genes, which are dispersed throughout the mammalian genome. The OR genes are expressed in a highly specialized type of cell, the olfactory sensory neuron. Each one of these neurons expresses one of the 2 alleles from one single OR gene type. The mechanisms underlying OR gene expression are unclear. Here we describe recent work demonstrating that the olfactory sensory neuron shows a particular nuclear architecture, and that the genomic OR loci are colocalized in silencing heterochromatin compartments within the nucleus. These discoveries highlight the important role played by epigenetic modifications and nuclear genome organization in the regulation of OR gene expression.

  8. Localization of SSeCKS in unmyelinated primary sensory neurons

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    Siegel Sandra M

    2008-03-01

    Full Text Available Abstract Background SSeCKS (Src SupprEssed C Kinase Substrate is a proposed protein kinase C substrate/A kinase anchoring protein (AKAP that has recently been characterized in the rat peripheral nervous system. It has been shown that approximately 40% of small primary sensory neurons contain SSeCKS-immunoreactivity in a population largely separate from substance P (95.2%, calcitonin gene related peptide (95.3%, or fluoride resistant acid phosphatase (55.0% labeled cells. In the spinal cord, it was found that SSeCKS-immunoreactive axon collaterals terminate in the dorsal third of lamina II outer in a region similar to that of unmyelinated C-, or small diameter myelinated Aδ-, fibers. However, the precise characterization of the anatomical profile of the primary sensory neurons containing SSeCKS remains to be determined. Here, immunohistochemical labeling at the light and ultrastructural level is used to clarify the myelination status of SSeCKS-containing sensory neuron axons and to further clarify the morphometric, and provide insight into the functional, classification of SSeCKS-IR sensory neurons. Methods Colocalization studies of SSeCKS with myelination markers, ultrastructural localization of SSeCKS labeling and ablation of largely unmyelinated sensory fibers by neonatal capsaicin administration were all used to establish whether SSeCKS containing sensory neurons represent a subpopulation of unmyelinated primary sensory C-fibers. Results Double labeling studies of SSeCKS with CNPase in the dorsal horn and Pzero in the periphery showed that SSeCKS immunoreactivity was observed predominantly in association with unmyelinated primary sensory fibers. At the ultrastructural level, SSeCKS immunoreactivity was most commonly associated with axonal membrane margins of unmyelinated fibers. In capsaicin treated rats, SSeCKS immunoreactivity was essentially obliterated in the dorsal horn while in dorsal root ganglia quantitative analysis revealed a 43

  9. N-cadherin induces partial differentiation of cholinergic presynaptic terminals in heterologous cultures of brainstem neurons and CHO cells

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    Richard J Flannery

    2012-12-01

    Full Text Available N-cadherin is a calcium-sensitive cell adhesion molecule commonly expressed at synaptic junctions and contributes to formation and maturation of synaptic contacts. This study used heterologous cell cultures of brainstem cholinergic neurons and transfected Chinese Hamster Ovary (CHO cells to examine whether N-cadherin is sufficient to induce differentiation of cholinergic presynaptic terminals. Brainstem nuclei isolated from transgenic mice expressing EGFP under the control of choline acetyltransferase transcriptional regulatory elements (ChATBACEGFP were cultured as tissue explants for five days and cocultured with transfected CHO cells for an additional two days. Immunostaining for synaptic vesicle proteins SV2 and synapsin I revealed a ~3-fold increase in the area of SV2 immunolabeling over N-cadherin expressing CHO cells, and this effect was enhanced by coexpression of p120-catenin. Synapsin I immunolabeling per axon length was also increased on N-cadherin expressing CHO cells but required coexpression of p120-catenin. To determine whether N-cadherin induces formation of neurotransmitter release sites, whole-cell voltage-clamp recordings of CHO cells expressing alpha-3 and beta-4 nicotinic acetylcholine receptor (nAChR subunits in contact with cholinergic axons were used to monitor excitatory postsynaptic potentials (EPSPs and miniature EPSPs (mEPSPs. EPSPs and mEPSPs were not detected in both, control and in N-cadherin expressing CHO cells in the absence or presence of tetrodotoxin. These results indicate that expression of N-cadherin in non-neuronal cells is sufficient to initiate differentiation of presynaptic cholinergic terminals by inducing accumulation of synaptic vesicles; however, development of readily detectable mature cholinergic release sites and/or clustering of postsynaptic nAChR may require expression of additional synaptogenic proteins.

  10. Diverse coupling of neurons to populations in sensory cortex.

    Science.gov (United States)

    Okun, Michael; Steinmetz, Nicholas; Cossell, Lee; Iacaruso, M Florencia; Ko, Ho; Barthó, Péter; Moore, Tirin; Hofer, Sonja B; Mrsic-Flogel, Thomas D; Carandini, Matteo; Harris, Kenneth D

    2015-05-28

    A large population of neurons can, in principle, produce an astronomical number of distinct firing patterns. In cortex, however, these patterns lie in a space of lower dimension, as if individual neurons were "obedient members of a huge orchestra". Here we use recordings from the visual cortex of mouse (Mus musculus) and monkey (Macaca mulatta) to investigate the relationship between individual neurons and the population, and to establish the underlying circuit mechanisms. We show that neighbouring neurons can differ in their coupling to the overall firing of the population, ranging from strongly coupled 'choristers' to weakly coupled 'soloists'. Population coupling is largely independent of sensory preferences, and it is a fixed cellular attribute, invariant to stimulus conditions. Neurons with high population coupling are more strongly affected by non-sensory behavioural variables such as motor intention. Population coupling reflects a causal relationship, predicting the response of a neuron to optogenetically driven increases in local activity. Moreover, population coupling indicates synaptic connectivity; the population coupling of a neuron, measured in vivo, predicted subsequent in vitro estimates of the number of synapses received from its neighbours. Finally, population coupling provides a compact summary of population activity; knowledge of the population couplings of n neurons predicts a substantial portion of their n(2) pairwise correlations. Population coupling therefore represents a novel, simple measure that characterizes the relationship of each neuron to a larger population, explaining seemingly complex network firing patterns in terms of basic circuit variables.

  11. Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex.

    Science.gov (United States)

    Song, Jiaojiao; Chen, Ming; Dong, Yi; Lai, Bin; Zheng, Ping

    2018-05-01

    Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Neurturin overexpression in dopaminergic neurons induces presynaptic and postsynaptic structural changes in rats with chronic 6-hydroxydopamine lesion.

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    David Reyes-Corona

    Full Text Available The structural effect of neurturin (NRTN on the nigrostriatal dopaminergic system in animals remains unknown, although NRTN has been shown to be effective in Parkinson's disease animal models. Herein, we aimed to demonstrate that NRTN overexpression in dopaminergic neurons stimulates both neurite outgrowths in the nigrostriatal pathway and striatal dendritic spines in aging rats with chronic 6-hydroxydopamine (6-OHDA lesion. At week 12 after lesion, pTracer-mNRTN-His or pGreenLantern-1 plasmids were intranigrally transfected using the NTS-polyplex nanoparticles system. We showed that the transgenic expression in dopaminergic neurons remained until the end of the study (12 weeks. Only animals expressing NRTN-His showed recovery of tyrosine hydroxylase (TH+ cells (28 ± 2%, their neurites (32 ± 2% and the neuron-specific cytoskeletal marker β-III-tubulin in the substantia nigra; striatal TH(+ fibers were also recovered (52 ± 3%, when compared to the healthy condition. Neurotensin receptor type 1 levels were also significantly recovered in the substantia nigra and striatum. Dopamine recovery was 70 ± 4% in the striatum and complete in the substantia nigra. The number of dendritic spines of striatal medium spiny neurons was also significantly increased, but the recovery was not complete. Drug-activated circling behavior decreased by 73 ± 2% (methamphetamine and 89 ± 1% (apomorphine. Similar decrease was observed in the spontaneous motor behavior. Our results demonstrate that NRTN causes presynaptic and postsynaptic restoration of the nigrostriatal dopaminergic system after a 6-OHDA-induced chronic lesion. However, those improvements did not reach the healthy condition, suggesting that NRTN exerts lesser neurotrophic effects than other neurotrophic approaches.

  13. [The mirror neuron system in motor and sensory rehabilitation].

    Science.gov (United States)

    Oouchida, Yutaka; Izumi, Shinichi

    2014-06-01

    The discovery of the mirror neuron system has dramatically changed the study of motor control in neuroscience. The mirror neuron system provides a conceptual framework covering the aspects of motor as well as sensory functions in motor control. Previous studies of motor control can be classified as studies of motor or sensory functions, and these two classes of studies appear to have advanced independently. In rehabilitation requiring motor learning, such as relearning movement after limb paresis, however, sensory information of feedback for motor output as well as motor command are essential. During rehabilitation from chronic pain, motor exercise is one of the most effective treatments for pain caused by dysfunction in the sensory system. In rehabilitation where total intervention unifying the motor and sensory aspects of motor control is important, learning through imitation, which is associated with the mirror neuron system can be effective and suitable. In this paper, we introduce the clinical applications of imitated movement in rehabilitation from motor impairment after brain damage and phantom limb pain after limb amputation.

  14. Ultrastructural description of rabies virus infection in cultured sensory neurons

    Directory of Open Access Journals (Sweden)

    Myriam L Velandia

    2007-06-01

    Full Text Available Primary cultures were made from adult mouse spinal ganglia for depicting an ultrastructural description of rabies virus (RABV infection in adult mouse sensory neuron cultures; they were infected with rabies virus for 24, 36, and 48 h. The monolayers were processed for transmission electron microscopy and immunochemistry studies at the end of each period. As previously reported, sensory neurons showed great susceptibility to infection by RABV; however, in none of the periods evaluated were assembled virions observed in the cytoplasm or seen to be associated with the cytoplasmic membrane. Instead, fibril matrices of aggregated ribonucleoprotein were detected in the cytoplasm. When infected culture lysate were inoculated into normal animals via intra-cerebral route it was observed that these animals developed clinical symptoms characteristic of infection and transmission electron microscopy revealed assembled virions in the cerebral cortex and other areas of the brain. Sensory neurons infected in vitro by RABV produced a large amount of unassembled viral ribonucleoprotein. However, this intracellular material was able to produce infection and virions on being intra-cerebrally inoculated. It can thus be suggested that the lack of intracellular assembly in sensory neurons forms part of an efficient dissemination strategy.

  15. Stochastic resonance in noisy spiking retinal and sensory neuron models.

    Science.gov (United States)

    Patel, Ashok; Kosko, Bart

    2005-01-01

    Two new theorems show that small amounts of additive white noise can improve the bit count or mutual information of several popular models of spiking retinal neurons and spiking sensory neurons. The first theorem gives necessary and sufficient conditions for this noise benefit or stochastic resonance (SR) effect for subthreshold signals in a standard family of Poisson spiking models of retinal neurons. The result holds for all types of finite-variance noise and for all types of infinite-variance stable noise: SR occurs if and only if a sum of noise means or location parameters falls outside a 'forbidden interval' of values. The second theorem gives a similar forbidden-interval sufficient condition for the SR effect for several types of spiking sensory neurons that include the Fitzhugh-Nagumo neuron, the leaky integrate-and-fire neuron, and the reduced Type I neuron model if the additive noise is Gaussian white noise. Simulations show that neither the forbidden-interval condition nor Gaussianity is necessary for the SR effect.

  16. Presynaptic neurones may contribute a unique glycoprotein to the extracellular matrix at the synapse

    Science.gov (United States)

    Caroni, Pico; Carlson, Steven S.; Schweitzer, Erik; Kelly, Regis B.

    1985-04-01

    As the extracellular matrix at the original site of a neuromuscular junction seems to play a major part in the specificity of synaptic regeneration1-5, considerable attention has been paid to unique molecules localized to this region6-11. Here we describe an extracellular matrix glycoprotein of the elasmobranch electric organ that is localized near the nerve endings. By immunological criteria, it is synthesized in the cell bodies, transported down the axons and is related to a glycoprotein in the synaptic vesicles of the neurones that innervate the electric organ. It is apparently specific for these neurones, as it cannot be detected elsewhere in the nervous system of the fish. Therefore, neurones seem to contribute unique extracellular matrix glycoproteins to the synaptic region. Synaptic vesicles could be involved in transporting these glycoproteins to or from the nerve terminal surface.

  17. Axotomy depletes intracellular calcium stores in primary sensory neurons.

    Science.gov (United States)

    Rigaud, Marcel; Gemes, Geza; Weyker, Paul D; Cruikshank, James M; Kawano, Takashi; Wu, Hsiang-En; Hogan, Quinn H

    2009-08-01

    The cellular mechanisms of neuropathic pain are inadequately understood. Previous investigations have revealed disrupted Ca signaling in primary sensory neurons after injury. The authors examined the effect of injury on intracellular Ca stores of the endoplasmic reticulum, which critically regulate the Ca signal and neuronal function. Intracellular Ca levels were measured with Fura-2 or mag-Fura-2 microfluorometry in axotomized fifth lumbar (L5) dorsal root ganglion neurons and adjacent L4 neurons isolated from hyperalgesic rats after L5 spinal nerve ligation, compared to neurons from control animals. Endoplasmic reticulum Ca stores released by the ryanodine-receptor agonist caffeine decreased by 46% in axotomized small neurons. This effect persisted in Ca-free bath solution, which removes the contribution of store-operated membrane Ca channels, and after blockade of the mitochondrial, sarco-endoplasmic Ca-ATPase and the plasma membrane Ca ATPase pathways. Ca released by the sarco-endoplasmic Ca-ATPase blocker thapsigargin and by the Ca-ionophore ionomycin was also diminished by 25% and 41%, respectively. In contrast to control neurons, Ca stores in axotomized neurons were not expanded by neuronal activation by K depolarization, and the proportionate rate of refilling by sarco-endoplasmic Ca-ATPase was normal. Luminal Ca concentration was also reduced by 38% in axotomized neurons in permeabilized neurons. The adjacent neurons of the L4 dorsal root ganglia showed modest and inconsistent changes after L5 spinal nerve ligation. Painful nerve injury leads to diminished releasable endoplasmic reticulum Ca stores and a reduced luminal Ca concentration. Depletion of Ca stores may contribute to the pathogenesis of neuropathic pain.

  18. Switch of rhodopsin expression in terminally differentiated Drosophila sensory neurons

    OpenAIRE

    Sprecher, Simon G.; Desplan, Claude

    2008-01-01

    Specificity of sensory neurons requires restricted expression of one sensory receptor gene and the exclusion of all others within a given cell. In the Drosophila retina, functional identity of photoreceptors depends on light-sensitive Rhodopsins (Rhs). The much simpler larval eye (Bolwig organ) is composed of about 12 photoreceptors, eight of which are green-sensitive (Rh6) and four blue-sensitive (Rh5)1. The larval eye becomes the adult extraretinal ‘eyelet’ composed of four green-sensitive ...

  19. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation.

    Science.gov (United States)

    Pinho-Ribeiro, Felipe A; Verri, Waldiceu A; Chiu, Isaac M

    2017-01-01

    Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Melatonin modulation of presynaptic nicotinic acetylcholine receptors located on short noradrenergic neurons of the rat vas deferens: a pharmacological characterization

    Directory of Open Access Journals (Sweden)

    Zago W.M.

    1999-01-01

    Full Text Available Melatonin, the pineal hormone produced during the dark phase of the light-dark cycle, modulates neuronal acetylcholine receptors located presynaptically on nerve terminals of the rat vas deferens. Recently we showed the presence of high affinity nicotine-binding sites during the light phase, and low and high affinity binding sites during the dark phase. The appearance of the low affinity binding sites was due to the nocturnal melatonin surge and could be mimicked by exposure to melatonin in vitro. The aim of the present research was to identify the receptor subtypes responsible for the functional response during the light and the dark phase. The rank order of potency of agonists was dimethylphenylpiperazinium (DMPP = cytisine > nicotine > carbachol and DMPP = nicotine = cytisine > carbachol, during the light and dark phase, respectively, due to an increase in apparent affinity for nicotine. Mecamylamine similarly blocked the DMPP response during the light and the dark phase, while the response to nicotine was more efficiently blocked during the light phase. In contrast, methyllycaconitine inhibited the nicotine-induced response only at 21:00 h. Since a7 nicotinic acetylcholine receptors (nAChRs have low affinity for nicotine in binding assays, we suggest that a mixed population composed of a3ß4 - plus a7-bearing nAChR subtypes is present at night. This plasticity in receptor subtypes is probably driven by melatonin since nicotine-induced contraction in organs from animals sacrificed at 15:00 h and incubated with melatonin (100 pg/ml, 4 h is not totally blocked by mecamylamine. Thus melatonin, by acting directly on the short adrenergic neurons that innervate the rat vas deferens, induces the appearance of the low affinity binding site, probably an a7 nAChR subtype.

  1. Sensory cortex lesion triggers compensatory neuronal plasticity.

    Science.gov (United States)

    Depner, Manfred; Tziridis, Konstantin; Hess, Andreas; Schulze, Holger

    2014-05-01

    Lesions to the human brain often cause dramatic impairments in the life of patients because of the very limited capacity of the mammalian nervous system to regenerate. On the other hand, neuronal tissue has a high capacity to reorganize itself so that loss of function due to brain damage may be compensated through neuroplastic reorganization of undamaged tissue in brain regions adjacent or contralateral to the lesion site. In this study we investigated the effect of serial lesions of the auditory cortices (AC) in both hemispheres of Mongolian gerbils on discrimination performance for fast amplitude modulated tones (AM). Healthy animals were trained to discriminate two fast AM, an ability that has previously been shown to critically depend on cortical processing. Their ability to maintain significant discrimination performance was retested after unilateral AC lesion, and again after lesion of the contralateral AC, with 15 days of continuing training in between the two lesions. After bilateral cortical ablation of both AC and 45 days of training the animals show no change in pure tone detection threshold as measured with modulation of the acoustic startle reflex which has been shown to rely on subcortical structures. In contrast to simultaneous bilateral ablation of AC that results in complete loss of AM discrimination ability in this paradigm we found compensatory plasticity that seems to be triggered by unilateral cortical ablation with subsequent training and that is able to almost fully compensate for the lost cortical functions. Our results demonstrate that AM discrimination ability that normally depends on AC may be transferred to other brain regions when the brain has time to activate compensatory plasticity between the lesions of the two AC hemispheres. For this process to take place obviously one intact AC hemisphere is needed. This finding may open perspectives for new therapeutic strategies that may alleviate the impairments after multiple ischemic strokes.

  2. Bacteria activate sensory neurons that modulate pain and inflammation.

    Science.gov (United States)

    Chiu, Isaac M; Heesters, Balthasar A; Ghasemlou, Nader; Von Hehn, Christian A; Zhao, Fan; Tran, Johnathan; Wainger, Brian; Strominger, Amanda; Muralidharan, Sriya; Horswill, Alexander R; Bubeck Wardenburg, Juliane; Hwang, Sun Wook; Carroll, Michael C; Woolf, Clifford J

    2013-09-05

    Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.

  3. Effects of Colored Noise on Stochastic Resonance in Sensory Neurons

    International Nuclear Information System (INIS)

    Nozaki, D.; Mar, D.J.; Collins, J.J.; Grigg, P.

    1999-01-01

    Noise can assist neurons in the detection of weak signals via a mechanism known as stochastic resonance (SR). We demonstrate experimentally that SR-type effects can be obtained in rat sensory neurons with white noise, 1/f noise, or 1/f 2 noise. For low-frequency input noise, we show that the optimal noise intensity is the lowest and the output signal-to-noise ratio the highest for conventional white noise. We also show that under certain circumstances, 1/f noise can be better than white noise for enhancing the response of a neuron to a weak signal. We present a theory to account for these results and discuss the biological implications of 1/f noise. copyright 1999 The American Physical Society

  4. Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

    Directory of Open Access Journals (Sweden)

    Barış Genç

    Full Text Available Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

  5. Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

    Science.gov (United States)

    Genç, Barış; Lagrimas, Amiko Krisa Bunag; Kuru, Pınar; Hess, Robert; Tu, Michael William; Menichella, Daniela Maria; Miller, Richard J; Paller, Amy S; Özdinler, P Hande

    2015-01-01

    Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

  6. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    Science.gov (United States)

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  7. Enhanced behavioral responses to cold stimuli following CGRPα sensory neuron ablation are dependent on TRPM8.

    Science.gov (United States)

    McCoy, Eric S; Zylka, Mark J

    2014-11-19

    Calcitonin gene-related peptide-α (CGRPα) is a classic marker of peptidergic nociceptive neurons and is expressed in myelinated and unmyelinated dorsal root ganglia (DRG) neurons. Recently, we found that ablation of Cgrpα-expressing sensory neurons reduced noxious heat sensitivity and enhanced sensitivity to cold stimuli in mice. These studies suggested that the enhanced cold responses were due to disinhibition of spinal neurons that receive inputs from cold-sensing/TRPM8 primary afferents; although a direct role for TRPM8 was not examined at the time. Here, we ablated Cgrpα-expressing sensory neurons in mice lacking functional TRPM8 and evaluated sensory responses to noxious heat, cold temperatures, and cold mimetics (acetone evaporative cooling and icilin). We also evaluated thermoregulation in these mice following an evaporative cold challenge. We found that ablation of Cgrpα-expressing sensory neurons in a Trpm8-/- background reduced sensitivity to noxious heat but did not enhance sensitivity to cold stimuli. Thermoregulation following the evaporative cold challenge was not affected by deletion of Trpm8 in control or Cgrpα-expressing sensory neuron-ablated mice. Our data indicate that the enhanced behavioral responses to cold stimuli in CGRPα sensory neuron-ablated mice are dependent on functional TRPM8, whereas the other sensory and thermoregulatory phenotypes caused by CGRPα sensory neuron ablation are independent of TRPM8.

  8. Integration of sensory quanta in cuneate nucleus neurons in vivo.

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    Fredrik Bengtsson

    Full Text Available Discriminative touch relies on afferent information carried to the central nervous system by action potentials (spikes in ensembles of primary afferents bundled in peripheral nerves. These sensory quanta are first processed by the cuneate nucleus before the afferent information is transmitted to brain networks serving specific perceptual and sensorimotor functions. Here we report data on the integration of primary afferent synaptic inputs obtained with in vivo whole cell patch clamp recordings from the neurons of this nucleus. We find that the synaptic integration in individual cuneate neurons is dominated by 4-8 primary afferent inputs with large synaptic weights. In a simulation we show that the arrangement with a low number of primary afferent inputs can maximize transfer over the cuneate nucleus of information encoded in the spatiotemporal patterns of spikes generated when a human fingertip contact objects. Hence, the observed distributions of synaptic weights support high fidelity transfer of signals from ensembles of tactile afferents. Various anatomical estimates suggest that a cuneate neuron may receive hundreds of primary afferents rather than 4-8. Therefore, we discuss the possibility that adaptation of synaptic weight distribution, possibly involving silent synapses, may function to maximize information transfer in somatosensory pathways.

  9. Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome.

    Science.gov (United States)

    Kang, Ji-Yong; Chadchankar, Jayashree; Vien, Thuy N; Mighdoll, Michelle I; Hyde, Thomas M; Mather, Robert J; Deeb, Tarek Z; Pangalos, Menelas N; Brandon, Nicholas J; Dunlop, John; Moss, Stephen J

    2017-04-21

    The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABA B ) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of G i/o , they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABA B receptors (GABA B Rs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABA B Rs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABA B Rs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABA B Rs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABA B R agonist ( R )-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABA B Rs contribute to the pathophysiology of FXS. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation

    Science.gov (United States)

    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Wood, John N.; von Andrian, Ulrich H.

    2014-01-01

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation1–4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear5,6. Here, we have exposed the skin of mice to imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation7,8. We show that a subset of sensory neurons expressing the ion channels TRPV1 and NaV1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors9–11, DDCs failed to produce IL-23 in IMQ exposed skin. Consequently, the local production of IL-23 dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response12. These findings indicate that TRPV1+NaV1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses. PMID:24759321

  11. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.

    Science.gov (United States)

    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Paust, Silke; Wood, John N; von Andrian, Ulrich H

    2014-06-05

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

  12. Phenotypic and Functional Characterization of Peripheral Sensory Neurons derived from Human Embryonic Stem Cells

    OpenAIRE

    Alshawaf, Abdullah Jawad; Viventi, Serena; Qiu, Wanzhi; D’Abaco, Giovanna; Nayagam, Bryony; Erlichster, Michael; Chana, Gursharan; Everall, Ian; Ivanusic, Jason; Skafidas, Efstratios; Dottori, Mirella

    2018-01-01

    The dorsal root ganglia (DRG) consist of a multitude of sensory neuronal subtypes that function to relay sensory stimuli, including temperature, pressure, pain and position to the central nervous system. Our knowledge of DRG sensory neurons have been predominantly driven by animal studies and considerably less is known about the human DRG. Human embryonic stem cells (hESC) are valuable resource to help close this gap. Our previous studies reported an efficient system for deriving neural crest...

  13. Morphology and intrinsic excitability of regenerating sensory and motor neurons grown on a line micropattern.

    Directory of Open Access Journals (Sweden)

    Ouafa Benzina

    Full Text Available Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 µm wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons.

  14. Morphology and intrinsic excitability of regenerating sensory and motor neurons grown on a line micropattern.

    Science.gov (United States)

    Benzina, Ouafa; Cloitre, Thierry; Martin, Marta; Raoul, Cédric; Gergely, Csilla; Scamps, Frédérique

    2014-01-01

    Axonal regeneration is one of the greatest challenges in severe injuries of peripheral nerve. To provide the bridge needed for regeneration, biological or synthetic tubular nerve constructs with aligned architecture have been developed. A key point for improving axonal regeneration is assessing the effects of substrate geometry on neuronal behavior. In the present study, we used an extracellular matrix-micropatterned substrate comprising 3 µm wide lines aimed to physically mimic the in vivo longitudinal axonal growth of mice peripheral sensory and motor neurons. Adult sensory neurons or embryonic motoneurons were seeded and processed for morphological and electrical activity analyses after two days in vitro. We show that micropattern-guided sensory neurons grow one or two axons without secondary branching. Motoneurons polarity was kept on micropattern with a long axon and small dendrites. The micro-patterned substrate maintains the growth promoting effects of conditioning injury and demonstrates, for the first time, that neurite initiation and extension could be differentially regulated by conditioning injury among DRG sensory neuron subpopulations. The micro-patterned substrate impacts the excitability of sensory neurons and promotes the apparition of firing action potentials characteristic for a subclass of mechanosensitive neurons. The line pattern is quite relevant for assessing the regenerative and developmental growth of sensory and motoneurons and offers a unique model for the analysis of the impact of geometry on the expression and the activity of mechanosensitive channels in DRG sensory neurons.

  15. Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release.

    Directory of Open Access Journals (Sweden)

    Seungwon Choi

    2015-07-01

    Full Text Available C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH, touch sensitive (ALM and PLM, and stretch sensing (DVA neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states.

  16. Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release

    Science.gov (United States)

    Chatzigeorgiou, Marios; Hu, Zhitao; Schafer, William R.; Kaplan, Joshua M.

    2015-01-01

    C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states. PMID:26154367

  17. touché is required for touch evoked generator potentials within vertebrate sensory neurons

    Science.gov (United States)

    Low, Sean E.; Ryan, Joel; Sprague, Shawn M.; Hirata, Hiromi; Cui, Wilson W.; Zhou, Weibin; Hume, Richard I.; Kuwada, John Y.; Saint-Amant, Louis

    2010-01-01

    The process by which light-touch in vertebrates is transformed into an electrical response in cutaneous mechanosensitive neurons is a largely unresolved question. To address this question we undertook a forward genetic screen in zebrafish (Danio rerio) to identify mutants exhibiting abnormal touch-evoked behaviors, despite the presence of sensory neurons and peripheral neurites. One family, subsequently named touché, was found to harbor a recessive mutation which produced offspring that were unresponsive to light-touch, but responded to a variety of other sensory stimuli. The optogenetic activation of motor behaviors by touché mutant sensory neurons expressing ChannelRhodopsin-2 suggested that the synaptic output of sensory neurons was intact, consistent with a defect in sensory neuron activation. To explore sensory neuron activation we developed an in vivo preparation permitting the precise placement of a combined electrical and tactile stimulating probe upon eGFP positive peripheral neurites. In wild type larva electrical and tactile stimulation of peripheral neurites produced action potentials detectable within the cell body. In a subset of these sensory neurons an underlying generator potential could be observed in response to subthreshold tactile stimuli. A closer examination revealed that the amplitude of the generator potential was proportional to the stimulus amplitude. When assayed touché mutant sensory neurons also responded to electrical stimulation of peripheral neurites similar to wild type larvae, however tactile stimulation of these neurites failed to uncover a subset of sensory neurons possessing generator potentials. These findings suggest that touché is required for generator potentials, and that generator potentials underlie responsiveness to light-touch in zebrafish. PMID:20631165

  18. Optogenetically enhanced axon regeneration: motor versus sensory neuron-specific stimulation.

    Science.gov (United States)

    Ward, Patricia J; Clanton, Scott L; English, Arthur W

    2018-02-01

    Brief neuronal activation in injured peripheral nerves is both necessary and sufficient to enhance motor axon regeneration, and this effect is specific to the activated motoneurons. It is less clear whether sensory neurons respond in a similar manner to neuronal activation following peripheral axotomy. Further, it is unknown to what extent enhancement of axon regeneration with increased neuronal activity relies on a reflexive interaction within the spinal circuitry. We used mouse genetics and optical tools to evaluate the precision and selectivity of system-specific neuronal activation to enhance axon regeneration in a mixed nerve. We evaluated sensory and motor axon regeneration in two different mouse models expressing the light-sensitive cation channel, channelrhodopsin (ChR2). We selectively activated either sensory or motor axons using light stimulation combined with transection and repair of the sciatic nerve. Regardless of genotype, the number of ChR2-positive neurons whose axons had regenerated successfully was greater following system-specific optical treatment, with no effect on the number of ChR2-negative neurons (whether motor or sensory neurons). We conclude that acute system-specific neuronal activation is sufficient to enhance both motor and sensory axon regeneration. This regeneration-enhancing effect is likely cell autonomous. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  19. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons.

    Science.gov (United States)

    Mardinly, A R; Spiegel, I; Patrizi, A; Centofante, E; Bazinet, J E; Tzeng, C P; Mandel-Brehm, C; Harmin, D A; Adesnik, H; Fagiolini, M; Greenberg, M E

    2016-03-17

    Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.

  20. Untuned But Not Irrelevant: The Role of Untuned Neurons In Sensory Information Coding

    OpenAIRE

    Zylberberg, Joel

    2017-01-01

    In the sensory systems, most neurons' firing rates are tuned to at least one aspect of the stimulus. Other neurons are appear to be untuned, meaning that their firing rates do not depend on the stimulus. Previous work on information coding in neural populations has ignored untuned neurons, based on the tacit assumption that they are unimportant. Recent experimental work has questioned this assumption, showing that in some circumstances, neurons with no apparent stimulus tuning can contribute ...

  1. The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity.

    Science.gov (United States)

    Fernández-Montoya, Julia; Avendaño, Carlos; Negredo, Pilar

    2017-12-27

    Glutamate is the most common neurotransmitter in both the central and the peripheral nervous system. Glutamate is present in all types of neurons in sensory ganglia, and is released not only from their peripheral and central axon terminals but also from their cell bodies. Consistently, these neurons express ionotropic and metabotropic receptors, as well as other molecules involved in the synthesis, transport and release of the neurotransmitter. Primary sensory neurons are the first neurons in the sensory channels, which receive information from the periphery, and are thus key players in the sensory transduction and in the transmission of this information to higher centers in the pathway. These neurons are tightly enclosed by satellite glial cells, which also express several ionotropic and metabotropic glutamate receptors, and display increases in intracellular calcium accompanying the release of glutamate. One of the main interests in our group has been the study of the implication of the peripheral nervous system in sensory-dependent plasticity. Recently, we have provided novel evidence in favor of morphological changes in first- and second-order neurons of the trigeminal system after sustained alterations of the sensory input. Moreover, these anatomical changes are paralleled by several molecular changes, among which those related to glutamatergic neurotransmission are particularly relevant. In this review, we will describe the state of the art of the glutamatergic system in sensory ganglia and its involvement in input-dependent plasticity, a fundamental ground for advancing our knowledge of the neural mechanisms of learning and adaptation, reaction to injury, and chronic pain.

  2. Phenotypic and Functional Characterization of Peripheral Sensory Neurons derived from Human Embryonic Stem Cells.

    Science.gov (United States)

    Alshawaf, Abdullah Jawad; Viventi, Serena; Qiu, Wanzhi; D'Abaco, Giovanna; Nayagam, Bryony; Erlichster, Michael; Chana, Gursharan; Everall, Ian; Ivanusic, Jason; Skafidas, Efstratios; Dottori, Mirella

    2018-01-12

    The dorsal root ganglia (DRG) consist of a multitude of sensory neuronal subtypes that function to relay sensory stimuli, including temperature, pressure, pain and position to the central nervous system. Our knowledge of DRG sensory neurons have been predominantly driven by animal studies and considerably less is known about the human DRG. Human embryonic stem cells (hESC) are valuable resource to help close this gap. Our previous studies reported an efficient system for deriving neural crest and DRG sensory neurons from hESC. Here we show that this differentiation system gives rise to heterogeneous populations of sensory neuronal subtypes as demonstrated by phenotypic and functional analyses. Furthermore, using microelectrode arrays the maturation rate of the hESC-derived sensory neuronal cultures was monitored over 8 weeks in culture, showing their spontaneous firing activities starting at about 12 days post-differentiation and reaching maximum firing at about 6 weeks. These studies are highly valuable for developing an in vitro platform to study the diversity of sensory neuronal subtypes found within the human DRG.

  3. Connexin43 Hemichannels in Satellite Glial Cells, Can They Influence Sensory Neuron Activity?

    Directory of Open Access Journals (Sweden)

    Mauricio A. Retamal

    2017-11-01

    Full Text Available In this review article, we summarize the current insight on the role of Connexin- and Pannexin-based channels as modulators of sensory neurons. The somas of sensory neurons are located in sensory ganglia (i.e., trigeminal and nodose ganglia. It is well known that within sensory ganglia, sensory neurons do not form neither electrical nor chemical synapses. One of the reasons for this is that each soma is surrounded by glial cells, known as satellite glial cells (SGCs. Recent evidence shows that connexin43 (Cx43 hemichannels and probably pannexons located at SGCs have an important role in paracrine communication between glial cells and sensory neurons. This communication may be exerted via the release of bioactive molecules from SGCs and their subsequent action on receptors located at the soma of sensory neurons. The glio-neuronal communication seems to be relevant for the establishment of chronic pain, hyperalgesia and pathologies associated with tissue inflammation. Based on the current literature, it is possible to propose that Cx43 hemichannels expressed in SGCs could be a novel pharmacological target for treating chronic pain, which need to be directly evaluated in future studies.

  4. Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22

    Directory of Open Access Journals (Sweden)

    Masaki Kobayashi

    2017-03-01

    Full Text Available Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN. Cajal bodies (CBs, unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN proteins was reduced – a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs, also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG, and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdown in vitro enhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy.

  5. Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain.

    Science.gov (United States)

    Berta, Temugin; Qadri, Yawar; Tan, Ping-Heng; Ji, Ru-Rong

    2017-07-01

    Currently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion: These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states.

  6. En masse in vitro functional profiling of the axonal mechanosensitivity of sensory neurons.

    Science.gov (United States)

    Usoskin, Dmitry; Zilberter, Misha; Linnarsson, Sten; Hjerling-Leffler, Jens; Uhlén, Per; Harkany, Tibor; Ernfors, Patrik

    2010-09-14

    Perception of the environment relies on somatosensory neurons. Mechanosensory, proprioceptor and many nociceptor subtypes of these neurons have specific mechanosensitivity profiles to adequately differentiate stimulus patterns. Nevertheless, the cellular basis of differential mechanosensation remains largely elusive. Successful transduction of sensory information relies on the recruitment of sensory neurons and mechanosensation occurring at their peripheral axonal endings in vivo. Conspicuously, existing in vitro models aimed to decipher molecular mechanisms of mechanosensation test single sensory neuron somata at any one time. Here, we introduce a compartmental in vitro chamber design to deliver precisely controlled mechanical stimulation of sensory axons with synchronous real-time imaging of Ca(2+) transients in neuronal somata that reliably reflect action potential firing patterns. We report of three previously not characterized types of mechanosensitive neuron subpopulations with distinct intrinsic axonal properties tuned specifically to static indentation or vibration stimuli, showing that different classes of sensory neurons are tuned to specific types of mechanical stimuli. Primary receptor currents of vibration neurons display rapidly adapting conductance reliably detected for every single stimulus during vibration and are consistently converted into action potentials. This result allows for the characterization of two critical steps of mechanosensation in vivo: primary signal detection and signal conversion into specific action potential firing patterns in axons.

  7. The formation of the cranial ganglia by placodally-derived sensory neuronal precursors.

    Science.gov (United States)

    Blentic, Aida; Chambers, David; Skinner, Adam; Begbie, Jo; Graham, Anthony

    2011-02-01

    The generation of the sensory ganglia involves the migration of a precursor population to the site of ganglion formation and the differentiation of sensory neurons. There is, however, a significant difference between the ganglia of the head and trunk in that while all of the sensory neurons of the trunk are derived from the neural crest, the majority of cranial sensory neurons are generated by the neurogenic placodes. In this study, we have detailed the route through which the placodally-derived sensory neurons are generated, and we find a number of important differences between the head and trunk. Although, the neurogenic placodes release neuroblasts that migrate internally to the site of ganglion formation, we find that there are no placodally-derived progenitor cells within the forming ganglia. The cells released by the placodes differentiate during migration and contribute to the cranial ganglia as post-mitotic neurons. In the trunk, it has been shown that progenitor cells persist in the forming Dorsal Root Ganglia and that much of the process of sensory neuronal differentiation occurs within the ganglion. We also find that the period over which neuronal cells delaminate from the placodes is significantly longer than the time frame over which neural crest cells populate the DRGs. We further show that placodal sensory neuronal differentiation can occur in the absence of local cues. Finally, we find that, in contrast to neural crest cells, the different mature neurogenic placodes seem to lack plasticity. Nodose neuroblasts cannot be diverted to form trigeminal neurons and vice versa. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. The critical period for peripheral specification of dorsal root ganglion neurons is related to the period of sensory neurogenesis

    International Nuclear Information System (INIS)

    Smith, C.L.

    1990-01-01

    Thoracic sensory neurons in bullfrog tadpoles can be induced to form connections typical of brachial sensory neurons by transplanting thoracic ganglia to the branchial level at stages when some thoracic sensory neurons already have formed connections. In order to find out how many postmitotic sensory neurons survive transplantation, [ 3 H]thymidine was administered to tadpoles in which thoracic ganglia were transplanted to the brachial level unilaterally at stages VII to IX. Between 16 and 37% of the neurons in transplanted ganglia were unlabeled, as compared to 46 to 60% in unoperated ganglia. Transplanted ganglia contained fewer unlabeled neurons than corresponding unoperated ganglia, indicating that transplantation caused degeneration of postmitotic neurons. Therefore, a large fraction of the neurons that formed connections typical of brachial sensory neurons probably differentiated while they were at the brachial level

  9. Inference of neuronal functional circuitry with spike-triggered non-negative matrix factorization.

    Science.gov (United States)

    Liu, Jian K; Schreyer, Helene M; Onken, Arno; Rozenblit, Fernando; Khani, Mohammad H; Krishnamoorthy, Vidhyasankar; Panzeri, Stefano; Gollisch, Tim

    2017-07-26

    Neurons in sensory systems often pool inputs over arrays of presynaptic cells, giving rise to functional subunits inside a neuron's receptive field. The organization of these subunits provides a signature of the neuron's presynaptic functional connectivity and determines how the neuron integrates sensory stimuli. Here we introduce the method of spike-triggered non-negative matrix factorization for detecting the layout of subunits within a neuron's receptive field. The method only requires the neuron's spiking responses under finely structured sensory stimulation and is therefore applicable to large populations of simultaneously recorded neurons. Applied to recordings from ganglion cells in the salamander retina, the method retrieves the receptive fields of presynaptic bipolar cells, as verified by simultaneous bipolar and ganglion cell recordings. The identified subunit layouts allow improved predictions of ganglion cell responses to natural stimuli and reveal shared bipolar cell input into distinct types of ganglion cells.How a neuron integrates sensory information requires knowledge about its functional presynaptic connections. Here the authors report a new method using non-negative matrix factorization to identify the layout of presynaptic bipolar cell inputs onto retinal ganglion cells and predict their responses to natural stimuli.

  10. Painful nerve injury decreases resting cytosolic calcium concentrations in sensory neurons of rats

    NARCIS (Netherlands)

    Fuchs, Andreas; Lirk, Philipp; Stucky, Cheryl; Abram, Stephen E.; Hogan, Quinn H.

    2005-01-01

    Neuropathic pain is difficult to treat and poorly understood at the cellular level. Although cytoplasmic calcium ([Ca]c) critically regulates neuronal function, the effects of peripheral nerve injury on resting sensory neuronal [Ca]c are unknown. Resting [Ca]c was determined by microfluorometry in

  11. Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold

    Science.gov (United States)

    McCoy, Eric S.; Taylor-Blake, Bonnie; Street, Sarah E.; Pribisko, Alaine L.; Zheng, Jihong; Zylka, Mark J.

    2013-01-01

    SUMMARY Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown if these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch—stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception. PMID:23523592

  12. Peripheral multidendritic sensory neurons are necessary for rhythmic locomotion behavior in Drosophila larvae

    Science.gov (United States)

    Song, Wei; Onishi, Maika; Jan, Lily Yeh; Jan, Yuh Nung

    2007-01-01

    From breathing to walking, rhythmic movements encompass physiological processes important across the entire animal kingdom. It is thought by many that the generation of rhythmic behavior is operated by a central pattern generator (CPG) and does not require peripheral sensory input. Sensory feedback is, however, required to modify or coordinate the motor activity in response to the circumstances of actual movement. In contrast to this notion, we report here that sensory input is necessary for the generation of Drosophila larval locomotion, a form of rhythmic behavior. Blockage of all peripheral sensory inputs resulted in cessation of larval crawling. By conditionally silencing various subsets of larval peripheral sensory neurons, we identified the multiple dendritic (MD) neurons as the neurons essential for the generation of rhythmic peristaltic locomotion. By recording the locomotive motor activities, we further demonstrate that removal of MD neuron input disrupted rhythmic motor firing pattern in a way that prolonged the stereotyped segmental motor firing duration and prevented the propagation of posterior to anterior segmental motor firing. These findings reveal that MD sensory neuron input is a necessary component in the neural circuitry that generates larval locomotion. PMID:17360325

  13. Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia.

    Science.gov (United States)

    Huang, M H; Horackova, M; Negoescu, R M; Wolf, S; Armour, J A

    1996-09-01

    To determine the response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Extracellular recordings were made from 54 spontaneously active and 5 normally quiescent dorsal root ganglion neurones (T2-T5) in 22 anaesthetized open-chest dogs under control conditions and during epicardial mechanical or chemical stimulation and myocardial ischaemia. The activity of 78% of spontaneously active and all quiescent neurones with left ventricular sensory fields was modified by left ventricular ischaemia. Forty-six spontaneously active neurones (85%) were polysensory with respect to mechanical and chemical stimuli. The 5 quiescent neurones responded only to chemical stimuli. Spontaneously active neurones associated with left ventricular mechanosensory endings (37 neurones) generated four different activity patterns in response to similar mechanical stimuli (high or low pressure active, high-low pressure active, high-low pressure inactive). A fifth group generated activity which was not related to chamber dynamics. Adenosine, adenosine 5'-triphosphate, substance P and bradykinin modified 72, 61, 65 and 63% of the spontaneously active neurones, respectively. Maximum local mechanical or chemical stimuli enhanced activity to similar degrees, as did ischaemia. Each ischaemia-sensitive neurone displayed unique activity patterns in response to similar mechanical or chemical stimuli. Most myocardial ischemia-sensitive dorsal root ganglion neurones associated with epicardial neurites sense mechanical and multiple chemical stimuli, a small population sensing only mechanical or chemical stimuli. Activity patterns generated by these neurones depend on their primary sensory characteristics or those of other neurones that may converge on them, as well as the type and magnitude of the stimuli that impinge upon their sensory fields, both normally and during ischaemia.

  14. Opening of pannexin and connexin based-channels increases the excitability of nodose ganglion sensory neurons.

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    Mauricio Antonio Retamal

    2014-06-01

    Full Text Available Satellite glial cells (SGCs are the main glia in sensory ganglia. They surround neuronal bodies and form a cap that prevents the formation of chemical or electrical synapses between neighboring neurons. SGCs have been suggested to establish bidirectional paracrine communication with sensory neurons. However, the molecular mechanism involved in this cellular communication is unknown. In the central nervous system, astrocytes present connexin43 (Cx43 hemichannels and pannexin1 (Panx1 channels, and their opening allows the release of signal molecules, such as ATP and glutamate. We propose that these channels could play a role in the glia-neuron communication in sensory ganglia. Therefore, we studied the expression and function of Cx43 and Panx1 in rat and mouse nodose-petrosal-jugular complex (NPJc by confocal immunofluorescence, molecular and electrophysiological techniques. Cx43 and Panx1 were detected in SGCs and sensory neurons, respectively. In the rat and mouse, the electrical activity of vagal nerve increased significantly after nodose neurons were exposed to Ca2+/ Mg2+-free solution, a condition that increases the open probability of Cx hemichannels. This response was partially mimicked by a cell-permeable peptide corresponding to the last 10 amino acids of Cx43 (TAT-Cx43CT. Enhanced neuronal activity was reduced by Cx hemichannel, Panx1 channel and P2X7 receptor blockers. Moreover, the role of Panx1 was confirmed in NPJc, because Panx1 knockout mouse showed a reduced increase of neuronal activity induced by Ca2+/Mg2+-free extracellular conditions. Data suggest that Cx hemichannels and Panx channels serve as paracrine communication pathways between SGCs and neurons by modulating the excitability of sensory neurons.

  15. Neuronal substrates of sensory gating within the human brain.

    NARCIS (Netherlands)

    Grunwald, T.; Boutros, N.N.; Pezer, N.; Oertzen, J. von; Fernandez, G.S.E.; Schaller, C.; Elger, C.E.

    2003-01-01

    BACKGROUND: For the human brain, habituation to irrelevant sensory input is an important function whose failure is associated with behavioral disturbances. Sensory gating can be studied by recording the brain's electrical responses to repeated clicks: the P50 potential is normally reduced to the

  16. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

    Science.gov (United States)

    Nishida, Kazuhiko; Matsumura, Shinji; Taniguchi, Wataru; Uta, Daisuke; Furue, Hidemasa; Ito, Seiji

    2014-01-01

    The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET)-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  17. Three-dimensional distribution of sensory stimulation-evoked neuronal activity of spinal dorsal horn neurons analyzed by in vivo calcium imaging.

    Directory of Open Access Journals (Sweden)

    Kazuhiko Nishida

    Full Text Available The spinal dorsal horn comprises heterogeneous populations of interneurons and projection neurons, which form neuronal circuits crucial for processing of primary sensory information. Although electrophysiological analyses have uncovered sensory stimulation-evoked neuronal activity of various spinal dorsal horn neurons, monitoring these activities from large ensembles of neurons is needed to obtain a comprehensive view of the spinal dorsal horn circuitry. In the present study, we established in vivo calcium imaging of multiple spinal dorsal horn neurons by using a two-photon microscope and extracted three-dimensional neuronal activity maps of these neurons in response to cutaneous sensory stimulation. For calcium imaging, a fluorescence resonance energy transfer (FRET-based calcium indicator protein, Yellow Cameleon, which is insensitive to motion artifacts of living animals was introduced into spinal dorsal horn neurons by in utero electroporation. In vivo calcium imaging following pinch, brush, and heat stimulation suggests that laminar distribution of sensory stimulation-evoked neuronal activity in the spinal dorsal horn largely corresponds to that of primary afferent inputs. In addition, cutaneous pinch stimulation elicited activities of neurons in the spinal cord at least until 2 spinal segments away from the central projection field of primary sensory neurons responsible for the stimulated skin point. These results provide a clue to understand neuronal processing of sensory information in the spinal dorsal horn.

  18. Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.

    Science.gov (United States)

    Zhang, Tianhe C; Janik, John J; Peters, Ryan V; Chen, Gang; Ji, Ru-Rong; Grill, Warren M

    2015-07-01

    Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry. Copyright © 2015 the American Physiological Society.

  19. Mathematical Relationships between Neuron Morphology and Neurite Growth Dynamics in Drosophila melanogaster Larva Class IV Sensory Neurons

    Science.gov (United States)

    Ganguly, Sujoy; Liang, Xin; Grace, Michael; Lee, Daniel; Howard, Jonathon

    The morphology of neurons is diverse and reflects the diversity of neuronal functions, yet the principles that govern neuronal morphogenesis are unclear. In an effort to better understand neuronal morphogenesis we will be focusing on the development of the dendrites of class IV sensory neuron in Drosophila melanogaster. In particular we attempt to determine how the the total length, and the number of branches of dendrites are mathematically related to the dynamics of neurite growth and branching. By imaging class IV neurons during early embryogenesis we are able to measure the change in neurite length l (t) as a function of time v (t) = dl / dt . We found that the distribution of v (t) is well characterized by a hyperbolic secant distribution, and that the addition of new branches per unit time is well described by a Poisson process. Combining these measurements with the assumption that branching occurs with equal probability anywhere along the dendrite we were able to construct a mathematical model that provides reasonable agreement with the observed number of branches, and total length of the dendrites of the class IV sensory neuron.

  20. Sensory experience shapes the integration of adult-born neurons into the olfactory bulb.

    Science.gov (United States)

    Hanson, Elizabeth; Swanson, Jessica; Arenkiel, Benjamin R

    2017-08-01

    Olfaction is an ancient sensory modality which is heavily involved in viscerally-important tasks like finding food and identifying mates. Olfactory processing involves interpreting stimuli from a non-continuous odor space, and translating them into an organized pattern of neuronal activity in the olfactory bulb. Additionally, olfactory processing is rapidly modulated by behavioral states and vice versa. This implies strong bidirectional neuromodulation between the olfactory bulb and other brain regions that include the cortex, hippocampus, and basal forebrain. Intriguingly, the olfactory bulb is one of the only brain regions where adult-born neurons are integrated into existing networks throughout life. The ongoing integration of adult-born neurons is known to be important for olfactory processing, odor discrimination, and odor learning. Furthermore, the survival and integration of the adult-born neurons is regulated by neuromodulatory signaling, sensory experience, and olfactory learning. Studies making use of new genetic markers to label and manipulate immature adult-born neurons reveal an increase in their population response to odors as they mature. Importantly, this reflects a period of developmental plasticity where adult-born neurons are especially sensitive to sensory experience and olfactory learning. In this review, we discuss the contribution of adult neurogenesis to olfactory bulb plasticity and information processing, with a focus on the developmental plasticity of adult born neurons, and how it is influenced by sensory experience and olfactory learning. Ultimately, recent studies raise important questions about behavioral-state-dependent effects on adult-born neurons, and the consequences of neuromodulation on the developmental plasticity of newborn neurons in the olfactory bulb.

  1. Central Projections of Antennal and Labial Palp Sensory Neurons in the Migratory Armyworm Mythimna separata

    Directory of Open Access Journals (Sweden)

    Bai-Wei Ma

    2017-11-01

    Full Text Available The oriental armyworm, Mythimna separata (Walker, is a polyphagous, migratory pest relying on olfactory cues to find mates, locate nectar, and guide long-distance flight behavior. In the present study, a combination of neuroanatomical techniques were utilized on this species, including backfills, confocal microscopy, and three-dimensional reconstructions, to trace the central projections of sensory neurons from the antenna and the labial pit organ, respectively. As previously shown, the axons of the labial sensory neurons project via the ipsilateral labial nerve and terminate in three main areas of the central nervous system: (1 the labial-palp pit organ glomerulus of each antennal lobe, (2 the gnathal ganglion, and (3 the prothoracic ganglion of the ventral nerve cord. Similarly, the antennal sensory axons project to multiple areas of the central nervous system. The ipsilateral antennal nerve targets mainly the antennal lobe, the antennal mechanosensory and motor center, and the prothoracic and mesothoracic ganglia. Specific staining experiments including dye application to each of the three antennal segments indicate that the antennal lobe receives input from flagellar olfactory neurons exclusively, while the antennal mechanosensory and motor center is innervated by mechanosensory neurons from the whole antenna, comprising the flagellum, pedicle, and scape. The terminals in the mechanosensory and motor center are organized in segregated zones relating to the origin of neurons. The flagellar mechanosensory axons target anterior zones, while the pedicular and scapal axons terminate in posterior zones. In the ventral nerve cord, the processes from the antennal sensory neurons terminate in the motor area of the thoracic ganglia, suggesting a close connection with motor neurons. Taken together, the numerous neuropils innervated by axons both from the antenna and labial palp indicate the multiple roles these sensory organs serve in insect behavior.

  2. The sensory neurone membrane protein SNMP1 contributes to the sensitivity of a pheromone detection system.

    Science.gov (United States)

    Pregitzer, P; Greschista, M; Breer, H; Krieger, J

    2014-12-01

    Male moths detect female-released sex pheromones with extraordinary sensitivity. The remarkable sensory ability is based on a cooperative interplay of pheromone binding proteins in the lymph of hair-like sensilla trichodea and pheromone receptors in the dendrites of sensory neurones. Here we examined whether in Heliothis virescens the so-called 'sensory neurone membrane protein 1' (SNMP1) may contribute to responsiveness to the pheromone component, (Z)-11-hexadecenal (Z11-16:Ald). By means of immunohistochemistry and in situ hybridization we demonstrated that SNMP1 is in fact present in cells expressing the Z11-16:Ald receptor HR13 and the dendrites of sensory neurones. To assess a possible function of SNMP1 we monitored the responsiveness of cell lines that expressed HR13 alone or the combination SNMP1/HR13 to stimulation with Z11-16:Ald by calcium imaging. It was found that SNMP1/HR13 cells were 1000-fold more sensitive to pheromone stimulation compared with HR13 cells. In contrast, cells that expressed HR13 and the non-neuronal SNMP2-type showed no change in pheromone sensitivity. Overall, our reconstitution experiments demonstrate that the presence of SNMP1 significantly increases the HR13-based responsiveness of cells to Z11-16:Ald, suggesting that SNMP1 also contributes to the response of the antennal neurones and thus to the remarkable sensitivity of the pheromone detection system. © 2014 The Royal Entomological Society.

  3. ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons

    Directory of Open Access Journals (Sweden)

    Fierro Leonardo

    2005-11-01

    Full Text Available Abstract Background ASIC3, the most sensitive of the acid-sensing ion channels, depolarizes certain rat sensory neurons when lactic acid appears in the extracellular medium. Two functions have been proposed for it: 1 ASIC3 might trigger ischemic pain in heart and muscle; 2 it might contribute to some forms of touch mechanosensation. Here, we used immunocytochemistry, retrograde labelling, and electrophysiology to ask whether the distribution of ASIC3 in rat sensory neurons is consistent with either of these hypotheses. Results Less than half (40% of dorsal root ganglion sensory neurons react with anti-ASIC3, and the population is heterogeneous. They vary widely in cell diameter and express different growth factor receptors: 68% express TrkA, the receptor for nerve growth factor, and 25% express TrkC, the NT3 growth factor receptor. Consistent with a role in muscle nociception, small ( Conclusion Our data indicates that: 1 ASIC3 is expressed in a restricted population of nociceptors and probably in some non-nociceptors; 2 co-expression of ASIC3 and CGRP, and the absence of P2X3, are distinguishing properties of a class of sensory neurons, some of which innervate blood vessels. We suggest that these latter afferents may be muscle metaboreceptors, neurons that sense the metabolic state of muscle and can trigger pain when there is insufficient oxygen.

  4. Calcium-activated chloride current expression in axotomized sensory neurons: what for?

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    Mathieu eBoudes

    2012-03-01

    Full Text Available Calcium-activated chloride currents (CaCCs are activated by an increase in intracellular calcium concentration. Peripheral nerve injury induces the expression of CaCCs in a subset of adult sensory neurons in primary culture including mechano-and proprioceptors, though not nociceptors. Functional screenings of potential candidate genes established that Best1 is a molecular determinant for CaCC expression among axotomized sensory neurons, while Tmem16a accounts for inflammation-induced CaCC expression in nociceptors. In nociceptors, such CaCCs are preferentially activated under receptor-induced calcium mobilization contributing to cell excitability and pain. In axotomized mechano- and proprioceptors, CaCC activation does not promote electrical activity and prevents firing, a finding consistent with electrical silencing for growth competence of adult sensory neurons. In favor of a role in the process of neurite growth, CaCC expression is temporally correlated to neurons displaying a regenerative mode of growth. This perspective focuses on the molecular identity and role of CaCC in axotomized sensory neurons and the future directions to decipher the cellular mechanisms regulating CaCC during neurite (regrowth.

  5. Bidirectional communication between sensory neurons and osteoblasts in an in vitro coculture system.

    Science.gov (United States)

    Kodama, Daisuke; Hirai, Takao; Kondo, Hisataka; Hamamura, Kazunori; Togari, Akifumi

    2017-02-01

    Recent studies have revealed that the sensory nervous system is involved in bone metabolism. However, the mechanism of communication between neurons and osteoblasts is yet to be elucidated. In this study, we investigated the signaling pathways between sensory neurons of the dorsal root ganglion (DRG) and the osteoblast-like MC3T3-E1 cells using an in vitro coculture system. Our findings indicate that signal transduction from DRG-derived neurons to MC3T3-E1 cells is suppressed by antagonists of the AMPA receptor and the NK 1 receptor. Conversely, signal transduction from MC3T3-E1 cells to DRG-derived neurons is suppressed by a P2X 7 receptor antagonist. Our results suggest that these cells communicate with each other by exocytosis of glutamate, substance P in the efferent signal, and ATP in the afferent signal. © 2017 Federation of European Biochemical Societies.

  6. The Drosophila female aphrodisiac pheromone activates ppk23(+) sensory neurons to elicit male courtship behavior.

    Science.gov (United States)

    Toda, Hirofumi; Zhao, Xiaoliang; Dickson, Barry J

    2012-06-28

    Females of many animal species emit chemical signals that attract and arouse males for mating. For example, the major aphrodisiac pheromone of Drosophila melanogaster females, 7,11-heptacosadiene (7,11-HD), is a potent inducer of male-specific courtship and copulatory behaviors. Here, we demonstrate that a set of gustatory sensory neurons on the male foreleg, defined by expression of the ppk23 marker, respond to 7,11-HD. Activity of these neurons is required for males to robustly court females or to court males perfumed with 7,11-HD. Artificial activation of these ppk23(+) neurons stimulates male-male courtship even without 7,11-HD perfuming. These data identify the ppk23(+) sensory neurons as the primary targets for female sex pheromones in Drosophila. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

  7. The Drosophila Female Aphrodisiac Pheromone Activates ppk23+ Sensory Neurons to Elicit Male Courtship Behavior

    Directory of Open Access Journals (Sweden)

    Hirofumi Toda

    2012-06-01

    Full Text Available Females of many animal species emit chemical signals that attract and arouse males for mating. For example, the major aphrodisiac pheromone of Drosophila melanogaster females, 7,11-heptacosadiene (7,11-HD, is a potent inducer of male-specific courtship and copulatory behaviors. Here, we demonstrate that a set of gustatory sensory neurons on the male foreleg, defined by expression of the ppk23 marker, respond to 7,11-HD. Activity of these neurons is required for males to robustly court females or to court males perfumed with 7,11-HD. Artificial activation of these ppk23+ neurons stimulates male-male courtship even without 7,11-HD perfuming. These data identify the ppk23+ sensory neurons as the primary targets for female sex pheromones in Drosophila.

  8. Synthesis and evaluation of the racemate and individual enantiomers of C-11 labeled methylphenidate as radioligands for the presynaptic dopaminergic neuron

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Y.S.; Fowler, J.S.; Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1994-05-01

    Methylphenidate (MP, ritalin) is a psychostimulant drug widely used to treat attention deficit hyperactivity disorder and narcolepsy. Its therapeutic properties are attributed to inhibition of the dopamine (DA) transporter enhancing synaptic DA. MP has two chiral centers and is marketed as the dl-threo racemic form. However, its pharmacological activity is believed due solely to the d-enantiomer. We have synthesized [{sup 11}C]d,l-threo-methylphenidate ([{sup 11}C]MP) in order to examine its pharmacokinetics in vivo and to examine its suitability as a radioligand for PET studies of the presynaptic DA neuron. [{sup 11}C]MP was prepared by O-{sup 11}C-alkylation of a protected derivative of ritalinic acid with labeled methyl iodide. Serial studies at baseline and after treatment with methylphenidate (0.5 mg/kg, 20 min prior); GBR 12909 (1.5 mg/kg; 30 min prior); tomoxetine (1.5 mg/kg, 20 min prior) and citalopram (2.0 mg/kg, 30 min prior) were performed to assess non-specific binding and binding to the DA, norepinephrine and serotonin transporters respectively. Only MP and GBR 12909 changed the SR/CB distribution volume ratio (decrease of 38 and 37% respectively) demonstrating selectivity for DA transporters over other monoamine transporters. We then pursued the synthesis of enantiomerically pure C-{sup 11} labeled d- and l-MP by using enantiomerically pure protected d- and l-ritalinic acids as precursors. A striking difference in SR/CB ratio (3.3 and 1.1 for d- and l-respectively at 1 hr. after i.v. injections) strongly suggests that the pharmacological specificity of MP resides entirely in the d-isomer and the binding of l-isomer was mostly non-specific. Further evaluations are underway. Radioligand reversibility, selectivity and the fact that MP is an approved drug are advantages of using [{sup 11}C]MP.

  9. PLCγ-activated signalling is essential for TrkB mediated sensory neuron structural plasticity

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    Rocha-Sanchez Sonia M

    2010-10-01

    Full Text Available Abstract Background The vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental. Results Here we report that a point mutation at the phospholipase Cγ (PLCγ docking site in the mouse neurotrophin tyrosine kinase receptor TrkB (Ntrk2 specifically impairs fiber guidance inside the vestibular sensory epithelia, but has limited effects on the survival of vestibular sensory neurons and growth of afferent processes toward the sensory epithelia. We also show that expression of the TRPC3 cation calcium channel, whose activity is known to be required for nerve-growth cone guidance induced by brain-derived neurotrophic factor (BDNF, is altered in these animals. In addition, we find that absence of the PLCγ mediated TrkB signalling interferes with the transformation of bouton type afferent terminals of vestibular dendrites into calyces (the largest synaptic contact of dendrites known in the mammalian nervous system on type I vestibular hair cells; the latter are normally distributed in these mutants as revealed by an unaltered expression pattern of the potassium channel KCNQ4 in these cells. Conclusions These results demonstrate a crucial involvement of the TrkB/PLCγ-mediated intracellular signalling in structural aspects of sensory neuron plasticity.

  10. Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons.

    Science.gov (United States)

    Bao, Lan

    2015-09-30

    Voltage-gated sodium channels (Navs) comprise at least nine pore-forming α subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

  11. Rat model of cancer-induced bone pain: changes in nonnociceptive sensory neurons in vivo

    Directory of Open Access Journals (Sweden)

    Yong Fang Zhu

    2017-08-01

    Conclusion:. After induction of the CIBP model, Aβ-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Aβ-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP.

  12. Acute exposure to high‐induction electromagnetic field affects activity of model peripheral sensory neurons

    Czech Academy of Sciences Publication Activity Database

    Průcha, J.; Krůšek, Jan; Dittert, Ivan; Sinica, Viktor; Kádková, Anna; Vlachová, Viktorie

    2018-01-01

    Roč. 22, č. 2 (2018), s. 1355-1362 ISSN 1582-4934 R&D Projects: GA MZd(CZ) NV16-28784A Institutional support: RVO:67985823 Keywords : electromagnetic field * primary sensory neuron * ion channel * bradykinin receptor * transient receptor potential channel Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 4.499, year: 2016

  13. Frequency-dependent depression of excitatory synaptic transmission is independent of activation of MCPG-sensitive presynaptic metabotropic glutamate receptors in cultured hippocampal neurons.

    Science.gov (United States)

    Maki, R; Cummings, D D; Dichter, M A

    1995-10-01

    1. A paired-pulse paradigm, and a high-frequency train followed by a test pulse, were used to investigate the possible role of presynaptic metabotropic glutamate receptors (mGluRs) in frequency-dependent modulation of the amplitude of excitatory post-synaptic currents (EPSCs). Paired whole cell patch-clamp recordings from monosynaptically connected hippocampal neurons maintained in very low-density cultures were performed, using the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 500 microM) and the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, 100 microM]. 2. Paired-pulse depression (PPD) was observed in all the excitatory pairs recorded. The average PPD ratio (amplitude of the 2nd EPSC divided by the amplitude of the 1st EPSC) was 0.80 +/- 0.1 (SD) (n = 8). Application of the mGluR antagonist MCPG had no effect on the amplitude of the EPSCs and did not affect the ratio of the two EPSCs (PPD ratio 0.79 +/- 0.2). 3. The amplitudes of 10 successive EPSCs stimulated at a high frequency (20 Hz) decremented on average in both 4 mM extracellular Ca2+ (n = 5) and in 1 mM extracellular Ca2+ (n = 6). In all pairs tested, posttetanic depression (PTD) was observed (PTD ratio 0.7 +/- 0.2). Bath application of MCPG (500 microM) did not affect the amplitudes of the EPSCs during the train; MCPG also did not affect PTD. 4. The mGluR agonist (1S,3R)-ACPD depressed the amplitudes of the EPSCs in both the paired-pulse (1st EPSC, 35 +/- 9%; 2nd EPSC, 36 +/- 10%) and posttetanic pulse (1 and 4 mM extracellular Ca2+) paradigms. The amount of depression observed, both PPD and PTD, remained unaffected by application of (1S,3R)-ACPD. Coapplication of the antagonist MCPG (500 microM) blocked the effects of (1S,3R)-ACPD (100 microM). 5. We conclude that frequency-dependent depression of EPSC amplitudes occurs independent of endogenous activation of MCPG-sensitive mGluRs in cultured hippocampal neurons. Moreover, we demonstrate that exogenous

  14. Intrinsic frequency response patterns in mechano-sensory neurons of the leech

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    Linda Fischer

    2017-07-01

    Full Text Available Animals employ mechano-sensory systems to detect and explore their environment. Mechano-sensation encompasses stimuli such as constant pressure, surface movement or vibrations at various intensities that need to be segregated in the central nervous system. Besides different receptor structures, sensory filtering via intrinsic response properties could provide a convenient way to solve this problem. In leech, three major mechano-sensory cell types can be distinguished, according to their stimulus sensitivity, as nociceptive, pressure and touch cells. Using intracellular recordings, we show that the different mechano-sensory neuron classes in Hirudo medicinalis differentially respond supra-threshold to distinct frequencies of sinusoidal current injections between 0.2 and 20 Hz. Nociceptive cells responded with a low-pass filter characteristic, pressure cells as high-pass filters and touch cells as an intermediate band-pass filter. Each class of mechano-sensory neurons is thus intrinsically tuned to a specific frequency range of voltage oscillation that could help segregate mechano-sensory information centrally.

  15. Intrinsic frequency response patterns in mechano-sensory neurons of the leech.

    Science.gov (United States)

    Fischer, Linda; Scherbarth, Frank; Chagnaud, Boris; Felmy, Felix

    2017-07-15

    Animals employ mechano-sensory systems to detect and explore their environment. Mechano-sensation encompasses stimuli such as constant pressure, surface movement or vibrations at various intensities that need to be segregated in the central nervous system. Besides different receptor structures, sensory filtering via intrinsic response properties could provide a convenient way to solve this problem. In leech, three major mechano-sensory cell types can be distinguished, according to their stimulus sensitivity, as nociceptive, pressure and touch cells. Using intracellular recordings, we show that the different mechano-sensory neuron classes in Hirudo medicinalis differentially respond supra-threshold to distinct frequencies of sinusoidal current injections between 0.2 and 20 Hz. Nociceptive cells responded with a low-pass filter characteristic, pressure cells as high-pass filters and touch cells as an intermediate band-pass filter. Each class of mechano-sensory neurons is thus intrinsically tuned to a specific frequency range of voltage oscillation that could help segregate mechano-sensory information centrally. © 2017. Published by The Company of Biologists Ltd.

  16. Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro

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    Brianna K. Swartwout

    2017-10-01

    Full Text Available Zika virus (ZIKV has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

  17. Zika Virus Persistently and Productively Infects Primary Adult Sensory Neurons In Vitro.

    Science.gov (United States)

    Swartwout, Brianna K; Zlotnick, Marta G; Saver, Ashley E; McKenna, Caroline M; Bertke, Andrea S

    2017-10-13

    Zika virus (ZIKV) has recently surged in human populations, causing an increase in congenital and Guillain-Barré syndromes. While sexual transmission and presence of ZIKV in urine, semen, vaginal secretions, and saliva have been established, the origin of persistent virus shedding into biological secretions is not clear. Using a primary adult murine neuronal culture model, we have determined that ZIKV persistently and productively infects sensory neurons of the trigeminal and dorsal root ganglia, which innervate glands and mucosa of the face and the genitourinary tract, respectively, without apparent injury. Autonomic neurons that innervate these regions are not permissive for infection. However, productive ZIKV infection of satellite glial cells that surround and support sensory and autonomic neurons in peripheral ganglia results in their destruction. Persistent infection of sensory neurons, without affecting their viability, provides a potential reservoir for viral shedding in biological secretions for extended periods of time after infection. Furthermore, viral destruction of satellite glial cells may contribute to the development of Guillain-Barré Syndrome via an alternative mechanism to the established autoimmune response.

  18. Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death

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    Fernandez Pierre-Alain

    2006-11-01

    Full Text Available Abstract Background The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS. Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause. Results We report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context. Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons. Conclusion Overall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor.

  19. Transcriptome Analysis of Chemically-Induced Sensory Neuron Ablation in Zebrafish.

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    Jane A Cox

    Full Text Available Peripheral glia are known to have a critical role in the initial response to axon damage and degeneration. However, little is known about the cellular responses of non-myelinating glia to nerve injury. In this study, we analyzed the transcriptomes of wild-type and mutant (lacking peripheral glia zebrafish larvae that were treated with metronidazole. This treatment allowed us to conditionally and selectively ablate cranial sensory neurons whose axons are ensheathed only by non-myelinating glia. While transcripts representing over 27,000 genes were detected by RNAseq, only a small fraction (~1% of genes were found to be differentially expressed in response to neuronal degeneration in either line at either 2 hrs or 5 hrs of metronidazole treatment. Analysis revealed that most expression changes (332 out of the total of 458 differentially expressed genes occurred over a continuous period (from 2 to 5 hrs of metronidazole exposure, with a small number of genes showing changes limited to only the 2 hr (55 genes or 5 hr (71 genes time points. For genes with continuous alterations in expression, some of the most meaningful sets of enriched categories in the wild-type line were those involving the inflammatory TNF-alpha and IL6 signaling pathways, oxidoreductase activities and response to stress. Intriguingly, these changes were not observed in the mutant line. Indeed, cluster analysis indicated that the effects of metronidazole treatment on gene expression was heavily influenced by the presence or absence of glia, indicating that the peripheral non-myelinating glia play a significant role in the transcriptional response to sensory neuron degeneration. This is the first transcriptome study of metronidazole-induced neuronal death in zebrafish and the response of non-myelinating glia to sensory neuron degeneration. We believe this study provides important insight into the mechanisms by which non-myelinating glia react to neuronal death and degeneration in

  20. p75 Is Required for the Establishment of Postnatal Sensory Neuron Diversity by Potentiating Ret Signaling.

    Science.gov (United States)

    Chen, Zhijiang; Donnelly, Christopher R; Dominguez, Bertha; Harada, Yoshinobu; Lin, Weichun; Halim, Alan S; Bengoechea, Tasha G; Pierchala, Brian A; Lee, Kuo-Fen

    2017-10-17

    Producing the neuronal diversity required to adequately discriminate all elements of somatosensation is a complex task during organogenesis. The mechanisms guiding this process during dorsal root ganglion (DRG) sensory neuron specification remain poorly understood. Here, we show that the p75 neurotrophin receptor interacts with Ret and its GFRα co-receptor upon stimulation with glial cell line-derived neurotrophic factor (GDNF). Furthermore, we demonstrate that p75 is required for GDNF-mediated Ret activation, survival, and cell surface localization of Ret in DRG neurons. In mice in which p75 is deleted specifically within sensory neurons beginning at E12.5, we observe that approximately 20% of neurons are lost between P14 and adulthood, and these losses selectively occur within a subpopulation of Ret + nonpeptidergic nociceptors, with neurons expressing low levels of Ret impacted most heavily. These results suggest that p75 is required for the development of the nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones

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    Ross Ruth

    2011-02-01

    Full Text Available Abstract The neuropeptide substance-P (SP is expressed from the TAC1 gene in sensory neurones where it acts as a key modulator of neurogenic inflammation. The promoter of TAC1 (TAC1prom plays a central role in the regulation of the TAC1 gene but requires the presence of a second regulatory element; ECR2, to support TAC1 expression in sensory neurones and to respond appropriately to signalling pathways such as MAPkinases and noxious induction by capsaicin. We examined whether the effect of capsaicin on ECR2-TAC1prom activity in larger diameter neurones was cell autonomous or non- cell autonomous. We demonstrate that TRPV1 is not expressed in all the same cells as SP following capsaicin induction suggesting the presence of a non-cell autonomous mechanism for TAC1 up-regulation following capsaicin induction. In addition, we demonstrate that induction of SP and ECR1-TAC1prom activity in these larger diameter neurones can be induced by potassium depolarisation suggesting that, in addition to capsaicin induction, transgene activity may be modulated by voltage gated calcium channels. Furthermore, we show that NK1 is expressed in all SP- expressing cells after capsaicin induction and that an agonist of NK1 can activate both SP and the transgene in larger diameter neurones. These observations suggest the presence of an autocrine loop that controls the expression of the TAC1 promoter in sensory neurones. In contrast, induction of the TAC1 promoter by LPS was not dependent on ECR2 and did not occur in large diameter neurones. These studies demonstrate the diversity of mechanisms modulating the activity of the TAC1 promoter and provide novel directions for the development of new anti-inflammatory therapies.

  2. Chronic odorant exposure upregulates acquisition of functional properties in cultured embryonic chick olfactory sensory neurons.

    Science.gov (United States)

    O'Neill, Grace; Musto, Christa; Gomez, George

    2017-05-01

    Neuronal development and differentiation is modulated by activity-dependent mechanisms that stimulate endogenous neurogenesis and differentiation to promote adaptive survival of the organism. Studies on bird odor imprinting have shown how sensory stimuli or environmental influences can affect neonatal behavior, presumably by remodeling the developing nervous system. It is unclear whether these changes originate from the sensory neurons themselves or from the brain. Thus, we attempted to address this by using an in vitro system to separate the peripheral neurons from their central connections. Olfactory neurons from embryonic day 17 Gallus domesticus chicks were isolated, cultured, and exposed to 100 µM amyl acetate or phenethyl alcohol in 12-hr bouts, alternated with periods of no-odor exposure. On days 4 and 5 in vitro, cells were immunostained for olfactory marker protein, neuron-specific tubulin, and olfactory GTP-binding protein, and tested for odorant sensitivity using calcium imaging. While odorant exposure did not result in a significant increase in the overall number of neurons, it promoted neuron differentiation: a larger proportion of odorant-exposed cells expressed olfactory marker protein and the olfactory GTP-binding protein. When cell responsiveness was tested using calcium imaging, a greater proportion of odorant-exposed cells responded to stimulation with 100 µM amyl acetate or phenethyl alcohol. Thus, odorant exposure during development modulated the developmental trajectories of individual neurons, resulting in changes in protein expression associated with odorant signaling. This suggests that the neuronal changes in the periphery have an important contribution to the overall long-term functional changes associated with odor imprinting. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Different requirements for GFRα2-signaling in three populations of cutaneous sensory neurons.

    Science.gov (United States)

    Kupari, Jussi; Airaksinen, Matti S

    2014-01-01

    Many primary sensory neurons in mouse dorsal root ganglia (DRG) express one or several GFRα's, the ligand-binding receptors of the GDNF family, and their common signaling receptor Ret. GFRα2, the principal receptor for neurturin, is expressed in most of the small nonpeptidergic DRG neurons, but also in some large DRG neurons that start to express Ret earlier. Previously, GFRα2 has been shown to be crucial for the soma size of small nonpeptidergic nociceptors and for their target innervation of glabrous epidermis. However, little is known about this receptor in other Ret-expressing DRG neuron populations. Here we have investigated two populations of Ret-positive low-threshold mechanoreceptors that innervate different types of hair follicles on mouse back skin: the small C-LTMRs and the large Aβ-LTMRs. Using GFRα2-KO mice and immunohistochemistry we found that, similar to the nonpeptidergic nociceptors, GFRα2 controls the cell size but not the survival of both C-LTMRs and Aβ-LTMRs. In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin. These results suggest that different factors drive target innervation in these three populations of neurons. In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

  4. Sensory Neuron Fates Are Distinguished by a Transcriptional Switch that Regulates Dendrite Branch Stabilization

    Science.gov (United States)

    Smith, Cody J.; O’Brien, Timothy; Chatzigeorgiou, Marios; Spencer, W. Clay; Feingold-Link, Elana; Husson, Steven J.; Hori, Sayaka; Mitani, Shohei; Gottschalk, Alexander; Schafer, William R.; Miller, David M.

    2013-01-01

    SUMMARY Sensory neurons adopt distinct morphologies and functional modalities to mediate responses to specific stimuli. Transcription factors and their downstream effectors orchestrate this outcome but are incompletely defined. Here, we show that different classes of mechanosensory neurons in C. elegans are distinguished by the combined action of the transcription factors MEC-3, AHR-1, and ZAG-1. Low levels of MEC-3 specify the elaborate branching pattern of PVD nociceptors, whereas high MEC-3 is correlated with the simple morphology of AVM and PVM touch neurons. AHR-1 specifies AVM touch neuron fate by elevating MEC-3 while simultaneously blocking expression of nociceptive genes such as the MEC-3 target, the claudin-like membrane protein HPO-30, that promotes the complex dendritic branching pattern of PVD. ZAG-1 exercises a parallel role to prevent PVM from adopting the PVD fate. The conserved dendritic branching function of the Drosophila AHR-1 homolog, Spineless, argues for similar pathways in mammals. PMID:23889932

  5. Depletion of calcium stores in injured sensory neurons: anatomic and functional correlates.

    Science.gov (United States)

    Gemes, Geza; Rigaud, Marcel; Weyker, Paul D; Abram, Stephen E; Weihrauch, Dorothee; Poroli, Mark; Zoga, Vasiliki; Hogan, Quinn H

    2009-08-01

    Painful nerve injury leads to disrupted Ca signaling in primary sensory neurons, including decreased endoplasmic reticulum (ER) Ca storage. This study examines potential causes and functional consequences of Ca store limitation after injury. Neurons were dissociated from axotomized fifth lumbar (L5) and the adjacent L4 dorsal root ganglia after L5 spinal nerve ligation that produced hyperalgesia, and they were compared to neurons from control animals. Intracellular Ca levels were measured with Fura-2 microfluorometry, and ER was labeled with probes or antibodies. Ultrastructural morphology was analyzed by electron microscopy of nondissociated dorsal root ganglia, and intracellular electrophysiological recordings were obtained from intact ganglia. Live neuron staining with BODIPY FL-X thapsigargin (Invitrogen, Carlsbad, CA) revealed a 40% decrease in sarco-endoplasmic reticulum Ca-ATPase binding in axotomized L5 neurons and a 34% decrease in L4 neurons. Immunocytochemical labeling for the ER Ca-binding protein calreticulin was unaffected by injury. Total length of ER profiles in electron micrographs was reduced by 53% in small axotomized L5 neurons, but it was increased in L4 neurons. Cisternal stacks of ER and aggregation of ribosomes occurred less frequently in axotomized neurons. Ca-induced Ca release, examined by microfluorometry with dantrolene, was eliminated in axotomized neurons. Pharmacologic blockade of Ca-induced Ca release with dantrolene produced hyperexcitability in control neurons, confirming its functional importance. After axotomy, ER Ca stores are reduced by anatomic loss and possibly diminished sarco-endoplasmic reticulum Ca-ATPase. The resulting disruption of Ca-induced Ca release and protein synthesis may contribute to the generation of neuropathic pain.

  6. Knockout of glial channel ACD-1 exacerbates sensory deficits in a C. elegans mutant by regulating calcium levels of sensory neurons.

    Science.gov (United States)

    Wang, Ying; D'Urso, Giulia; Bianchi, Laura

    2012-01-01

    Degenerin/epithelial Na(+) channels (DEG/ENaCs) are voltage-independent Na(+) or Na(+)/Ca(2+) channels expressed in many tissues and are needed for a wide range of physiological functions, including sensory perception and transepithelial Na(+) transport. In the nervous system, DEG/ENaCs are expressed in both neurons and glia. However, the role of glial vs. neuronal DEG/ENaCs remains unclear. We recently reported the characterization of a novel DEG/ENaC in Caenorhabditis elegans that we named ACD-1. ACD-1 is expressed in glial amphid sheath cells. The glial ACD-1, together with the neuronal DEG/ENaC DEG-1, is necessary for acid avoidance and attraction to lysine. We report presently that knockout of acd-1 in glia exacerbates sensory deficits caused by another mutant: the hypomorphic allele of the cGMP-gated channel subunit tax-2. Furthermore, sensory deficits caused by mutations in G(i) protein odr-3 and guanylate cyclase daf-11, which regulate the activity of TAX-2/TAX-4 channels, are worsened by knockout of acd-1. We also show that sensory neurons of acd-1 tax-2(p694) double mutants fail to undergo changes in intracellular Ca(2+) when animals are exposed to low concentrations of attractant. Finally, we show that exogenous expression of TRPV1 in sensory neurons and exposure to capsaicin rescue sensory deficits of acd-1 tax-2(p694) mutants, suggesting that sensory deficits of these mutants are bypassed by increasing neuronal excitability. Our data suggest a role of glial DEG/ENaC channel ACD-1 in supporting neuronal activity.

  7. The Drosophila Female Aphrodisiac Pheromone Activates ppk23+ Sensory Neurons to Elicit Male Courtship Behavior

    OpenAIRE

    Toda, Hirofumi; Zhao, Xiaoliang; Dickson, Barry J.

    2012-01-01

    Females of many animal species emit chemical signals that attract and arouse males for mating. For example, the major aphrodisiac pheromone of Drosophila melanogaster females, 7,11-heptacosadiene (7,11-HD), is a potent inducer of male-specific courtship and copulatory behaviors. Here, we demonstrate that a set of gustatory sensory neurons on the male foreleg, defined by expression of the ppk23 marker, respond to 7,11-HD. Activity of these neurons is required for males to robustly court female...

  8. Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates.

    Science.gov (United States)

    Yajima, Hiroshi; Suzuki, Makoto; Ochi, Haruki; Ikeda, Keiko; Sato, Shigeru; Yamamura, Ken-ichi; Ogino, Hajime; Ueno, Naoto; Kawakami, Kiyoshi

    2014-05-29

    Various senses and sensory nerve architectures of animals have evolved during adaptation to exploit diverse environments. In craniates, the trunk sensory system has evolved from simple mechanosensory neurons inside the spinal cord (intramedullary), called Rohon-Beard (RB) cells, to multimodal sensory neurons of dorsal root ganglia (DRG) outside the spinal cord (extramedullary). The fish and amphibian trunk sensory systems switch from RB cells to DRG during development, while amniotes rely exclusively on the DRG system. The mechanisms underlying the ontogenic switching and its link to phylogenetic transition remain unknown. In Xenopus, Six1 overexpression promoted precocious apoptosis of RB cells and emergence of extramedullary sensory neurons, whereas Six1 knockdown delayed the reduction in RB cell number. Genetic ablation of Six1 and Six4 in mice led to the appearance of intramedullary sensory neuron-like cells as a result of medial migration of neural crest cells into the spinal cord and production of immature DRG neurons and fused DRG. Restoration of SIX1 expression in the neural crest-linage partially rescued the phenotype, indicating the cell autonomous requirements of SIX1 for normal extramedullary sensory neurogenesis. Mouse Six1 enhancer that mediates the expression in DRG neurons activated transcription in Xenopus RB cells earlier than endogenous six1 expression, suggesting earlier onset of mouse SIX1 expression than Xenopus during sensory development. The results indicated the critical role of Six1 in transition of RB cells to DRG neurons during Xenopus development and establishment of exclusive DRG system of mice. The study provided evidence that early appearance of SIX1 expression, which correlated with mouse Six1 enhancer, is essential for the formation of DRG-dominant system in mice, suggesting that heterochronic changes in Six1 enhancer sequence play an important role in alteration of trunk sensory architecture and contribute to the evolution of the

  9. Inflammatory mediator bradykinin increases population of sensory neurons expressing functional T-type Ca(2+) channels.

    Science.gov (United States)

    Huang, Dongyang; Liang, Ce; Zhang, Fan; Men, Hongchao; Du, Xiaona; Gamper, Nikita; Zhang, Hailin

    2016-04-29

    T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude. When applied individually, BK and ATP also increased the population size of LVA-positive neurons while NE and PGE2 had no effect. The PLC inhibitor U-73122 and B2 receptor antagonist, Hoe-140, both abolished the increase of the population of LVA-positive DRG neurons. Inflammatory treatment did not affect CaV3.2 mRNA or protein levels in DRG cultures. Furthermore, an ubiquitination inhibitor, MG132, did not increase the population of LVA-positive neurons. Our data suggest that inflammatory mediators BK and ATP increase the abundance of LVA-positive DRG neurons in total neuronal population by stimulating the recruitment of a 'reserve pool' of CaV3.2 channels, particularly in neurons that do not display measurable LVA currents under control conditions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Ebi/AP-1 suppresses pro-apoptotic genes expression and permits long-term survival of Drosophila sensory neurons.

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    Young-Mi Lim

    Full Text Available Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1 is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box-like and WD40 repeats-containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1 and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration.

  11. A presynaptic role for PKA in synaptic tagging and memory

    NARCIS (Netherlands)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer H K; Luczak, Vincent; Nie, Ting; Huang, Ted; Abel, Ted

    2014-01-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and

  12. The Site of Spontaneous Ectopic Spike Initiation Facilitates Signal Integration in a Sensory Neuron.

    Science.gov (United States)

    Städele, Carola; Stein, Wolfgang

    2016-06-22

    a single-cell sensory neuron in the stomatogastric nervous system. Action potentials were consistently initiated at a specific region of the axon trunk, near a motor neuropil. Spike frequency was regulated by motor neuron activity, but only if spike initiation occurred at this location. Neuromodulation of the axon dislocated the site of initiation, resulting in abolishment of signal integration from motor neurons. Thus, neuromodulation allows for a dynamic adjustment of axonal signal integration. Copyright © 2016 the authors 0270-6474/16/366718-14$15.00/0.

  13. Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination.

    Science.gov (United States)

    Clark, Alex J; Kaller, Malte S; Galino, Jorge; Willison, Hugh J; Rinaldi, Simon; Bennett, David L H

    2017-04-01

    See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1.2) at the juxtaparanode. Expression of type III neuregulin-1 (TIIINRG1) in induced pluripotent stem cell-derived sensory neurons strongly enhances myelination, while conversely pharmacological blockade of the NRG1-ErbB pathway prevents myelination, providing direct evidence for the ability of this pathway to promote the myelination of human sensory axons. The β-secretase, BACE1 is a protease needed to generate active NRG1 from the full-length form. Due to the fact that it also cleaves amyloid precursor protein, BACE1 is a therapeutic target in Alzheimer's disease, however, consistent with its role in NRG1 processing we find that BACE1 inhibition significantly impairs myelination in our co-culture system. In order to exploit co-cultures to address other clinically relevant problems, they were exposed to anti-disialosyl ganglioside antibodies, including those derived from a patient with a sensory predominant, inflammatory neuropathy with mixed axonal and demyelinating electrophysiology. The co-cultures reveal that both mouse and human disialosyl antibodies target the nodal axolemma, induce acute axonal degeneration in the presence of complement, and impair myelination. The human, neuropathy-associated IgM antibody is also shown to induce complement-independent demyelination

  14. Conserved RNA-Binding Proteins Required for Dendrite Morphogenesis in Caenorhabditis elegans Sensory Neurons

    Science.gov (United States)

    Antonacci, Simona; Forand, Daniel; Wolf, Margaret; Tyus, Courtney; Barney, Julia; Kellogg, Leah; Simon, Margo A.; Kerr, Genevieve; Wells, Kristen L.; Younes, Serena; Mortimer, Nathan T.; Olesnicky, Eugenia C.; Killian, Darrell J.

    2015-01-01

    The regulation of dendritic branching is critical for sensory reception, cell−cell communication within the nervous system, learning, memory, and behavior. Defects in dendrite morphology are associated with several neurologic disorders; thus, an understanding of the molecular mechanisms that govern dendrite morphogenesis is important. Recent investigations of dendrite morphogenesis have highlighted the importance of gene regulation at the posttranscriptional level. Because RNA-binding proteins mediate many posttranscriptional mechanisms, we decided to investigate the extent to which conserved RNA-binding proteins contribute to dendrite morphogenesis across phyla. Here we identify a core set of RNA-binding proteins that are important for dendrite morphogenesis in the PVD multidendritic sensory neuron in Caenorhabditis elegans. Homologs of each of these genes were previously identified as important in the Drosophila melanogaster dendritic arborization sensory neurons. Our results suggest that RNA processing, mRNA localization, mRNA stability, and translational control are all important mechanisms that contribute to dendrite morphogenesis, and we present a conserved set of RNA-binding proteins that regulate these processes in diverse animal species. Furthermore, homologs of these genes are expressed in the human brain, suggesting that these RNA-binding proteins are candidate regulators of dendrite development in humans. PMID:25673135

  15. Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

    Science.gov (United States)

    Wieland, Sebastian; Schindler, Sebastian; Huber, Cathrin; Köhr, Georg; Oswald, Manfred J; Kelsch, Wolfgang

    2015-07-08

    Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum. Copyright © 2015 the authors 0270-6474/15/359946-11$15.00/0.

  16. Cutaneous TRPM8-expressing sensory afferents are a small population of neurons with unique firing properties.

    Science.gov (United States)

    Jankowski, Michael P; Rau, Kristofer K; Koerber, H Richard

    2017-04-01

    It has been well documented that the transient receptor potential melastatin 8 (TRPM8) receptor is involved in environmental cold detection. The role that this receptor plays in nociception however, has been somewhat controversial since conflicting reports have shown different neurochemical identities and responsiveness of TRPM8 neurons. In order to functionally characterize cutaneous TRMP8 fibers, we used two ex vivo somatosensory recording preparations to functionally characterize TRPM8 neurons that innervate the hairy skin in mice genetically engineered to express GFP from the TRPM8 locus. We found several types of cold-sensitive neurons that innervate the hairy skin of the mouse but the TRPM8-expressing neurons were found to be of two specific populations that responded with rapid firing to cool temperatures. The first group was mechanically insensitive but the other did respond to high threshold mechanical deformation of the skin. None of these fibers were found to contain calcitonin gene-related peptide, transient receptor potential vanilloid type 1 or bind isolectin B4. These results taken together with other reports suggest that TRPM8 containing sensory neurons are environmental cooling detectors that may be nociceptive or non-nociceptive depending on the sensitivity of individual fibers to different combinations of stimulus modalities. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  17. How optimal stimuli for sensory neurons are constrained by network architecture.

    Science.gov (United States)

    DiMattina, Christopher; Zhang, Kechen

    2008-03-01

    Identifying the optimal stimuli for a sensory neuron is often a difficult process involving trial and error. By analyzing the relationship between stimuli and responses in feedforward and stable recurrent neural network models, we find that the stimulus yielding the maximum firing rate response always lies on the topological boundary of the collection of all allowable stimuli, provided that individual neurons have increasing input-output relations or gain functions and that the synaptic connections are convergent between layers with nondegenerate weight matrices. This result suggests that in neurophysiological experiments under these conditions, only stimuli on the boundary need to be tested in order to maximize the response, thereby potentially reducing the number of trials needed for finding the most effective stimuli. Even when the gain functions allow firing rate cutoff or saturation, a peak still cannot exist in the stimulus-response relation in the sense that moving away from the optimum stimulus always reduces the response. We further demonstrate that the condition for nondegenerate synaptic connections also implies that proper stimuli can independently perturb the activities of all neurons in the same layer. One example of this type of manipulation is changing the activity of a single neuron in a given processing layer while keeping that of all others constant. Such stimulus perturbations might help experimentally isolate the interactions of selected neurons within a network.

  18. Decision-related activity in sensory neurons may depend on the columnar architecture of cerebral cortex.

    Science.gov (United States)

    Nienborg, Hendrikje; Cumming, Bruce G

    2014-03-05

    Many studies have reported correlations between the activity of sensory neurons and animals' judgments in discrimination tasks. Here, we suggest that such neuron-behavior correlations may require a cortical map for the task relevant features. This would explain why studies using discrimination tasks based on disparity in area V1 have not found these correlations: V1 contains no map for disparity. This scheme predicts that activity of V1 neurons correlates with decisions in an orientation-discrimination task. To test this prediction, we trained two macaque monkeys in a coarse orientation discrimination task using band-pass-filtered dynamic noise. The two orientations were always 90° apart and task difficulty was controlled by varying the orientation bandwidth of the filter. While the trained animals performed this task, we recorded from orientation-selective V1 neurons (n = 82, n = 31 for Monkey 1, n = 51 for Monkey 2). For both monkeys, we observed significant correlation (quantified as "choice probabilities") of the V1 activity with the monkeys' perceptual judgments (mean choice probability 0.54, p = 10(-5)). In one of these animals, we had previously measured choice probabilities in a disparity discrimination task in V1, which had been at chance (0.49, not significantly different from 0.5). The choice probabilities in this monkey for the orientation discrimination task were significantly larger than those for the disparity discrimination task (p = 0.032). These results are predicted by our suggestion that choice probabilities are only observed for cortical sensory neurons that are organized in maps for the task-relevant feature.

  19. Competition model for aperiodic stochastic resonance in a Fitzhugh-Nagumo model of cardiac sensory neurons.

    Science.gov (United States)

    Kember, G C; Fenton, G A; Armour, J A; Kalyaniwalla, N

    2001-04-01

    Regional cardiac control depends upon feedback of the status of the heart from afferent neurons responding to chemical and mechanical stimuli as transduced by an array of sensory neurites. Emerging experimental evidence shows that neural control in the heart may be partially exerted using subthreshold inputs that are amplified by noisy mechanical fluctuations. This amplification is known as aperiodic stochastic resonance (ASR). Neural control in the noisy, subthreshold regime is difficult to see since there is a near absence of any correlation between input and the output, the latter being the average firing (spiking) rate of the neuron. This lack of correlation is unresolved by traditional energy models of ASR since these models are unsuitable for identifying "cause and effect" between such inputs and outputs. In this paper, the "competition between averages" model is used to determine what portion of a noisy, subthreshold input is responsible, on average, for the output of sensory neurons as represented by the Fitzhugh-Nagumo equations. A physiologically relevant conclusion of this analysis is that a nearly constant amount of input is responsible for a spike, on average, and this amount is approximately independent of the firing rate. Hence, correlation measures are generally reduced as the firing rate is lowered even though neural control under this model is actually unaffected.

  20. EGL-13/SoxD Specifies Distinct O2 and CO2 Sensory Neuron Fates in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Gramstrup Petersen, Jakob; Rojo Romanos, Teresa; Juozaityte, Vaida

    2013-01-01

    that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms......Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral...

  1. Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons

    Science.gov (United States)

    Katzenell, Sarah

    2016-01-01

    neurons defend against virus infection is poorly understood, but such defense is at least partially mediated by autophagy, an intracellular pathway by which pathogens and other unwanted cargoes are degraded. The study demonstrates and investigates a new autophagic structure that appears to be specific to the interaction between neurotropic herpesviruses and murine primary sensory neurons. This work may therefore have important implications for our understanding of latency and reactivation. PMID:26912623

  2. Differential response of olfactory sensory neuron populations to copper ion exposure in zebrafish

    International Nuclear Information System (INIS)

    Lazzari, Maurizio; Bettini, Simone; Milani, Liliana; Maurizii, Maria Gabriella; Franceschini, Valeria

    2017-01-01

    Highlights: • Copper exposure affects ciliated olfactory receptors more than microvillar cells. • Crypt olfactory sensory neurons are not affected by copper exposure. • Copper exposure induces an increase in the amount of sensory epithelium. - Abstract: The peripheral olfactory system of fish is in direct contact with the external aqueous environment, so dissolved contaminants can easily impair sensory functions and cause neurobehavioral injuries. The olfactory epithelium of fish is arranged in lamellae forming a rosette in the olfactory cavity and contains three main types of olfactory sensory neurons (OSNs): ciliated (cOSNs) and microvillous olfactory sensory neurons (mOSNs), common to all vertebrates, and a third minor group of olfactory neurons, crypt cells, absent in tetrapods. Since copper is a ubiquitously diffusing olfactory toxicant and a spreading contaminant in urban runoff, we investigated the effect of low copper concentration on the three different OSNs in the olfactory epithelium of zebrafish, a model system widely used in biological research. Image analysis was applied for morphometry and quantification of immunohistochemically detected OSNs. Copper exposure resulted in an evident decrease in olfactory epithelium thickness. Moreover, after exposure, the lamellae of the dorsal and ventral halves of the olfactory rosettes showed a different increase in their sensory areas, suggesting a lateral migration of new cells into non-sensory regions. The results of the present study provide clear evidence of a differential response of the three neural cell populations of zebrafish olfactory mucosa after 96 h of exposure to copper ions at the sublethal concentration of 30 μg L −1 . Densitometric values of cONS, immunostained with anti-G αolf , decreased of about 60% compared to the control. When the fish were transferred to water without copper addition and examined after 3, 10 and 30 days, we observed a partial restoration of anti-G αolf staining

  3. Differential response of olfactory sensory neuron populations to copper ion exposure in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Lazzari, Maurizio, E-mail: maurizio.lazzari@unibo.it; Bettini, Simone; Milani, Liliana; Maurizii, Maria Gabriella; Franceschini, Valeria

    2017-02-15

    Highlights: • Copper exposure affects ciliated olfactory receptors more than microvillar cells. • Crypt olfactory sensory neurons are not affected by copper exposure. • Copper exposure induces an increase in the amount of sensory epithelium. - Abstract: The peripheral olfactory system of fish is in direct contact with the external aqueous environment, so dissolved contaminants can easily impair sensory functions and cause neurobehavioral injuries. The olfactory epithelium of fish is arranged in lamellae forming a rosette in the olfactory cavity and contains three main types of olfactory sensory neurons (OSNs): ciliated (cOSNs) and microvillous olfactory sensory neurons (mOSNs), common to all vertebrates, and a third minor group of olfactory neurons, crypt cells, absent in tetrapods. Since copper is a ubiquitously diffusing olfactory toxicant and a spreading contaminant in urban runoff, we investigated the effect of low copper concentration on the three different OSNs in the olfactory epithelium of zebrafish, a model system widely used in biological research. Image analysis was applied for morphometry and quantification of immunohistochemically detected OSNs. Copper exposure resulted in an evident decrease in olfactory epithelium thickness. Moreover, after exposure, the lamellae of the dorsal and ventral halves of the olfactory rosettes showed a different increase in their sensory areas, suggesting a lateral migration of new cells into non-sensory regions. The results of the present study provide clear evidence of a differential response of the three neural cell populations of zebrafish olfactory mucosa after 96 h of exposure to copper ions at the sublethal concentration of 30 μg L{sup −1}. Densitometric values of cONS, immunostained with anti-G {sub αolf}, decreased of about 60% compared to the control. When the fish were transferred to water without copper addition and examined after 3, 10 and 30 days, we observed a partial restoration of anti-G {sub

  4. Associative Memory Extinction Is Accompanied by Decayed Plasticity at Motor Cortical Neurons and Persistent Plasticity at Sensory Cortical Neurons.

    Science.gov (United States)

    Guo, Rui; Ge, Rongjing; Zhao, Shidi; Liu, Yulong; Zhao, Xin; Huang, Li; Guan, Sodong; Lu, Wei; Cui, Shan; Wang, Shirlene; Wang, Jin-Hui

    2017-01-01

    Associative memory is essential for cognition, in which associative memory cells and their plasticity presumably play important roles. The mechanism underlying associative memory extinction vs. maintenance remains unclear, which we have studied in a mouse model of cross-modal associative learning. Paired whisker and olfaction stimulations lead to a full establishment of odorant-induced whisker motion in training day 10, which almost disappears if paired stimulations are not given in a week, and then recovers after paired stimulation for an additional day. In mice that show associative memory, extinction and recovery, we have analyzed the dynamical plasticity of glutamatergic neurons in layers II-III of the barrel cortex and layers IV-V of the motor cortex. Compared with control mice, the rate of evoked spikes as well as the amplitude and frequency of excitatory postsynaptic currents increase, whereas the amplitude and frequency of inhibitory postsynaptic currents (IPSC) decrease at training day 10 in associative memory mice. Without paired training for a week, these plastic changes are persistent in the barrel cortex and decayed in the motor cortex. If paired training is given for an additional day to revoke associative memory, neuronal plasticity recovers in the motor cortex. Our study indicates persistent neuronal plasticity in the barrel cortex for cross-modal memory maintenance as well as the dynamical change of neuronal plasticity in the motor cortex for memory retrieval and extinction. In other words, the sensory cortices are essential for long-term memory while the behavior-related cortices with the inability of memory retrieval are correlated to memory extinction.

  5. Aging in Sensory and Motor Neurons Results in Learning Failure in Aplysia californica.

    Directory of Open Access Journals (Sweden)

    Andrew T Kempsell

    Full Text Available The physiological and molecular mechanisms of age-related memory loss are complicated by the complexity of vertebrate nervous systems. This study takes advantage of a simple neural model to investigate nervous system aging, focusing on changes in learning and memory in the form of behavioral sensitization in vivo and synaptic facilitation in vitro. The effect of aging on the tail withdrawal reflex (TWR was studied in Aplysia californica at maturity and late in the annual lifecycle. We found that short-term sensitization in TWR was absent in aged Aplysia. This implied that the neuronal machinery governing nonassociative learning was compromised during aging. Synaptic plasticity in the form of short-term facilitation between tail sensory and motor neurons decreased during aging whether the sensitizing stimulus was tail shock or the heterosynaptic modulator serotonin (5-HT. Together, these results suggest that the cellular mechanisms governing behavioral sensitization are compromised during aging, thereby nearly eliminating sensitization in aged Aplysia.

  6. Connectivity from OR37 expressing olfactory sensory neurons to distinct cell types in the hypothalamus

    Directory of Open Access Journals (Sweden)

    Andrea eBader

    2012-11-01

    Full Text Available Olfactory sensory neurons which express a member from the OR37 subfamily of odorant receptor genes are wired to the main olfactory bulb in a unique monoglomerular fashion; from these glomeruli an untypical connectivity into higher brain centers exists. In the present study we have investigated by DiI and transsynaptic tracing approaches how the connection pattern from these glomeruli into distinct hypothalamic nuclei is organized. The application of DiI onto the ventral domain of the bulb which harbors the OR37 glomeruli resulted in the labeling of fibers within the paraventricular and supraoptic nucleus of the hypothalamus; some of these fibers were covered with varicose-like structures. No DiI-labeled cell somata were detectable in these nuclei. The data indicate that projection neurons which originate in the OR37 region of the main olfactory bulb form direct connections into these nuclei. The cells that were labeled by the transsynaptic tracer WGA in these nuclei were further characterized. Their distribution pattern in the paraventricular nucleus was reminiscent of cells which produce distinct neuropeptides. Double labeling experiments confirmed that they contained vasopressin, but not the related neuropeptide oxytocin. Morphological analysis revealed that they comprise of magno- and parvocellular cells. A comparative investigation of the WGA-positive cells in the supraoptic nucleus demonstrated that these were vasopressin-positive, as well, whereas oxytocin-producing cells of this nucleus also contained no transsynaptic tracer. Together, the data demonstrate a connectivity from OR37 expressing sensory neurons to distinct hypothalamic neurons with the same neuropeptide content.

  7. Rapid Integration of Artificial Sensory Feedback during Operant Conditioning of Motor Cortex Neurons.

    Science.gov (United States)

    Prsa, Mario; Galiñanes, Gregorio L; Huber, Daniel

    2017-02-22

    Neuronal motor commands, whether generating real or neuroprosthetic movements, are shaped by ongoing sensory feedback from the displacement being produced. Here we asked if cortical stimulation could provide artificial feedback during operant conditioning of cortical neurons. Simultaneous two-photon imaging and real-time optogenetic stimulation were used to train mice to activate a single neuron in motor cortex (M1), while continuous feedback of its activity level was provided by proportionally stimulating somatosensory cortex. This artificial signal was necessary to rapidly learn to increase the conditioned activity, detect correct performance, and maintain the learned behavior. Population imaging in M1 revealed that learning-related activity changes are observed in the conditioned cell only, which highlights the functional potential of individual neurons in the neocortex. Our findings demonstrate the capacity of animals to use an artificially induced cortical channel in a behaviorally relevant way and reveal the remarkable speed and specificity at which this can occur. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. A5-Positive Primary Sensory Neurons Are Nonpermissive for Productive Infection with Herpes Simplex Virus 1 In Vitro▿

    Science.gov (United States)

    Bertke, Andrea S.; Swanson, Sophia M.; Chen, Jenny; Imai, Yumi; Kinchington, Paul R.; Margolis, Todd P.

    2011-01-01

    Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency and express the latency-associated transcript (LAT) preferentially in different murine sensory neuron populations, with most HSV-1 LAT expression in A5+ neurons and most HSV-2 LAT expression in KH10+ neurons. To study the mechanisms regulating the establishment of HSV latency in specific subtypes of neurons, cultured dissociated adult murine trigeminal ganglion (TG) neurons were assessed for relative permissiveness for productive infection. In contrast to that for neonatal TG, the relative distribution of A5+ and KH10+ neurons in cultured adult TG was similar to that seen in vivo. Productive infection with HSV was restricted, and only 45% of cultured neurons could be productively infected with either HSV-1 or HSV-2. A5+ neurons supported productive infection with HSV-2 but were selectively nonpermissive for productive infection with HSV-1, a phenomenon that was not due to restricted viral entry or DNA uncoating, since HSV-1 expressing β-galactosidase under the control of the neurofilament promoter was detected in ∼90% of cultured neurons, with no preference for any neuronal subtype. Infection with HSV-1 reporter viruses expressing enhanced green fluorescent protein (EGFP) from immediate early (IE), early, and late gene promoters indicated that the block to productive infection occurred before IE gene expression. Trichostatin A treatment of quiescently infected neurons induced productive infection preferentially from non-A5+ neurons, demonstrating that the nonpermissive neuronal subtype is also nonpermissive for reactivation. Thus, HSV-1 is capable of entering the majority of sensory neurons in vitro; productive infection occurs within a subset of these neurons; and this differential distribution of productive infection is determined at or before the expression of the viral IE genes. PMID:21507969

  9. The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb

    Directory of Open Access Journals (Sweden)

    Rajapaksha Tharinda W

    2011-12-01

    Full Text Available Abstract Background The β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1, is a prime therapeutic target for lowering cerebral β-amyloid (Aβ levels in Alzheimer's disease (AD. Clinical development of BACE1 inhibitors is being intensely pursued. However, little is known about the physiological functions of BACE1, and the possibility exists that BACE1 inhibition may cause mechanism-based side effects. Indeed, BACE1-/- mice exhibit a complex neurological phenotype. Interestingly, BACE1 co-localizes with presynaptic neuronal markers, indicating a role in axons and/or terminals. Moreover, recent studies suggest axon guidance molecules are potential BACE1 substrates. Here, we used a genetic approach to investigate the function of BACE1 in axon guidance of olfactory sensory neurons (OSNs, a well-studied model of axon targeting in vivo. Results We bred BACE1-/- mice with gene-targeted mice in which GFP is expressed from the loci of two odorant-receptors (ORs, MOR23 and M72, and olfactory marker protein (OMP to produce offspring that were heterozygous for MOR23-GFP, M72-GFP, or OMP-GFP and were either BACE1+/+ or BACE1-/-. BACE1-/- mice had olfactory bulbs (OBs that were smaller and weighed less than OBs of BACE1+/+ mice. In wild-type mice, BACE1 was present in OSN axon terminals in OB glomeruli. In whole-mount preparations and tissue sections, many OB glomeruli from OMP-GFP; BACE1-/- mice were malformed compared to wild-type glomeruli. MOR23-GFP; BACE1-/- mice had an irregular MOR23 glomerulus that was innervated by randomly oriented, poorly fasciculated OSN axons compared to BACE1+/+ mice. Most importantly, M72-GFP; BACE1-/- mice exhibited M72 OSN axons that were mis-targeted to ectopic glomeruli, indicating impaired axon guidance in BACE1-/- mice. Conclusions Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in

  10. Transient receptor potential V2 expressed in sensory neurons is activated by probenecid.

    Science.gov (United States)

    Bang, Sangsu; Kim, Kyung Yoon; Yoo, Sungjae; Lee, Sang-Heon; Hwang, Sun Wook

    2007-09-25

    Temperature-activated transient receptor potential ion channels (thermoTRPs) are known to function as ambient temperature sensors and are also involved in peripheral pain sensation. The thermoTRPs are activated by a variety of chemicals, of which specific activators have been utilized to explore the physiology of particular channels and sensory nerve subtypes. The use of capsaicin for TRPV1 is an exemplary case for nociceptor studies. In contrast, specific agents for another vanilloid subtype channel, TRPV2 have been lacking. Here, we show that probenecid is able to activate TRPV2 using electrophysiological and calcium imaging techniques with TRPV2-expressing HEK293T cells. Five other sensory thermoTRPs-TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1-failed to show a response to this drug in the same heterologous expression system, suggesting that probenecid is a specific activator for TRPV2. Probenecid-evoked responses were also reproduced in a distinct subset of cultured trigeminal neurons that were responsive to 2-aminoethoxydiphenyl borate, a TRPV1-3 activator. The probenecid-sensitive neurons were mainly distributed in a medium to large-diameter population, in agreement with previous observations with TRPV2 immunolocalization. Under inflammation, probenecid elicited nociceptive behaviors in in vivo assays. These results suggest that TRPV2 is specifically activated by probenecid and that this chemical might be useful for investigation of pain-related TRPV2 function.

  11. Noise Enhances Action Potential Generation in Mouse Sensory Neurons via Stochastic Resonance.

    Science.gov (United States)

    Onorato, Irene; D'Alessandro, Giuseppina; Di Castro, Maria Amalia; Renzi, Massimiliano; Dobrowolny, Gabriella; Musarò, Antonio; Salvetti, Marco; Limatola, Cristina; Crisanti, Andrea; Grassi, Francesca

    2016-01-01

    Noise can enhance perception of tactile and proprioceptive stimuli by stochastic resonance processes. However, the mechanisms underlying this general phenomenon remain to be characterized. Here we studied how externally applied noise influences action potential firing in mouse primary sensory neurons of dorsal root ganglia, modelling a basic process in sensory perception. Since noisy mechanical stimuli may cause stochastic fluctuations in receptor potential, we examined the effects of sub-threshold depolarizing current steps with superimposed random fluctuations. We performed whole cell patch clamp recordings in cultured neurons of mouse dorsal root ganglia. Noise was added either before and during the step, or during the depolarizing step only, to focus onto the specific effects of external noise on action potential generation. In both cases, step + noise stimuli triggered significantly more action potentials than steps alone. The normalized power norm had a clear peak at intermediate noise levels, demonstrating that the phenomenon is driven by stochastic resonance. Spikes evoked in step + noise trials occur earlier and show faster rise time as compared to the occasional ones elicited by steps alone. These data suggest that external noise enhances, via stochastic resonance, the recruitment of transient voltage-gated Na channels, responsible for action potential firing in response to rapid step-wise depolarizing currents.

  12. Dystonin/Bpag1 is a necessary endoplasmic reticulum/nuclear envelope protein in sensory neurons

    International Nuclear Information System (INIS)

    Young, Kevin G.; Kothary, Rashmi

    2008-01-01

    Dystonin/Bpag1 proteins are cytoskeletal linkers whose loss of function in mice results in a hereditary sensory neuropathy with a progressive loss of limb coordination starting in the second week of life. These mice, named dystonia musculorum (dt), succumb to the disease and die of unknown causes prior to sexual maturity. Previous evidence indicated that cytoskeletal defects in the axon are a primary cause of dt neurodegeneration. However, more recent data suggests that other factors may be equally important contributors to the disease process. In the present study, we demonstrate perikaryal defects in dorsal root ganglion (DRG) neurons at stages preceding the onset of loss of limb coordination in dt mice. Abnormalities include alterations in endoplasmic reticulum (ER) chaperone protein expression, indicative of an ER stress response. Dystonin in sensory neurons localized in association with the ER and nuclear envelope (NE). A fusion protein ofthe dystonin-a2 isoform, which harbors an N-terminal transmembrane domain, associated with and reorganized the ER in cell culture. This isoform also interacts with the NE protein nesprin-3α, but not nesprin-3β. Defects in dt mice, as demonstrated here, may ultimately result in pathogenesis involving ER dysfunction and contribute significantly to the dt phenotype

  13. BMP and Delta/Notch signaling control the development of amphioxus epidermal sensory neurons: insights into the evolution of the peripheral sensory system.

    Science.gov (United States)

    Lu, Tsai-Ming; Luo, Yi-Jyun; Yu, Jr-Kai

    2012-06-01

    The evolution of the nervous system has been a topic of great interest. To gain more insight into the evolution of the peripheral sensory system, we used the cephalochordate amphioxus. Amphioxus is a basal chordate that has a dorsal central nervous system (CNS) and a peripheral nervous system (PNS) comprising several types of epidermal sensory neurons (ESNs). Here, we show that a proneural basic helix-loop-helix gene (Ash) is co-expressed with the Delta ligand in ESN progenitor cells. Using pharmacological treatments, we demonstrate that Delta/Notch signaling is likely to be involved in the specification of amphioxus ESNs from their neighboring epidermal cells. We also show that BMP signaling functions upstream of Delta/Notch signaling to induce a ventral neurogenic domain. This patterning mechanism is highly similar to that of the peripheral sensory neurons in the protostome and vertebrate model animals, suggesting that they might share the same ancestry. Interestingly, when BMP signaling is globally elevated in amphioxus embryos, the distribution of ESNs expands to the entire epidermal ectoderm. These results suggest that by manipulating BMP signaling levels, a conserved neurogenesis circuit can be initiated at various locations in the epidermal ectoderm to generate peripheral sensory neurons in amphioxus embryos. We hypothesize that during chordate evolution, PNS progenitors might have been polarized to different positions in various chordate lineages owing to differential regulation of BMP signaling in the ectoderm.

  14. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

    Science.gov (United States)

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  15. Modulation of specific sensory cortical areas by segregated basal forebrain cholinergic neurons demonstrated by neuronal tracing and optogenetic stimulation in mice

    Directory of Open Access Journals (Sweden)

    Irene eChaves-Coira

    2016-04-01

    Full Text Available Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-gold and Fast Blue fluorescent retrograde tracers were deposited into the primary somatosensory (S1 and primary auditory (A1 cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP under the control of the choline-acetyl transferase promoter (ChAT. Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  16. Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

    Science.gov (United States)

    Xie, Ya-Bin; Zhao, Huan; Wang, Ying; Song, Kai; Zhang, Ming; Meng, Fan-Cheng; Yang, Yu-Jie; He, Yang-Song; Kuang, Fang; You, Si-Wei; You, Hao-Jun; Xu, Hui

    2016-01-01

    To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD) in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3) was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat. PMID:26819761

  17. Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

    Directory of Open Access Journals (Sweden)

    Ya-Bin Xie

    2016-01-01

    Full Text Available To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3 was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat.

  18. Increased Nerve Growth Factor Signaling in Sensory Neurons of Early Diabetic Rats Is Corrected by Electroacupuncture

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    Stefania Lucia Nori

    2013-01-01

    Full Text Available Diabetic polyneuropathy (DPN, characterized by early hyperalgesia and increased nerve growth factor (NGF, evolves in late irreversible neuropathic symptoms with reduced NGF support to sensory neurons. Electroacupuncture (EA modulates NGF in the peripheral nervous system, being effective for the treatment of DPN symptoms. We hypothesize that NGF plays an important pathogenic role in DPN development, while EA could be useful in the therapy of DPN by modulating NGF expression/activity. Diabetes was induced in rats by streptozotocin (STZ injection. One week after STZ, EA was started and continued for three weeks. NGF system and hyperalgesia-related mediators were analyzed in the dorsal root ganglia (DRG and in their spinal cord and skin innervation territories. Our results show that four weeks long diabetes increased NGF and NGF receptors and deregulated intracellular signaling mediators of DRG neurons hypersensitization; EA in diabetic rats decreased NGF and NGF receptors, normalized c-Jun N-terminal and p38 kinases activation, decreased transient receptor potential vanilloid-1 ion channel, and possibly activated the nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB. In conclusion, NGF signaling deregulation might play an important role in the development of DPN. EA represents a supportive tool to control DPN development by modulating NGF signaling in diabetes-targeted neurons.

  19. Generation of Otic Sensory Neurons from Mouse Embryonic Stem Cells in 3D Culture

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    Michael Perny

    2017-12-01

    Full Text Available The peripheral hearing process taking place in the cochlea mainly depends on two distinct sensory cell types: the mechanosensitive hair cells and the spiral ganglion neurons (SGNs. The first respond to the mechanical stimulation exerted by sound pressure waves on their hair bundles by releasing neurotransmitters and thereby activating the latter. Loss of these sensorineural cells is associated with permanent hearing loss. Stem cell-based approaches aiming at cell replacement or in vitro drug testing to identify potential ototoxic, otoprotective, or regenerative compounds have lately gained attention as putative therapeutic strategies for hearing loss. Nevertheless, they rely on efficient and reliable protocols for the in vitro generation of cochlear sensory cells for their implementation. To this end, we have developed a differentiation protocol based on organoid culture systems, which mimics the most important steps of in vivo otic development, robustly guiding mouse embryonic stem cells (mESCs toward otic sensory neurons (OSNs. The stepwise differentiation of mESCs toward ectoderm was initiated using a quick aggregation method in presence of Matrigel in serum-free conditions. Non-neural ectoderm was induced via activation of bone morphogenetic protein (BMP signaling and concomitant inhibition of transforming growth factor beta (TGFβ signaling to prevent mesendoderm induction. Preplacodal and otic placode ectoderm was further induced by inhibition of BMP signaling and addition of fibroblast growth factor 2 (FGF2. Delamination and differentiation of SGNs was initiated by plating of the organoids on a 2D Matrigel-coated substrate. Supplementation with brain-derived neurotrophic factor (BDNF and neurotrophin-3 (NT-3 was used for further maturation until 15 days of in vitro differentiation. A large population of neurons with a clear bipolar morphology and functional excitability was derived from these cultures. Immunostaining and gene expression

  20. Proteasome inhibition induces DNA damage and reorganizes nuclear architecture and protein synthesis machinery in sensory ganglion neurons.

    Science.gov (United States)

    Palanca, Ana; Casafont, Iñigo; Berciano, María T; Lafarga, Miguel

    2014-05-01

    Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague-Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.

  1. Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons

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    Langeslag Michiel

    2011-12-01

    Full Text Available Abstract Oncostatin M (OSM is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/- and gp130 floxed (gp130fl/fl mice. Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo. The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.

  2. Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury.

    Science.gov (United States)

    Cao, Xiaoyu C; Pappalardo, Laura W; Waxman, Stephen G; Tan, Andrew M

    2017-01-01

    Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure-function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury.

  3. Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons

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    Andy A. Yanez

    2017-02-01

    Full Text Available Herpes simplex viruses (HSV1 and HSV2 establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs. Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG and sympathetic superior cervical ganglia (SCG after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.

  4. Sensory deprivation differentially impacts the dendritic development of pyramidal versus non-pyramidal neurons in layer 6 of mouse barrel cortex.

    Science.gov (United States)

    Chen, Chia-Chien; Tam, Danny; Brumberg, Joshua C

    2012-04-01

    Early postnatal sensory experience can have profound impacts on the structure and function of cortical circuits affecting behavior. Using the mouse whisker-to-barrel system we chronically deprived animals of normal sensory experience by bilaterally trimming their whiskers every other day from birth for the first postnatal month. Brain tissue was then processed for Golgi staining and neurons in layer 6 of barrel cortex were reconstructed in three dimensions. Dendritic and somatic parameters were compared between sensory-deprived and normal sensory experience groups. Results demonstrated that layer 6 non-pyramidal neurons in the chronically deprived group showed an expansion of their dendritic arbors. The pyramidal cells responded to sensory deprivation with increased somatic size and basilar dendritic arborization but overall decreased apical dendritic parameters. In sum, sensory deprivation impacted on the neuronal architecture of pyramidal and non-pyramidal neurons in layer 6, which may provide a substrate for observed physiological and behavioral changes resulting from whisker trimming.

  5. Spike propagation through the dorsal root ganglia in an unmyelinated sensory neuron: a modeling study.

    Science.gov (United States)

    Sundt, Danielle; Gamper, Nikita; Jaffe, David B

    2015-12-01

    Unmyelinated C-fibers are a major type of sensory neurons conveying pain information. Action potential conduction is regulated by the bifurcation (T-junction) of sensory neuron axons within the dorsal root ganglia (DRG). Understanding how C-fiber signaling is influenced by the morphology of the T-junction and the local expression of ion channels is important for understanding pain signaling. In this study we used biophysical computer modeling to investigate the influence of axon morphology within the DRG and various membrane conductances on the reliability of spike propagation. As expected, calculated input impedance and the amplitude of propagating action potentials were both lowest at the T-junction. Propagation reliability for single spikes was highly sensitive to the diameter of the stem axon and the density of voltage-gated Na(+) channels. A model containing only fast voltage-gated Na(+) and delayed-rectifier K(+) channels conducted trains of spikes up to frequencies of 110 Hz. The addition of slowly activating KCNQ channels (i.e., KV7 or M-channels) to the model reduced the following frequency to 30 Hz. Hyperpolarization produced by addition of a much slower conductance, such as a Ca(2+)-dependent K(+) current, was needed to reduce the following frequency to 6 Hz. Attenuation of driving force due to ion accumulation or hyperpolarization produced by a Na(+)-K(+) pump had no effect on following frequency but could influence the reliability of spike propagation mutually with the voltage shift generated by a Ca(2+)-dependent K(+) current. These simulations suggest how specific ion channels within the DRG may contribute toward therapeutic treatments for chronic pain. Copyright © 2015 the American Physiological Society.

  6. Changes in Olfactory Sensory Neuron Physiology and Olfactory Perceptual Learning After Odorant Exposure in Adult Mice.

    Science.gov (United States)

    Kass, Marley D; Guang, Stephanie A; Moberly, Andrew H; McGann, John P

    2016-02-01

    The adult olfactory system undergoes experience-dependent plasticity to adapt to the olfactory environment. This plasticity may be accompanied by perceptual changes, including improved olfactory discrimination. Here, we assessed experience-dependent changes in the perception of a homologous aldehyde pair by testing mice in a cross-habituation/dishabituation behavioral paradigm before and after a week-long ester-odorant exposure protocol. In a parallel experiment, we used optical neurophysiology to observe neurotransmitter release from olfactory sensory neuron (OSN) terminals in vivo, and thus compared primary sensory representations of the aldehydes before and after the week-long ester-odorant exposure in individual animals. Mice could not discriminate between the aldehydes during pre-exposure testing, but ester-exposed subjects spontaneously discriminated between the homologous pair after exposure, whereas home cage control mice cross-habituated. Ester exposure did not alter the spatial pattern, peak magnitude, or odorant-selectivity of aldehyde-evoked OSN input to olfactory bulb glomeruli, but did alter the temporal dynamics of that input to make the time course of OSN input more dissimilar between odorants. Together, these findings demonstrate that odor exposure can induce both physiological and perceptual changes in odor processing, and suggest that changes in the temporal patterns of OSN input to olfactory bulb glomeruli could induce differences in odor quality. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. TRPM7 is required within zebrafish sensory neurons for the activation of touch-evoked escape behaviors

    Science.gov (United States)

    Low, Sean E.; Amburgey, Kimberly; Horstick, Eric; Linsley, Jeremy; Sprague, Shawn M.; Cui, Wilson W.; Zhou, Weibin; Hirata, Hiromi; Saint-Amant, Louis; Hume, Richard I.; Kuwada, John Y.

    2011-01-01

    Mutations in the gene encoding TRPM7 (trpm7), a member of the TRP superfamily of cation channels that possesses an enzymatically active kinase at its carboxyl terminus, cause the touch-unresponsive zebrafish mutant touchdown. We identified and characterized a new allele of touchdown, as well as two previously reported alleles, and found that all three alleles harbor mutations which abolish channel activity. Through the selective restoration of TRPM7 expression in sensory neurons we found that TRPM7’s kinase activity, and selectivity for divalent cations over monovalent cations, were dispensable for touch-evoked activation of escape behaviors in zebrafish. Additional characterization revealed that sensory neurons were present and capable of responding to tactile stimuli in touchdown mutants, indicating that TRPM7 is not required for sensory neuron survival or mechanosensation. Finally, exposure to elevated concentrations of divalent cations was found to restore touch-evoked behaviors in touchdown mutants. Collectively these findings are consistent with a role for zebrafish TRPM7 within sensory neurons in the modulation of neurotransmitter release at central synapses, similar to that proposed for mammalian TRPM7 at peripheral synapses. PMID:21832193

  8. Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli.

    Science.gov (United States)

    Tornero, Daniel; Tsupykov, Oleg; Granmo, Marcus; Rodriguez, Cristina; Grønning-Hansen, Marita; Thelin, Jonas; Smozhanik, Ekaterina; Laterza, Cecilia; Wattananit, Somsak; Ge, Ruimin; Tatarishvili, Jemal; Grealish, Shane; Brüstle, Oliver; Skibo, Galina; Parmar, Malin; Schouenborg, Jens; Lindvall, Olle; Kokaia, Zaal

    2017-03-01

    Transplanted neurons derived from stem cells have been proposed to improve function in animal models of human disease by various mechanisms such as neuronal replacement. However, whether the grafted neurons receive functional synaptic inputs from the recipient's brain and integrate into host neural circuitry is unknown. Here we studied the synaptic inputs from the host brain to grafted cortical neurons derived from human induced pluripotent stem cells after transplantation into stroke-injured rat cerebral cortex. Using the rabies virus-based trans-synaptic tracing method and immunoelectron microscopy, we demonstrate that the grafted neurons receive direct synaptic inputs from neurons in different host brain areas located in a pattern similar to that of neurons projecting to the corresponding endogenous cortical neurons in the intact brain. Electrophysiological in vivo recordings from the cortical implants show that physiological sensory stimuli, i.e. cutaneous stimulation of nose and paw, can activate or inhibit spontaneous activity in grafted neurons, indicating that at least some of the afferent inputs are functional. In agreement, we find using patch-clamp recordings that a portion of grafted neurons respond to photostimulation of virally transfected, channelrhodopsin-2-expressing thalamo-cortical axons in acute brain slices. The present study demonstrates, for the first time, that the host brain regulates the activity of grafted neurons, providing strong evidence that transplanted human induced pluripotent stem cell-derived cortical neurons can become incorporated into injured cortical circuitry. Our findings support the idea that these neurons could contribute to functional recovery in stroke and other conditions causing neuronal loss in cerebral cortex. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Anatomical and molecular consequences of Unilateral Naris Closure on two populations of olfactory sensory neurons expressing defined odorant receptors.

    Science.gov (United States)

    Molinas, Adrien; Aoudé, Imad; Soubeyre, Vanessa; Tazir, Bassim; Cadiou, Hervé; Grosmaitre, Xavier

    2016-07-28

    Mammalian olfactory sensory neurons (OSNs), the primary elements of the olfactory system, are located in the olfactory epithelium lining the nasal cavity. Exposed to the environment, their lifespan is short. Consequently, OSNs are regularly regenerated and several reports show that activity strongly modulates their development and regeneration: the peripheral olfactory system can adjust to the amount of stimulus through compensatory mechanisms. Unilateral naris occlusion (UNO) was frequently used to investigate this mechanism at the entire epithelium level. However, there is little data regarding the effects of UNO at the cellular level, especially on individual neuronal populations expressing a defined odorant receptor. Here, using UNO during the first three postnatal weeks, we analyzed the anatomical and molecular consequences of sensory deprivation in OSNs populations expressing the MOR23 and M71 receptors. The density of MOR23-expressing neurons is decreased in the closed side while UNO does not affect the density of M71-expressing neurons. Using Real Time qPCR on isolated neurons, we observed that UNO modulates the transcript levels for transduction pathway proteins (odorant receptors, CNGA2, PDE1c). The transcripts modulated by UNO will differ between populations depending on the receptor expressed. These results suggest that sensory deprivation will have different effects on different OSNs' populations. As a consequence, early experience will shape the functional properties of OSNs differently depending on the type of odorant receptor they express. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Park, Yong Seek; Park, Cheung-Seog [Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Jin, Young-Ho, E-mail: jinyh@khu.ac.kr [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of)

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  11. Development of a sensory neuronal cell model for the estimation of mild eye irritation.

    Science.gov (United States)

    Lilja, Johanna; Forsby, Anna

    2004-10-01

    In an attempt to improve the in vitro test strategy for the estimation of eye irritation, a neuronal cell model has been developed, with cells expressing vanilloid receptor type 1 (VR1) nociceptors. The currently accepted method for measuring eye irritancy is the ethically and scientifically criticised Draize rabbit eye test, despite the fact that alternative in vitro methods are available which have proved to be reliable and reproducible for predicting severe ocular toxicity. However, no alternative tests for measuring neuronal stimulation have yet been developed, and the prediction of eye irritation in the mild range is therefore insufficient. VR1 is a nociceptor localised in C-fibre neurons innervating the cornea and the surrounding tissue, and it responds to potentially damaging stimuli by releasing Ca2+ into the cytoplasm. As a sensory endpoint, [Ca2+]i was measured in VR1 transfected cells, as well as in control cells. Short-term cell cytotoxicity studies (cell membrane rupture and morphological divergence) were used to determine the non-corrosive concentrations of the test chemicals. Preliminary results indicated that hygiene products used daily may induce eye irritation via VR1 nociceptors. The lowest toxic concentration (0.025%) of liquid hand soap, as determined by morphologic divergences of cells, generated an 80% increase in [Ca2+]i over the basal [Ca2+]i in VR1 transfected cells, whereas the non-specific [Ca2+]i increased by 33%. Furthermore, all the endpoints studied indicated that shampoo for children was less active than shampoo for adults. If this method is successfully validated with standardised reference chemicals, the model could complete the test battery of in vitro alternatives, resulting in the saving of thousands of laboratory animals.

  12. APE1, the DNA base excision repair protein, regulates the removal of platinum adducts in sensory neuronal cultures by NER

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyun-Suk [Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202 (United States); Guo, Chunlu; Thompson, Eric L. [Department of Pharmacology and Toxicology, Indianapolis, IN 46202 (United States); Jiang, Yanlin [Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Kelley, Mark R. [Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202 (United States); Department of Pharmacology and Toxicology, Indianapolis, IN 46202 (United States); Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Vasko, Michael R. [Department of Pharmacology and Toxicology, Indianapolis, IN 46202 (United States); Lee, Suk-Hee, E-mail: slee@iu.edu [Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202 (United States)

    2015-09-15

    Peripheral neuropathy is one of the major side effects of treatment with the anticancer drug, cisplatin. One proposed mechanism for this neurotoxicity is the formation of platinum adducts in sensory neurons that could contribute to DNA damage. Although this damage is largely repaired by nuclear excision repair (NER), our previous findings suggest that augmenting the base excision repair pathway (BER) by overexpressing the repair protein APE1 protects sensory neurons from cisplatin-induced neurotoxicity. The question remains whether APE1 contributes to the ability of the NER pathway to repair platinum-damage in neuronal cells. To examine this, we manipulated APE1 expression in sensory neuronal cultures and measured Pt-removal after exposure to cisplatin. When neuronal cultures were treated with increasing concentrations of cisplatin for two or three hours, there was a concentration-dependent increase in Pt-damage that peaked at four hours and returned to near baseline levels after 24 h. In cultures where APE1 expression was reduced by ∼80% using siRNA directed at APE1, there was a significant inhibition of Pt-removal over eight hours which was reversed by overexpressing APE1 using a lentiviral construct for human wtAPE1. Overexpressing a mutant APE1 (C65 APE1), which only has DNA repair activity, but not its other significant redox-signaling function, mimicked the effects of wtAPE1. Overexpressing DNA repair activity mutant APE1 (226 + 177APE1), with only redox activity was ineffective suggesting it is the DNA repair function of APE1 and not its redox-signaling, that restores the Pt-damage removal. Together, these data provide the first evidence that a critical BER enzyme, APE1, helps regulate the NER pathway in the repair of cisplatin damage in sensory neurons.

  13. APE1, the DNA base excision repair protein, regulates the removal of platinum adducts in sensory neuronal cultures by NER

    International Nuclear Information System (INIS)

    Kim, Hyun-Suk; Guo, Chunlu; Thompson, Eric L.; Jiang, Yanlin; Kelley, Mark R.; Vasko, Michael R.; Lee, Suk-Hee

    2015-01-01

    Peripheral neuropathy is one of the major side effects of treatment with the anticancer drug, cisplatin. One proposed mechanism for this neurotoxicity is the formation of platinum adducts in sensory neurons that could contribute to DNA damage. Although this damage is largely repaired by nuclear excision repair (NER), our previous findings suggest that augmenting the base excision repair pathway (BER) by overexpressing the repair protein APE1 protects sensory neurons from cisplatin-induced neurotoxicity. The question remains whether APE1 contributes to the ability of the NER pathway to repair platinum-damage in neuronal cells. To examine this, we manipulated APE1 expression in sensory neuronal cultures and measured Pt-removal after exposure to cisplatin. When neuronal cultures were treated with increasing concentrations of cisplatin for two or three hours, there was a concentration-dependent increase in Pt-damage that peaked at four hours and returned to near baseline levels after 24 h. In cultures where APE1 expression was reduced by ∼80% using siRNA directed at APE1, there was a significant inhibition of Pt-removal over eight hours which was reversed by overexpressing APE1 using a lentiviral construct for human wtAPE1. Overexpressing a mutant APE1 (C65 APE1), which only has DNA repair activity, but not its other significant redox-signaling function, mimicked the effects of wtAPE1. Overexpressing DNA repair activity mutant APE1 (226 + 177APE1), with only redox activity was ineffective suggesting it is the DNA repair function of APE1 and not its redox-signaling, that restores the Pt-damage removal. Together, these data provide the first evidence that a critical BER enzyme, APE1, helps regulate the NER pathway in the repair of cisplatin damage in sensory neurons

  14. MAP2 Defines a Pre-axonal Filtering Zone to Regulate KIF1- versus KIF5-Dependent Cargo Transport in Sensory Neurons

    NARCIS (Netherlands)

    Gumy, Laura F|info:eu-repo/dai/nl/337608334; Katrukha, Eugene A; Grigoriev, Ilya; Jaarsma, Dick; Kapitein, Lukas C|info:eu-repo/dai/nl/298806630; Akhmanova, Anna|info:eu-repo/dai/nl/156410591; Hoogenraad, Casper C|info:eu-repo/dai/nl/227263502

    2017-01-01

    Polarized cargo transport is essential for neuronal function. However, the minimal basic components required for selective cargo sorting and distribution in neurons remain elusive. We found that in sensory neurons the axon initial segment is largely absent and that microtubule-associated protein 2

  15. Reproductive experience modified dendritic spines on cortical pyramidal neurons to enhance sensory perception and spatial learning in rats

    Science.gov (United States)

    Chen, Jeng-Rung; Lim, Seh Hong; Chung, Sin-Cun; Lee, Yee-Fun; Wang, Yueh-Jan; Tseng, Guo-Fang; Wang, Tsyr-Jiuan

    2016-01-01

    Behavioral adaptations during motherhood are aimed at increasing reproductive success. Alterations of hormones during motherhood could trigger brain morphological changes to underlie behavioral alterations. Here we investigated whether motherhood changes a rat’s sensory perception and spatial memory in conjunction with cortical neuronal structural changes. Female rats of different statuses, including virgin, pregnant, lactating, and primiparous rats were studied. Behavioral test showed that the lactating rats were most sensitive to heat, while rats with motherhood and reproduction experience outperformed virgin rats in a water maze task. By intracellular dye injection and computer-assisted 3-dimensional reconstruction, the dendritic arbors and spines of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons were revealed for closer analysis. The results showed that motherhood and reproductive experience increased dendritic spines but not arbors or the lengths of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons. In addition, lactating rats had a higher incidence of spines than pregnant or primiparous rats. The increase of dendritic spines was coupled with increased expression of the glutamatergic postsynaptic marker protein (PSD-95), especially in lactating rats. On the basis of the present results, it is concluded that motherhood enhanced rat sensory perception and spatial memory and was accompanied by increases in dendritic spines on output neurons of the somatosensory cortex and CA1 hippocampus. The effect was sustained for at least 6 weeks after the weaning of the pups. PMID:27784858

  16. Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor.

    Science.gov (United States)

    Li, Chao; Chi, Xian Xuan; Xie, Wenrui; Strong, J A; Zhang, J-M; Nicol, G D

    2012-09-01

    Previously we demonstrated that sphingosine 1-phosphate receptor 1 (S1PR(1)) played a prominent, but not exclusive, role in enhancing the excitability of small-diameter sensory neurons, suggesting that other S1PRs can modulate neuronal excitability. To examine the potential role of S1PR(2) in regulating neuronal excitability we used the established selective antagonist of S1PR(2), JTE-013. Here we report that exposure to JTE-013 alone produced a significant increase in excitability in a time- and concentration-dependent manner in 70-80% of recorded neurons. Internal perfusion of sensory neurons with guanosine 5'-O-(2-thiodiphosphate) (GDP-β-S) via the recording pipette inhibited the sensitization produced by JTE-013 as well as prostaglandin E(2). Pretreatment with pertussis toxin or the selective S1PR(1) antagonist W146 blocked the sensitization produced by JTE-013. These results indicate that JTE-013 might act as an agonist at other G protein-coupled receptors. In neurons that were sensitized by JTE-013, single-cell RT-PCR studies demonstrated that these neurons did not express the mRNA for S1PR(2). In behavioral studies, injection of JTE-013 into the rat's hindpaw produced a significant increase in the mechanical sensitivity in the ipsilateral, but not contralateral, paw. Injection of JTE-013 did not affect the withdrawal latency to thermal stimulation. Thus JTE-013 augments neuronal excitability independently of S1PR(2) by unknown mechanisms that may involve activation of other G protein-coupled receptors such as S1PR(1). Clearly, further studies are warranted to establish the causal nature of this increased sensitivity, and future studies of neuronal function using JTE-013 should be interpreted with caution.

  17. Injury-induced CRMP4 expression in adult sensory neurons; a possible target gene for ciliary neurotrophic factor.

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    Jang, So Young; Shin, Yoon Kyung; Jung, Junyang; Lee, Sang Hwa; Seo, Su-Yeong; Suh, Duk Joon; Park, Hwan Tae

    2010-11-12

    Neurotrophic cytokines, such as ciliary neurotrophic factor (CNTF) play an important role in the development and regeneration of the nervous system. In the present study, we screened gene expression induced by CNTF in adult dorsal root ganglion (DRG) neurons using the Illumina microarray. We found that the expression of both short and long forms of collapsin response-mediator protein 4 (CRMP4) was increased in cultured primary sensory neurons by CNTF. In addition, sciatic nerve injury induced the expression of CRMP4 mRNA and protein in DRG neurons. Finally, the increased CRMP4 protein was transported into peripheral axons following nerve injury. These findings indicate that CRMP4 may be a target gene for CNTF in the regenerative axon growth of DRG neurons after injury. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. Modeling and analysis of the molecular basis of pain in sensory neurons.

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    Sang Ok Song

    Full Text Available Intracellular calcium dynamics are critical to cellular functions like pain transmission. Extracellular ATP plays an important role in modulating intracellular calcium levels by interacting with the P2 family of surface receptors. In this study, we developed a mechanistic mathematical model of ATP-induced P2 mediated calcium signaling in archetype sensory neurons. The model architecture, which described 90 species connected by 162 interactions, was formulated by aggregating disparate molecular modules from literature. Unlike previous models, only mass action kinetics were used to describe the rate of molecular interactions. Thus, the majority of the 252 unknown model parameters were either association, dissociation or catalytic rate constants. Model parameters were estimated from nine independent data sets taken from multiple laboratories. The training data consisted of both dynamic and steady-state measurements. However, because of the complexity of the calcium network, we were unable to estimate unique model parameters. Instead, we estimated a family or ensemble of probable parameter sets using a multi-objective thermal ensemble method. Each member of the ensemble met an error criterion and was located along or near the optimal trade-off surface between the individual training data sets. The model quantitatively reproduced experimental measurements from dorsal root ganglion neurons as a function of extracellular ATP forcing. Hypothesized architecture linking phosphoinositide regulation with P2X receptor activity explained the inhibition of P2X-mediated current flow by activated metabotropic P2Y receptors. Sensitivity analysis using individual and the whole system outputs suggested which molecular subsystems were most important following P2 activation. Taken together, modeling and analysis of ATP-induced P2 mediated calcium signaling generated qualitative insight into the critical interactions controlling ATP induced calcium dynamics

  19. Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules.

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    Umemori, Hisashi; Sanes, Joshua R

    2008-12-05

    Formation of chemical synapses requires exchange of organizing signals between the synaptic partners. Using synaptic vesicle aggregation in cultured neurons as a marker of presynaptic differentiation, we purified candidate presynaptic organizers from mouse brain. A major bioactive species was the extracellular domain of signal regulatory protein alpha (SIRP-alpha), a transmembrane immunoglobulin superfamily member concentrated at synapses. The extracellular domain of SIRP-alpha is cleaved and shed in a developmentally regulated manner. The presynaptic organizing activity of SIRP-alpha is mediated in part by CD47. SIRP-alpha homologues, SIRP-beta and -gamma also have synaptic vesicle clustering activity. The effects of SIRP-alpha are distinct from those of another presynaptic organizer, FGF22: the two proteins induced vesicle clusters of different sizes, differed in their ability to promote neurite branching, and acted through different receptors and signaling pathways. SIRP family proteins may act together with other organizing molecules to pattern synapses.

  20. Regulatory role of voltage-gated sodium channel β subunits in sensory neurons

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    Mohamed eChahine

    2011-11-01

    Full Text Available Voltage-gated Na+ channels are transmembrane-bound proteins incorporating aqueous conduction pores that are highly selective for Na+. The opening of these channels results in the rapid influx of Na+ ions that depolarize the cell and drive the rapid upstroke of nerve and muscle action potentials. While the concept of a Na+-selective ion channel had been formulated in the 1940s, it was not until the 1980s that the biochemical properties of the 260-kDa and 36-kDa auxiliary β subunits (β1, β2 were first described. Subsequent cloning and heterologous expression studies revealed that the  subunit forms the core of the channel and is responsible for both voltage-dependent gating and ionic selectivity. To date, ten isoforms of the Na+ channel α subunit have been identified that vary in their primary structures, tissue distribution, biophysical properties, and sensitivity to neurotoxins. Four β subunits (β1-β4 and two splice variants (β1A, β1B have been identified that modulate the subcellular distribution, cell surface expression, and functional properties of the α subunits. The purpose of this review is to provide a broad overview of β subunit expression and function in peripheral sensory neurons and examine their contributions to neuropathic pain.

  1. Intracellular recording, sensory field mapping, and culturing identified neurons in the leech, Hirudo medicinalis.

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    Titlow, Josh; Majeed, Zana R; Nicholls, John G; Cooper, Robin L

    2013-11-04

    The freshwater leech, Hirudo medicinalis, is a versatile model organism that has been used to address scientific questions in the fields of neurophysiology, neuroethology, and developmental biology. The goal of this report is to consolidate experimental techniques from the leech system into a single article that will be of use to physiologists with expertise in other nervous system preparations, or to biology students with little or no electrophysiology experience. We demonstrate how to dissect the leech for recording intracellularly from identified neural circuits in the ganglion. Next we show how individual cells of known function can be removed from the ganglion to be cultured in a Petri dish, and how to record from those neurons in culture. Then we demonstrate how to prepare a patch of innervated skin to be used for mapping sensory or motor fields. These leech preparations are still widely used to address basic electrical properties of neural networks, behavior, synaptogenesis, and development. They are also an appropriate training module for neuroscience or physiology teaching laboratories.

  2. Development of primary sensory neurons in the trigeminal nervous system; dependency on neurotrophins and other substances

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    Hiroyuki Ichikawa

    2012-02-01

    Full Text Available This review presents information about the development of primary sensory neurons in the trigeminal nervous system. The deficiency of high affinity receptors for nerve growth factor (trkA and neurotrophin-3 (trk-C causesa reduction of primary nociceptors in the trigeminal ganglion (TG. The disruption of trkB, a receptor for brain-derived neurotrophic factor and neurotrophin-4, causes a loss of Meissner endings in the palate and Ruffini endings in the periodontal ligament. The number of Merkel cells in palatal rugae is also severely reduced by the absence of trkA, trkB or trkC. In the mesencephalic trigeminal tract nucleus (Mes5, primary proprioceptors are decreased by 50% in trkC null mutant mice. On the other hand, the deficiency of Brn-3a, a member of the POU family of transcription factors, decreases primary nociceptors and low-threshold mechanoreceptors in the TG. In the Mes5 of Brn-3a knockout mice, primary proprioceptors are completely lost. In addition, the disruption of dystonin which is a member of the plakin family of high molecular weight cytoskeletal linker proteins causes a reduction of nociceptors in the TG but not proprioceptors in the Mes5. The dependency of primary nociceptors, low-threshold mechanoreceptors and proprioceptors on neurotrophins, Brn-3a and dystonin in the trigeminal nervous system is discussed.

  3. Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation

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    Raisa Eng S

    2010-01-01

    Full Text Available Abstract The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG. Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes.

  4. Calcium-sensing receptor in rat vagal bronchopulmonary sensory neurons regulates the function of the capsaicin receptor TRPV1.

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    Gu, Qihai; Vysotskaya, Zhanna V; Moss, Charles R; Kagira, Martin K; Gilbert, Carolyn A

    2013-11-01

    Extracellular calcium-sensing receptor (CaSR) has been known to play a critical role in the maintainance of systemic Ca(2+) homeostasis. Recent studies have shown that CaSR is also expressed in many tissues that are not directly related to plasma Ca(2+) regulation, such as the central and peripheral nervous system, where the function of this receptor remains to be defined. In this study, we aimed to investigate the expression of CaSR and its potential interaction with transient receptor potential vanilloid receptor type 1 (TRPV1) in rat vagal bronchopulmonary sensory neurons. Our immunohistochemical experiments demonstrated the expression of CaSR in these sensory neurons as well as in trachea and lung parenchyma. Results from our whole-cell patch-clamp recordings in isolated neurons showed that strong activation of CaSR with high concentrations of its agonists, including spermine, NPS R-568 and Ca(2+), inhibited the capsaicin-evoked whole-cell inward current. Blockade of CaSR with its antagonists NPS 2390 and NPS 2143 significantly enhanced the capsaicin-evoked TRPV1 current. These data suggest that CaSR is likely to be involved in the integration of primary bronchopulmonary sensory inputs in physiological and/or pathophysiological conditions.

  5. Regulation of ASIC channels by a stomatin/STOML3 complex located in a mobile vesicle pool in sensory neurons.

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    Lapatsina, Liudmila; Jira, Julia A; Smith, Ewan St J; Poole, Kate; Kozlenkov, Alexey; Bilbao, Daniel; Lewin, Gary R; Heppenstall, Paul A

    2012-06-01

    A complex of stomatin-family proteins and acid-sensing (proton-gated) ion channel (ASIC) family members participate in sensory transduction in invertebrates and vertebrates. Here, we have examined the role of the stomatin-family protein stomatin-like protein-3 (STOML3) in this process. We demonstrate that STOML3 interacts with stomatin and ASIC subunits and that this occurs in a highly mobile vesicle pool in dorsal root ganglia (DRG) neurons and Chinese hamster ovary cells. We identify a hydrophobic region in the N-terminus of STOML3 that is required for vesicular localization of STOML3 and regulates physical and functional interaction with ASICs. We further characterize STOML3-containing vesicles in DRG neurons and show that they are Rab11-positive, but not part of the early-endosomal, lysosomal or Rab14-dependent biosynthetic compartment. Moreover, uncoupling of vesicles from microtubules leads to incorporation of STOML3 into the plasma membrane and increased acid-gated currents. Thus, STOML3 defines a vesicle pool in which it associates with molecules that have critical roles in sensory transduction. We suggest that the molecular features of this vesicular pool may be characteristic of a 'transducosome' in sensory neurons.

  6. Genes that act downstream of sensory neurons to influence longevity, dauer formation, and pathogen responses in Caenorhabditis elegans.

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    Marta M Gaglia

    Full Text Available The sensory systems of multicellular organisms are designed to provide information about the environment and thus elicit appropriate changes in physiology and behavior. In the nematode Caenorhabditis elegans, sensory neurons affect the decision to arrest during development in a diapause state, the dauer larva, and modulate the lifespan of the animals in adulthood. However, the mechanisms underlying these effects are incompletely understood. Using whole-genome microarray analysis, we identified transcripts whose levels are altered by mutations in the intraflagellar transport protein daf-10, which result in impaired development and function of many sensory neurons in C. elegans. In agreement with existing genetic data, the expression of genes regulated by the transcription factor DAF-16/FOXO was affected by daf-10 mutations. In addition, we found altered expression of transcriptional targets of the DAF-12/nuclear hormone receptor in the daf-10 mutants and showed that this pathway influences specifically the dauer formation phenotype of these animals. Unexpectedly, pathogen-responsive genes were repressed in daf-10 mutant animals, and these sensory mutants exhibited altered susceptibility to and behavioral avoidance of bacterial pathogens. Moreover, we found that a solute transporter gene mct-1/2, which was induced by daf-10 mutations, was necessary and sufficient for longevity. Thus, sensory input seems to influence an extensive transcriptional network that modulates basic biological processes in C. elegans. This situation is reminiscent of the complex regulation of physiology by the mammalian hypothalamus, which also receives innervations from sensory systems, most notably the visual and olfactory systems.

  7. Two different avian cold-sensitive sensory neurons: Transient receptor potential melastatin 8 (TRPM8)-dependent and -independent activation mechanisms.

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    Yamamoto, A; Takahashi, K; Saito, S; Tominaga, M; Ohta, T

    2016-12-01

    Sensing the ambient temperature is an important function for survival in animals. Some TRP channels play important roles as detectors of temperature and irritating chemicals. There are functional differences of TRP channels among species. TRPM8 in mammals is activated by cooling compounds and cold temperature, but less information is available on the functional role of TRPM8 in avian species. Here we investigated the pharmacological properties and thermal sensitivities of chicken TRPM8 (cTRPM8) and cold-sensitive mechanisms in avian sensory neurons. In heterologously expressed cTRPM8, menthol and its derivative, WS-12 elicited [Ca 2+ ] i increases, but icilin did not. In chicken sensory neurons, icilin increased [Ca 2+ ] i, in a TRPA1-dependent manner. Icilin selectively stimulated heterologously expressed chicken TRPA1 (cTRPA1). Similar to mammalian orthologue, cTRPM8 was activated by cold. Both heterologous and endogenous expressed cTRPM8 were sensitive to mammalian TRPM8 antagonists. There are two types of cold-sensitive cells regarding menthol sensitivity in chicken sensory neurons. The temperature threshold of menthol-insensitive neurons was significantly lower than that of menthol-sensitive ones. The population of menthol-insensitive neurons was large in chicken but almost little in mammals. The cold-induced [Ca 2+ ] i increases were not abolished by the external Ca 2+ removal or by blockades of PLC-IP 3 pathways and ryanodine channels. The cold stimulation failed to evoke [Ca 2+ ] i increases after intracellular Ca 2+ store-depletion. These results indicate that cTRPM8 acts as a cold-sensor similar to mammals. It is noteworthy that TRPM8-independent cold-sensitive neurons are abundant in chicken sensory neurons. Our results suggest that most of the cold-induced [Ca 2+ ] i increases are mediated via Ca 2+ release from intracellular stores and that these mechanisms may be specific to avian species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice

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    Belén Mollá

    2017-08-01

    Full Text Available Friedreich’s ataxia (FRDA is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

  9. Primary sensory neurons regulate Toll-like receptor-4-dependent activity of glial cells in dorsal root ganglia.

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    Tse, K-H; Chow, K B S; Leung, W K; Wong, Y H; Wise, H

    2014-10-24

    Toll-like receptor-4 (TLR4) has been identified in primary sensory neurons, both in vivo and in vitro, but is reportedly absent from satellite glial cells (SGCs). Herein we reveal that, in rat dorsal root ganglia (DRG), SGCs do express TLR4 but this expression is inhibited by direct contact with neurons. Thus, TLR4 mRNA and protein is strongly up-regulated in isolated DRG glial cells in the absence of neurons. Lipopolysaccharide (LPS) increased cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNFα) mRNA expression with greater efficacy in DRG glial cell cultures than in mixed DRG cell cultures containing TLR4-positive neurons. Using an insert co-culture system, we have shown that neuronal inhibition of glial cell TLR4 is likely to be dependent on cell-cell contact rather than diffusible factors from neurons. LPS stimulated prostaglandin E2 (PGE2) production from DRG glial cells in a TLR4- and COX-2-dependent manner. In addition, exogenous PGE2 potentiated LPS-stimulated COX-2 mRNA while inhibiting TNFα mRNA expression by DRG cells, suggestive of a complex regulatory system to control inflammation within the DRG. In addition to LPS, conditioned medium from heat-shocked DRG neurons also increased COX-2 mRNA expression in DRG glial cells in a partially TLR4-dependent manner. We therefore hypothesize that neuronal suppression of glial TLR4 activity is a protective mechanism to prevent uncontrolled inflammation within the DRG. Under conditions where DRG neuronal viability is compromised, DRG glial cells become responsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (danger-associated molecular patterns) and generate a range of classical inflammatory responses. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. PROS-1/Prospero Is a Major Regulator of the Glia-Specific Secretome Controlling Sensory-Neuron Shape and Function in C. elegans.

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    Wallace, Sean W; Singhvi, Aakanksha; Liang, Yupu; Lu, Yun; Shaham, Shai

    2016-04-19

    Sensory neurons are an animal's gateway to the world, and their receptive endings, the sites of sensory signal transduction, are often associated with glia. Although glia are known to promote sensory-neuron functions, the molecular bases of these interactions are poorly explored. Here, we describe a post-developmental glial role for the PROS-1/Prospero/PROX1 homeodomain protein in sensory-neuron function in C. elegans. Using glia expression profiling, we demonstrate that, unlike previously characterized cell fate roles, PROS-1 functions post-embryonically to control sense-organ glia-specific secretome expression. PROS-1 functions cell autonomously to regulate glial secretion and membrane structure, and non-cell autonomously to control the shape and function of the receptive endings of sensory neurons. Known glial genes controlling sensory-neuron function are PROS-1 targets, and we identify additional PROS-1-dependent genes required for neuron attributes. Drosophila Prospero and vertebrate PROX1 are expressed in post-mitotic sense-organ glia and astrocytes, suggesting conserved roles for this class of transcription factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones

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    Lynne Shanley

    2010-12-01

    Full Text Available Changes in the expression of the neuropeptide substance P (SP in different populations of sensory neurones are associated with the progression of chronic inflammatory disease. Thus, understanding the genomic and cellular mechanisms driving the expression of the TAC1 gene, which encodes SP, in sensory neurones is essential to understanding its role in inflammatory disease. We used a novel combination of computational genomics, primary-cell culture and mouse transgenics to determine the genomic and cellular mechanisms that control the expression of TAC1 in sensory neurones. Intriguingly, we demonstrated that the promoter of the TAC1 gene must act in synergy with a remote enhancer, identified using comparative genomics, to respond to MAPK signalling that modulates the expression of TAC1 in sensory neurones. We also reveal that noxious stimulation of sensory neurones triggers this synergy in larger diameter sensory neurones – an expression of SP associated with hyperalgesia. This noxious stimulation of TAC1 enhancer-promotor synergy could be strongly blocked by antagonism of the MEK pathway. This study provides a unique insight into the role of long-range enhancer-promoter synergy and selectivity in the tissue-specific response of promoters to specific signal transduction pathways and suggests a possible new avenue for the development of novel anti-inflammatory therapies.

  12. Identification and Characterization of Two "Sensory Neuron Membrane Proteins" (SNMPs) of the Desert Locust, Schistocerca gregaria (Orthoptera: Acrididae).

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    Jiang, Xingcong; Pregitzer, Pablo; Grosse-Wilde, Ewald; Breer, Heinz; Krieger, Jürgen

    2016-01-01

    Pheromone-responsive neurons of insects not only require specific receptors but in addition several auxiliary components, including the "sensory neuron membrane protein," SNMP. Accordingly, SNMP is considered as a marker for neurons responding to pheromones. For the desert locust Schistocerca gregaria, it is known that the behavior, including aggregation behavior and courtship inhibition, is largely controlled by pheromones. However, little is known about pheromones, their receptors, and the pheromone-responsive cells in locusts. In this study, we have identified two SNMP subtypes, SNMP1 and SNMP2, and compared their phylogenetic relationship and primary structure motifs with SNMPs from other species. Both SNMPs were found in chemosensory tissues, especially the antennae. Employing double in situ hybridization, we identified and localized the SNMP-expressing cells in the antennae. Cells expressing SNMP1 were localized to sensilla trichodea but also to sensilla basiconica, which in locust respond to pheromones. One or a few cells express SNMP1 within the multineuron clusters from sensilla basiconica, whereas the SNMP2 subtype was expressed in cells surrounding the neuron clusters, possibly supporting cells. Based on the finding that SNMP1 is expressed in distinct neurons under chemosensory sensilla, it is conceivable that these cells may represent pheromone-responsive neurons of the desert locust. © The Author 2016. Published by Oxford University Press on behalf of the Entomological Society of America.

  13. Expression of ionotropic receptors in terrestrial hermit crab’s olfactory sensory neurons

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    Katrin Christine Groh-Lunow

    2015-02-01

    Full Text Available Coenobitidae are one out of at least five crustacean lineages which independently succeeded in the transition from water to land. This change in lifestyle required adaptation of the peripheral olfactory organs, the antennules, in order to sense chemical cues in the new terrestrial habitat. Hermit crab olfactory aesthetascs are arranged in a field on the distal segment of the antennular flagellum. Aesthetascs house approximately 300 dendrites with their cell bodies arranged in spindle-like complexes of ca. 150 cell bodies each. While the aesthetascs of aquatic crustaceans have been shown to be the place of odor uptake and previous studies identified ionotropic receptors (IRs as the putative chemosensory receptors expressed in decapod antennules, the expression of IRs besides the IR co-receptors IR25a and IR93a in olfactory sensory neurons (OSNs has not been documented yet. Our goal was to reveal the expression and distribution pattern of non-co-receptor IRs in OSNs of Coenobita clypeatus, a terrestrial hermit crab, with RNA in situ hybridization. We expanded our previously published RNAseq dataset, and revealed 22 novel IR candidates in the Coenobita antennules. We then used RNA probes directed against three different IRs to visualize their expression within the OSN cell body complexes. Furthermore we aimed to characterize ligand spectra of single aesthetascs by recording local field potentials and responses from individual dendrites. This also allowed comparison to functional data from insect OSNs expressing antennal IRs. We show that this orphan receptor subgroup with presumably non-olfactory function in insects is likely the basis of olfaction in terrestrial hermit crabs.

  14. Multidendritic sensory neurons in the adult Drosophila abdomen: origins, dendritic morphology, and segment- and age-dependent programmed cell death

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    Sugimura Kaoru

    2009-10-01

    Full Text Available Abstract Background For the establishment of functional neural circuits that support a wide range of animal behaviors, initial circuits formed in early development have to be reorganized. One way to achieve this is local remodeling of the circuitry hardwiring. To genetically investigate the underlying mechanisms of this remodeling, one model system employs a major group of Drosophila multidendritic sensory neurons - the dendritic arborization (da neurons - which exhibit dramatic dendritic pruning and subsequent growth during metamorphosis. The 15 da neurons are identified in each larval abdominal hemisegment and are classified into four categories - classes I to IV - in order of increasing size of their receptive fields and/or arbor complexity at the mature larval stage. Our knowledge regarding the anatomy and developmental basis of adult da neurons is still fragmentary. Results We identified multidendritic neurons in the adult Drosophila abdomen, visualized the dendritic arbors of the individual neurons, and traced the origins of those cells back to the larval stage. There were six da neurons in abdominal hemisegment 3 or 4 (A3/4 of the pharate adult and the adult just after eclosion, five of which were persistent larval da neurons. We quantitatively analyzed dendritic arbors of three of the six adult neurons and examined expression in the pharate adult of key transcription factors that result in the larval class-selective dendritic morphologies. The 'baseline design' of A3/4 in the adult was further modified in a segment-dependent and age-dependent manner. One of our notable findings is that a larval class I neuron, ddaE, completed dendritic remodeling in A2 to A4 and then underwent caspase-dependent cell death within 1 week after eclosion, while homologous neurons in A5 and in more posterior segments degenerated at pupal stages. Another finding is that the dendritic arbor of a class IV neuron, v'ada, was immediately reshaped during post

  15. TRPA1 is functionally expressed primarily by IB4-binding, non-peptidergic mouse and rat sensory neurons.

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    Marie E Barabas

    Full Text Available Subpopulations of somatosensory neurons are characterized by functional properties and expression of receptor proteins and surface markers. CGRP expression and IB4-binding are commonly used to define peptidergic and non-peptidergic subpopulations. TRPA1 is a polymodal, plasma membrane ion channel that contributes to mechanical and cold hypersensitivity during tissue injury, making it a key target for pain therapeutics. Some studies have shown that TRPA1 is predominantly expressed by peptidergic sensory neurons, but others indicate that TRPA1 is expressed extensively within non-peptidergic, IB4-binding neurons. We used FURA-2 calcium imaging to define the functional distribution of TRPA1 among peptidergic and non-peptidergic adult mouse (C57BL/6J DRG neurons. Approximately 80% of all small-diameter (<27 µm neurons from lumbar 1-6 DRGs that responded to TRPA1 agonists allyl isothiocyanate (AITC; 79% or cinnamaldehyde (84% were IB4-positive. Retrograde labeling via plantar hind paw injection of WGA-Alexafluor594 showed similarly that most (81% cutaneous neurons responding to TRPA1 agonists were IB4-positive. Additionally, we cultured DRG neurons from a novel CGRP-GFP mouse where GFP expression is driven by the CGRPα promoter, enabling identification of CGRP-expressing live neurons. Interestingly, 78% of TRPA1-responsive neurons were CGRP-negative. Co-labeling with IB4 revealed that the majority (66% of TRPA1 agonist responders were IB4-positive but CGRP-negative. Among TRPA1-null DRGs, few small neurons (2-4% responded to either TRPA1 agonist, indicating that both cinnamaldehyde and AITC specifically target TRPA1. Additionally, few large neurons (≥27 µm diameter responded to AITC (6% or cinnamaldehyde (4%, confirming that most large-diameter somata lack functional TRPA1. Comparison of mouse and rat DRGs showed that the majority of TRPA1-responsive neurons in both species were IB4-positive. Together, these data demonstrate that TRPA1 is

  16. Blood oxygenation level dependent signal and neuronal adaptation to optogenetic and sensory stimulation in somatosensory cortex in awake animals.

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    Aksenov, Daniil P; Li, Limin; Miller, Michael J; Wyrwicz, Alice M

    2016-11-01

    The adaptation of neuronal responses to stimulation, in which a peak transient response is followed by a sustained plateau, has been well-studied. The blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal has also been shown to exhibit adaptation on a longer time scale. However, some regions such as the visual and auditory cortices exhibit significant BOLD adaptation, whereas other such as the whisker barrel cortex may not adapt. In the sensory cortex a combination of thalamic inputs and intracortical activity drives hemodynamic changes, although the relative contributions of these components are not entirely understood. The aim of this study is to assess the role of thalamic inputs vs. intracortical processing in shaping BOLD adaptation during stimulation in the somatosensory cortex. Using simultaneous fMRI and electrophysiology in awake rabbits, we measured BOLD, local field potentials (LFPs), single- and multi-unit activity in the cortex during whisker and optogenetic stimulation. This design allowed us to compare BOLD and haemodynamic responses during activation of the normal thalamocortical sensory pathway (i.e., both inputs and intracortical activity) vs. the direct optical activation of intracortical circuitry alone. Our findings show that whereas LFP and multi-unit (MUA) responses adapted, neither optogenetic nor sensory stimulation produced significant BOLD adaptation. We observed for both paradigms a variety of excitatory and inhibitory single unit responses. We conclude that sensory feed-forward thalamic inputs are not primarily responsible for shaping BOLD adaptation to stimuli; but the single-unit results point to a role in this behaviour for specific excitatory and inhibitory neuronal sub-populations, which may not correlate with aggregate neuronal activity. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  17. A PKM Generated by Calpain Cleavage of a Classical PKC Is Required for Activity-Dependent Intermediate-Term Facilitation in the Presynaptic Sensory Neuron of "Aplysia"

    Science.gov (United States)

    Farah, Carole A.; Hastings, Margaret H.; Dunn, Tyler W.; Gong, Katrina; Baker-Andresen, Danay; Sossin, Wayne S.

    2017-01-01

    Atypical PKM, a persistently active form of atypical PKC, is proposed to be a molecular memory trace, but there have been few examinations of the role of PKMs generated from other PKCs. We demonstrate that inhibitors used to inhibit PKMs generated from atypical PKCs are also effective inhibitors of other PKMs. In contrast, we demonstrate that…

  18. Block of voltage-gated potassium channels by Pacific ciguatoxin-1 contributes to increased neuronal excitability in rat sensory neurons

    International Nuclear Information System (INIS)

    Birinyi-Strachan, Liesl C.; Gunning, Simon J.; Lewis, Richard J.; Nicholson, Graham M.

    2005-01-01

    The present study investigated the actions of the polyether marine toxin Pacific ciguatoxin-1 (P-CTX-1) on neuronal excitability in rat dorsal root ganglion (DRG) neurons using patch-clamp recording techniques. Under current-clamp conditions, bath application of 2-20 nM P-CTX-1 caused a rapid, concentration-dependent depolarization of the resting membrane potential in neurons expressing tetrodotoxin (TTX)-sensitive voltage-gated sodium (Na v ) channels. This action was completely suppressed by the addition of 200 nM TTX to the external solution, indicating that this effect was mediated through TTX-sensitive Na v channels. In addition, P-CTX-1 also prolonged action potential and afterhyperpolarization (AHP) duration. In a subpopulation of neurons, P-CTX-1 also produced tonic action potential firing, an effect that was not accompanied by significant oscillation of the resting membrane potential. Conversely, in neurons expressing TTX-resistant Na v currents, P-CTX-1 failed to alter any parameter of neuronal excitability examined in this study. Under voltage-clamp conditions in rat DRG neurons, P-CTX-1 inhibited both delayed-rectifier and 'A-type' potassium currents in a dose-dependent manner, actions that occurred in the absence of alterations to the voltage dependence of activation. These actions appear to underlie the prolongation of the action potential and AHP, and contribute to repetitive firing. These data indicate that a block of potassium channels contributes to the increase in neuronal excitability, associated with a modulation of Na v channel gating, observed clinically in response to ciguatera poisoning

  19. Failure of action potential propagation in sensory neurons: mechanisms and loss of afferent filtering in C-type units after painful nerve injury

    NARCIS (Netherlands)

    Gemes, Geza; Koopmeiners, Andrew; Rigaud, Marcel; Lirk, Philipp; Sapunar, Damir; Bangaru, Madhavi Latha; Vilceanu, Daniel; Garrison, Sheldon R.; Ljubkovic, Marko; Mueller, Samantha J.; Stucky, Cheryl L.; Hogan, Quinn H.

    2013-01-01

    The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of

  20. Peripheral multidendritic sensory neurons are necessary for rhythmic locomotion behavior in Drosophila larvae

    OpenAIRE

    Song, Wei; Onishi, Maika; Jan, Lily Yeh; Jan, Yuh Nung

    2007-01-01

    From breathing to walking, rhythmic movements encompass physiological processes important across the entire animal kingdom. It is thought by many that the generation of rhythmic behavior is operated by a central pattern generator (CPG) and does not require peripheral sensory input. Sensory feedback is, however, required to modify or coordinate the motor activity in response to the circumstances of actual movement. In contrast to this notion, we report here that sensory input is necessary for ...

  1. Restoring the encoding properties of a stochastic neuron model by an exogenous noise

    Directory of Open Access Journals (Sweden)

    Alessandra ePaffi

    2015-05-01

    Full Text Available Here we evaluate the possibility of improving the encoding properties of an impaired neuronal system by superimposing an exogenous noise to an external electric stimulation signal. The approach is based on the use of mathematical neuron models consisting of stochastic HH-like circuit, where the impairment of the endogenous presynaptic inputs is described as a subthreshold injected current and the exogenous stimulation signal is a sinusoidal voltage perturbation across the membrane. Our results indicate that a correlated Gaussian noise, added to the sinusoidal signal can significantly increase the encoding properties of the impaired system, through the Stochastic Resonance (SR phenomenon. These results suggest that an exogenous noise, suitably tailored, could improve the efficacy of those stimulation techniques used in neuronal systems, where the presynaptic sensory neurons are impaired and have to be artificially bypassed.

  2. Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons.

    Science.gov (United States)

    Ives, Angela M; Bertke, Andrea S

    2017-07-01

    Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with the exacerbation of clinical symptoms and the induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive HSV-1 and HSV-2 infections within sensory and autonomic neurons, we analyzed viral DNA and the production of viral progeny after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal ganglion (TG) and sympathetic superior cervical ganglion (SCG) neurons expressed adrenergic receptors (activated by epinephrine) and the glucocorticoid receptor (activated by corticosterone). Productive HSV infection colocalized with these receptors in SCG but not in TG neurons. In productively infected neuronal cultures, epinephrine treatment significantly increased the levels of HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased the levels of HSV-2 DNA replication and production of viral progeny in SCG neurons but not in TG neurons. Thus, the stress-related hormones epinephrine and corticosterone selectively modulate acute HSV-1 and HSV-2 infections in autonomic, but not sensory, neurons. IMPORTANCE Stress exacerbates acute disease symptoms resulting from HSV-1 and HSV-2 infections and is associated with the appearance of recurrent skin lesions in millions of people. Although stress hormones are thought to impact HSV-1 and HSV-2 through immune system suppression, sensory and autonomic neurons that become

  3. Intrinsic Innate Immunity Fails To Control Herpes Simplex Virus and Vesicular Stomatitis Virus Replication in Sensory Neurons and Fibroblasts

    Science.gov (United States)

    Rosato, Pamela C.

    2014-01-01

    ABSTRACT Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG), wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 acute replication. We therefore sought to further investigate this response in TG neurons cultured from adult mice deficient in a variety of IFN signaling components. Parallel experiments were also performed in fibroblasts isolated concurrently. We showed that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons and fibroblasts. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN-β pretreatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in γ34.5, while wild-type HSV-1 replication was unaffected. This was in contrast to fibroblasts in which all viruses were restricted by the addition of IFN-β. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN-β, and HSV-1 combats this response through γ34.5. These results further our understanding of the antiviral response of neurons and highlight the importance of paracrine IFN-β signaling in establishing an antiviral state. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a ubiquitous virus that establishes a lifelong latent infection in neurons. Reactivation from latency can cause cold sores, blindness, and death from encephalitis. Humans with deficiencies in innate immunity have significant problems controlling HSV infections. In this study, we therefore sought to elucidate the role of neuronal innate immunity in the control of viral infection. Using neurons isolated from mice, we found that the intrinsic capacity of neurons to restrict virus replication was unaffected by the presence

  4. Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system.

    Science.gov (United States)

    Poole, Daniel P; Lee, Mike; Tso, Patrick; Bunnett, Nigel W; Yo, Sek Jin; Lieu, TinaMarie; Shiu, Amy; Wang, Jen-Chywan; Nomura, Daniel K; Aponte, Gregory W

    2014-04-15

    Lymphatic fluid is a plasma filtrate that can be viewed as having biological activity through the passive accumulation of molecules from the interstitial fluid. The possibility that lymphatic fluid is part of an active self-contained signaling process that parallels the endocrine system, through the activation of G-protein coupled receptors (GPCR), has remained unexplored. We show that the GPCR lysophosphatidic acid 5 (LPA5) is found in sensory nerve fibers expressing calcitonin gene-related peptide (CGRP) that innervate the lumen of lymphatic lacteals and enteric nerves. Using LPA5 as a model for nutrient-responsive GPCRs present on sensory nerves, we demonstrate that dietary protein hydrolysate (peptone) can induce c-Fos expression in enterocytes and nerves that express LPA5. Mesenteric lymphatic fluid (MLF) mobilizes intracellular calcium in cell models expressing LPA5 upon feeding in a time- and dose-dependent manner. Primary cultured neurons of the dorsal root ganglia expressing CGRP are activated by MLF, which is enhanced upon LPA5 overexpression. Activation is independent of the known LPA5 agonists, lysophosphatidic acid and farnesyl pyrophosphate. These data bring forth a pathway for the direct stimulation of sensory nerves by luminal contents and interstitial fluid. Thus, by activating LPA5 on sensory nerves, MLF provides a means for known and yet to be identified constituents of the interstitial fluid to act as signals to comprise a "neurolymphocrine" system.

  5. The HMX/NKX homeodomain protein MLS-2 specifies the identity of the AWC sensory neuron type via regulation of the ceh-36 Otx gene in C. elegans

    Science.gov (United States)

    Kim, Kyuhyung; Kim, Rinho; Sengupta, Piali

    2010-01-01

    The differentiated features of postmitotic neurons are dictated by the expression of specific transcription factors. The mechanisms by which the precise spatiotemporal expression patterns of these factors are regulated are poorly understood. In C. elegans, the ceh-36 Otx homeobox gene is expressed in the AWC sensory neurons throughout postembryonic development, and regulates terminal differentiation of this neuronal subtype. Here, we show that the HMX/NKX homeodomain protein MLS-2 regulates ceh-36 expression specifically in the AWC neurons. Consequently, the AWC neurons fail to express neuron type-specific characteristics in mls-2 mutants. mls-2 is expressed transiently in postmitotic AWC neurons, and directly initiates ceh-36 expression. CEH-36 subsequently interacts with a distinct site in its cis-regulatory sequences to maintain its own expression, and also directly regulates the expression of AWC-specific terminal differentiation genes. We also show that MLS-2 acts in additional neuron types to regulate their development and differentiation. Our analysis describes a transcription factor cascade that defines the unique postmitotic characteristics of a sensory neuron subtype, and provides insights into the spatiotemporal regulatory mechanisms that generate functional diversity in the sensory nervous system. PMID:20150279

  6. Ciliary neurotrophic factor reverses aberrant mitochondrial bioenergetics through the JAK/STAT pathway in cultured sensory neurons derived from streptozotocin-induced diabetic rodents.

    Science.gov (United States)

    Chowdhury, Subir Roy; Saleh, Ali; Akude, Eli; Smith, Darrell R; Morrow, Dwane; Tessler, Lori; Calcutt, Nigel A; Fernyhough, Paul

    2014-07-01

    Mitochondrial dysfunction occurs in sensory neurons and contributes to diabetic neuropathy. Ciliary neurotrophic factor (CNTF) stimulates axon regeneration in type 1 diabetic rodents and prevents deficits in axonal caliber, nerve conduction, and thermal sensation. We tested the hypothesis that CNTF enhances sensory neuron function in diabetes through JAK/STAT (Janus kinase/signal transducers and activators of transcription) signaling to normalize impaired mitochondrial bioenergetics. The effect of CNTF on gene expression and neurite outgrowth of cultured adult dorsal root ganglia (DRG) sensory neurons derived from control and streptozotocin (STZ)-induced diabetic rodents was quantified. Polarization status and bioenergetics profile of mitochondria from cultured sensory neurons were determined. CNTF treatment prevented reduced STAT3 phosphorylation (Tyr 705) in DRG of STZ-diabetic mice and also enhanced STAT3 phosphorylation in rat DRG cultures. CNTF normalized polarization status of the mitochondrial inner membrane and corrected the aberrant oligomycin-induced mitochondrial hyperpolarization in axons of diabetic neurons. The mitochondrial bioenergetics profile demonstrated that spare respiratory capacity and respiratory control ratio were significantly depressed in sensory neurons cultured from STZ-diabetic rats and were corrected by acute CNTF treatment. The positive effects of CNTF on neuronal mitochondrial function were significantly inhibited by the specific JAK inhibitor, AG490. Neurite outgrowth of sensory neurons from age-matched control and STZ-induced diabetic rats was elevated by CNTF and blocked by AG490. We propose that CNTF's ability to enhance axon regeneration and protect from fiber degeneration in diabetes is associated with its targeting of mitochondrial function and improvement of cellular bioenergetics, in part, through JAK/STAT signaling.

  7. Dync1h1 Mutation Causes Proprioceptive Sensory Neuron Loss and Impaired Retrograde Axonal Transport of Dorsal Root Ganglion Neurons.

    Science.gov (United States)

    Zhao, Jing; Wang, Yi; Xu, Huan; Fu, Yuan; Qian, Ting; Bo, Deng; Lu, Yan-Xin; Xiong, Yi; Wan, Jun; Zhang, Xiang; Dong, Qiang; Chen, Xiang-Jun

    2016-07-01

    Sprawling (Swl) is a radiation-induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. To display the phenotype of Swl mutant mice, we examined the embryos of homozygous (Swl/Swl) and heterozygous (Swl/+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl/+ mice. The Swl/+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/+ DRG neurons was revealed during E11.5-E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein-driven nerve growth factor (NGF). Mitochondria, another dynein-driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild-type (WT) neurons. Nevertheless, the Swl, Loa, and Cra mutations did not affect homodimerization of DYNC1H1. The Swl/Swl mutation of Dync1h1 gene led to embryonic mal-development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein-driven cargos and excessive apoptosis during mid- to late-developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1. © 2016 John Wiley & Sons Ltd.

  8. Notch is required in adult Drosophila sensory neurons for morphological and functional plasticity of the olfactory circuit.

    Directory of Open Access Journals (Sweden)

    Simon Kidd

    2015-05-01

    Full Text Available Olfactory receptor neurons (ORNs convey odor information to the central brain, but like other sensory neurons were thought to play a passive role in memory formation and storage. Here we show that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila ORNs for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. Specifically, we show that Notch activity in ORNs is necessary for the odor specific increase in the volume of glomeruli that occurs as a consequence of prolonged odor exposure. Calcium imaging experiments indicate that Notch in ORNs is also required for the chronic odor induced changes in the physiology of ORNs and the ensuing changes in the physiological response of their second order projection neurons (PNs. We further show that Notch in ORNs acts by both canonical cleavage-dependent and non-canonical cleavage-independent pathways. The Notch ligand Delta (Dl in PNs switches the balance between the pathways. These data define a circuit whereby, in conjunction with odor, N activity in the periphery regulates the activity of neurons in the central brain and Dl in the central brain regulates N activity in the periphery. Our work highlights the importance of experience dependent plasticity at the first olfactory synapse.

  9. Cyclophosphamide-induced cystitis reduces ASIC channel but enhances TRPV1 receptor function in rat bladder sensory neurons.

    Science.gov (United States)

    Dang, Khoa; Bielefeldt, Klaus; Gebhart, G F

    2013-07-01

    Using patch-clamp techniques, we studied the plasticity of acid-sensing ion channels (ASIC) and transient receptor potential V1 (TRPV1) channel function in dorsal root ganglia (DRG) neurons retrogradely labeled from the bladder. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally on days 1, 3, and 5. On day 6, lumbosacral (LS, L6-S2) or thoracolumbar (TL, T13-L2) DRG were removed and dissociated. Bladders and bladder DRG neurons from CYP-treated rats showed signs of inflammation (greater myeloperoxidase activity; lower intramuscular wall pH) and increased size (whole cell capacitance), respectively, compared with controls. Most bladder neurons (>90%) responded to protons and capsaicin. Protons produced multiphasic currents with distinct kinetics, whereas capsaicin always triggered a sustained response. The TRPV1 receptor antagonist A-425619 abolished capsaicin-triggered currents and raised the threshold of heat-activated currents. Prolonged exposure to an acidic environment (pH range: 7.2 to 6.6) inhibited proton-evoked currents, potentiated the capsaicin-evoked current, and reduced the threshold of heat-activated currents in LS and TL bladder neurons. CYP treatment reduced density but not kinetics of all current components triggered by pH 5. In contrast, CYP-treatment was associated with an increased current density in response to capsaicin in LS and TL bladder neurons. Correspondingly, heat triggered current at a significantly lower temperature in bladder neurons from CYP-treated rats compared with controls. These results reveal that cystitis differentially affects TRPV1- and ASIC-mediated currents in both bladder sensory pathways. Acidification of the bladder wall during inflammation may contribute to changes in nociceptive transmission mediated through the TRPV1 receptor, suggesting a role for TRPV1 in hypersensitivity associated with cystitis.

  10. Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation.

    Science.gov (United States)

    Li, Xiling; Goel, Pragya; Chen, Catherine; Angajala, Varun; Chen, Xun; Dickman, Dion K

    2018-04-05

    Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic Homeostatic Plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments. © 2018, Li et al.

  11. Glycolysis selectively shapes the presynaptic action potential waveform.

    Science.gov (United States)

    Lujan, Brendan; Kushmerick, Christopher; Banerjee, Tania Das; Dagda, Ruben K; Renden, Robert

    2016-12-01

    Mitochondria are major suppliers of cellular energy in neurons; however, utilization of energy from glycolysis vs. mitochondrial oxidative phosphorylation (OxPhos) in the presynaptic compartment during neurotransmission is largely unknown. Using presynaptic and postsynaptic recordings from the mouse calyx of Held, we examined the effect of acute selective pharmacological inhibition of glycolysis or mitochondrial OxPhos on multiple mechanisms regulating presynaptic function. Inhibition of glycolysis via glucose depletion and iodoacetic acid (1 mM) treatment, but not mitochondrial OxPhos, rapidly altered transmission, resulting in highly variable, oscillating responses. At reduced temperature, this same treatment attenuated synaptic transmission because of a smaller and broader presynaptic action potential (AP) waveform. We show via experimental manipulation and ion channel modeling that the altered AP waveform results in smaller Ca 2+ influx, resulting in attenuated excitatory postsynaptic currents (EPSCs). In contrast, inhibition of mitochondria-derived ATP production via extracellular pyruvate depletion and bath-applied oligomycin (1 μM) had no significant effect on Ca 2+ influx and did not alter the AP waveform within the same time frame (up to 30 min), and the resultant EPSC remained unaffected. Glycolysis, but not mitochondrial OxPhos, is thus required to maintain basal synaptic transmission at the presynaptic terminal. We propose that glycolytic enzymes are closely apposed to ATP-dependent ion pumps on the presynaptic membrane. Our results indicate a novel mechanism for the effect of hypoglycemia on neurotransmission. Attenuated transmission likely results from a single presynaptic mechanism at reduced temperature: a slower, smaller AP, before and independent of any effect on synaptic vesicle release or receptor activity. Copyright © 2016 the American Physiological Society.

  12. Sensory Processing Dysfunction in the Personal Experience and Neuronal Machinery of Schizophrenia

    Science.gov (United States)

    Javitt, Daniel C.; Freedman, Robert

    2015-01-01

    Sensory processing deficits, first investigated by Kraeplin and Bleuler as possible pathophysiological mechanisms in schizophrenia, are now being re-characterized in the context of modern understanding of the involved molecular and neurobiological brain mechanisms. The National Institute of Mental Health Research Domain Criteria position these deficits as intermediaries between molecular and cellular mechanisms and clinical symptoms of schizophrenia such as hallucinations. The pre-pulse inhibition of startle responses by a weaker preceding tone, the inhibitory gating of response to paired sensory stimuli characterized using the auditory P50 evoked response, and the detection of slightly different stimuli that elicits the cortical Mismatch Negativity potential demonstrate deficits in early sensory processing mechanisms, whose molecular and neurobiological bases are increasingly well understood. Deficits in sensory processing underlie more complex cognitive dysfunction and, vice versa, are affected by higher-level cognitive difficulties. These deficits are now being used to identify genes involved in familial transmission of the illness and to monitor potentially therapeutic drug effects for both treatment and prevention. This research also provides a clinical reminder that patients’ sensory perception of the surrounding world, even during treatment sessions, may differ considerable from others’ perceptions. A person’s ability to understand and interact effectively with surrounding world ultimately depends upon an underlying sensory experience of it. PMID:25553496

  13. The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons.

    Science.gov (United States)

    Helley, M P; Abate, W; Jackson, S K; Bennett, J H; Thompson, S W N

    2015-12-03

    The recent discovery that mammalian nociceptors express Toll-like receptors (TLRs) has raised the possibility that these cells directly detect and respond to pathogens with implications for either direct nociceptor activation or sensitization. A range of neuronal TLRs have been identified, however a detailed description regarding the distribution of expression of these receptors within sub-populations of sensory neurons is lacking. There is also some debate as to the composition of the TLR4 receptor complex on sensory neurons. Here we use a range of techniques to quantify the expression of TLR4, TLR7 and some associated molecules within neurochemically-identified sub-populations of trigeminal (TG) and dorsal root (DRG) ganglion sensory neurons. We also detail the pattern of expression and co-expression of two isoforms of lysophosphatidylcholine acyltransferase (LPCAT), a phospholipid remodeling enzyme previously shown to be involved in the lipopolysaccharide-dependent TLR4 response in monocytes, within sensory ganglia. Immunohistochemistry shows that both TLR4 and TLR7 preferentially co-localize with transient receptor potential vallinoid 1 (TRPV1) and purinergic receptor P2X ligand-gated ion channel 3 (P2X3), markers of nociceptor populations, within both TG and DRG. A gene expression profile shows that TG sensory neurons express a range of TLR-associated molecules. LPCAT1 is expressed by a proportion of both nociceptors and non-nociceptive neurons. LPCAT2 immunostaining is absent from neuronal profiles within both TG and DRG and is confined to non-neuronal cell types under naïve conditions. Together, our results show that nociceptors express the molecular machinery required to directly respond to pathogenic challenge independently from the innate immune system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Involvement of spinal sensory pathway in ALS and specificity of cord atrophy to lower motor neuron degeneration.

    Science.gov (United States)

    Cohen-Adad, Julien; El Mendili, Mohamed-Mounir; Morizot-Koutlidis, Régine; Lehéricy, Stéphane; Meininger, Vincent; Blancho, Sophie; Rossignol, Serge; Benali, Habib; Pradat, Pierre-François

    2013-01-01

    Our objective was to demonstrate that ALS patients have sensory pathway involvement and that local cord atrophy reflects segmental lower motor neuron involvement. Twenty-nine ALS patients with spinal onset and twenty-one healthy controls were recruited. Diffusion tensor imaging (DTI), magnetization transfer and atrophy index were measured in the spinal cord, complemented with transcranial magnetic stimulations. Metrics were quantified within the lateral corticospinal and the dorsal segments of the cervical cord. Significant differences were detected between patients and controls for DTI and magnetization transfer metrics in the lateral and dorsal segments of the spinal cord. Fractional anisotropy correlated with ALSFRS-R (p = 0.04) and motor threshold (p = 0.02). Stepwise linear regression detected local spinal cord atrophy associated with weakness in the corresponding muscle territory, i.e. C4 level for deltoid and C7 level for hand muscles. In conclusion, impairment of spinal sensory pathways was detected at an early stage of the disease. Our data also demonstrate an association between muscle deficits and local spinal cord atrophy, suggesting that atrophy is a sensitive biomarker for lower motor neurons degeneration.

  15. Adeno-associated Virus Vectors Efficiently Transduce Mouse and Rabbit Sensory Neurons Coinfected with Herpes Simplex Virus 1 following Peripheral Inoculation.

    Science.gov (United States)

    Watson, Zachary L; Ertel, Monica K; Lewin, Alfred S; Tuli, Sonal S; Schultz, Gregory S; Neumann, Donna M; Bloom, David C

    2016-09-01

    Following infection of epithelial tissues, herpes simplex virus 1 (HSV-1) virions travel via axonal transport to sensory ganglia and establish a lifelong latent infection within neurons. Recent studies have revealed that, following intraganglionic or intrathecal injection, recombinant adeno-associated virus (rAAV) vectors can also infect sensory neurons and are capable of stable, long-term transgene expression. We sought to determine if application of rAAV to peripheral nerve termini at the epithelial surface would allow rAAV to traffic to sensory ganglia in a manner similar to that seen with HSV. We hypothesized that footpad or ocular inoculation with rAAV8 would result in transduction of dorsal root ganglia (DRG) or trigeminal ganglia (TG), respectively. To test this, we inoculated the footpads of mice with various amounts of rAAV as well as rAAV capsid mutants. We demonstrated that this method of inoculation can achieve a transduction rate of >90% of the sensory neurons in the DRG that innervate the footpad. Similarly, we showed that corneal inoculation with rAAV vectors in the rabbit efficiently transduced >70% of the TG neurons in the optic tract. Finally, we demonstrated that coinfection of mouse footpads or rabbit eyes with rAAV vectors and HSV-1 resulted in colocalization in nearly all of the HSV-1-positive neurons. These results suggest that rAAV is a useful tool for the study of HSV-1 infection and may provide a means to deliver therapeutic cargos for the treatment of HSV infections or of dysfunctions of sensory ganglia. Adeno-associated virus (AAV) has been shown to transduce dorsal root ganglion sensory neurons following direct intraganglionic sciatic nerve injection and intraperitoneal and intravenous injection as well as intrathecal injection. We sought to determine if rAAV vectors would be delivered to the same sensory neurons that herpes simplex virus (HSV-1) infects when applied peripherally at an epithelial surface that had been treated to expose

  16. Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study.

    Science.gov (United States)

    Lopes, L C G; Galhardoni, R; Silva, V; Jorge, F M H; Yeng, L T; Callegaro, D; Chadi, G; Teixeira, M J; Ciampi de Andrade, D

    2018-01-01

    Motor neuron diseases (MND) represent a group of disorders that evolve with inexorable muscle weakness and medical management is based on symptom control. However, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on pain and sensory changes. Eighty patients (31 females, 55.7 ± 12.9 years old) with MND underwent a neurological examination, pain, mood, catastrophizing and psychophysics assessments [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], and were compared to sex- and age-matched healthy controls (HC). Chronic pain was present in 46% of patients (VAS =5.18 ± 2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p catastrophism, and spasticity scores were inversely correlated with CPM (ρ = -0.30, p = 0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate the most appropriate treatment strategies for these patients. We report a comprehensive evaluation of pain and sensory abnormalities in motor neuron disease (MND) patients. We assessed the different pain syndromes present in MND with validated tools, and described the QST and conditioned pain modulation profiles in a controlled design. © 2017 European Pain Federation - EFIC®.

  17. Sensory Neurons Derived from Diabetic Rats Have Diminished Internal Ca2+ Stores Linked to Impaired Re-uptake by the Endoplasmic Reticulum

    Directory of Open Access Journals (Sweden)

    Elena Zherebitskaya

    2011-12-01

    Full Text Available Distal symmetrical sensory neuropathy in diabetes involves the dying back of axons, and the pathology equates with axonal dystrophy generated under conditions of aberrant Ca2+ signalling. Previous work has described abnormalities in Ca2+ homoeostasis in sensory and dorsal horn neurons acutely isolated from diabetic rodents. We extended this work by testing the hypothesis that sensory neurons exposed to long-term Type 1 diabetes in vivo would exhibit abnormal axonal Ca2+ homoeostasis and focused on the role of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase. DRG (dorsal root ganglia sensory neurons from age-matched normal and 3–5-month-old STZ (streptozotocin-diabetic rats (an experimental model of Type 1 diabetes were cultured. At 1–2 days in vitro an array of parameters were measured to investigate Ca2+ homoeostasis including (i axonal levels of intracellular Ca2+, (ii Ca2+ uptake by the ER (endoplasmic reticulum, (iii assessment of Ca2+ signalling following a long-term thapsigargin-induced blockade of SERCA and (iv determination of expression of ER mass and stress markers using immunocytochemistry and Western blotting. KCl- and caffeine-induced Ca2+ transients in axons were 2-fold lower in cultures of diabetic neurons compared with normal neurons indicative of reduced ER calcium loading. The rate of uptake of Ca2+ into the ER was reduced by 2-fold (P<0.05 in diabetic neurons, while markers for ER mass and ER stress were unchanged. Abnormalities in Ca2+ homoeostasis in diabetic neurons could be mimicked via long-term inhibition of SERCA in normal neurons. In summary, axons of neurons from diabetic rats exhibited aberrant Ca2+ homoeostasis possibly triggered by suboptimal SERCA activity that could contribute to the distal axonopathy observed in diabetes.

  18. The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons.

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    Zinn, Sebastian; Sisignano, Marco; Kern, Katharina; Pierre, Sandra; Tunaru, Sorin; Jordan, Holger; Suo, Jing; Treutlein, Elsa-Marie; Angioni, Carlo; Ferreiros, Nerea; Leffler, Andreas; DeBruin, Natasja; Offermanns, Stefan; Geisslinger, Gerd; Scholich, Klaus

    2017-04-14

    Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for leukotriene B4 (100-200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher leukotriene B4 concentrations (>0.5 μm) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. A presynaptic role for PKA in synaptic tagging and memory.

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    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer Hk; Luczak, Vince; Nie, Ting; Huang, Ted; Abel, Ted

    2014-10-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Sensorimotor experience and verb-category mapping in human sensory, motor and parietal neurons.

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    Yang, Ying; Dickey, Michael Walsh; Fiez, Julie; Murphy, Brian; Mitchell, Tom; Collinger, Jennifer; Tyler-Kabara, Elizabeth; Boninger, Michael; Wang, Wei

    2017-07-01

    Semantic grounding is the process of relating meaning to symbols (e.g., words). It is the foundation for creating a representational symbolic system such as language. Semantic grounding for verb meaning is hypothesized to be achieved through two mechanisms: sensorimotor mapping, i.e., directly encoding the sensorimotor experiences the verb describes, and verb-category mapping, i.e., encoding the abstract category a verb belongs to. These two mechanisms were investigated by examining neuronal-level spike (i.e. neuronal action potential) activities from the motor, somatosensory and parietal areas in two human participants. Motor and a portion of somatosensory neurons were found to be involved in primarily sensorimotor mapping, while parietal and some somatosensory neurons were found to be involved in both sensorimotor and verb-category mapping. The time course of the spike activities and the selective tuning pattern of these neurons indicate that they belong to a large neural network used for semantic processing. This study is the first step towards understanding how words are processed by neurons. Published by Elsevier Ltd.

  1. Central Projection of Antennal Sensory Neurons in the Central Nervous System of the Mirid Bug Apolygus lucorum (Meyer-Dür).

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    Xie, Gui-Ying; Zhao, Xin-Cheng; Ma, Bai-Wei; Guo, Pei; Li, Guo-Ping; Feng, Hong-Qiang; Wu, Guo-Liang

    2016-01-01

    The mirid bug Apolygus lucorum (Meyer-Dür), a polyphagous pest, is dependent on olfactory cues to locate various host plant species and mates. In this study, we traced the projection pathway of the antennal sensory neurons and visualized their projection patterns in the central nervous system of A. lucorum through confocal microscopy and digital reconstructions. We also examined the glomerular organization of the primary olfactory center of the brain, the antennal lobe, and created a three-dimensional model of the glomeruli. We found that the axons of the sensory neurons project into the brain via the ipsilateral antennal nerve, and descend further into the gnathal ganglion, prothoracic ganglion, mesothoracic ganglion, and metathoracic ganglion, and reach as far as to the abdominal ganglion. Such a projection pattern indicates that antennal sensory neurons of A. lucorum may be potentially directly connected to motor neurons. The antennal lobe, however, is the major target area of antennal sensory neurons. The antennal lobe is composed of a large number of glomeruli, i.e. 70-80 glomeruli in one AL of A. lucorum. The results of this study which provide information about the basic anatomical arrangement of the brain olfactory center of A. lucorum, are important for further investigations of chemosensory encoding mechanisms of the mirid bug.

  2. Regulation of the Na,K-ATPase gamma-subunit FXYD2 by Runx1 and Ret signaling in normal and injured non-peptidergic nociceptive sensory neurons.

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    Stéphanie Ventéo

    Full Text Available Dorsal root ganglia (DRGs contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury.

  3. Central Projection of Antennal Sensory Neurons in the Central Nervous System of the Mirid Bug Apolygus lucorum (Meyer-Dür.

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    Gui-Ying Xie

    Full Text Available The mirid bug Apolygus lucorum (Meyer-Dür, a polyphagous pest, is dependent on olfactory cues to locate various host plant species and mates. In this study, we traced the projection pathway of the antennal sensory neurons and visualized their projection patterns in the central nervous system of A. lucorum through confocal microscopy and digital reconstructions. We also examined the glomerular organization of the primary olfactory center of the brain, the antennal lobe, and created a three-dimensional model of the glomeruli. We found that the axons of the sensory neurons project into the brain via the ipsilateral antennal nerve, and descend further into the gnathal ganglion, prothoracic ganglion, mesothoracic ganglion, and metathoracic ganglion, and reach as far as to the abdominal ganglion. Such a projection pattern indicates that antennal sensory neurons of A. lucorum may be potentially directly connected to motor neurons. The antennal lobe, however, is the major target area of antennal sensory neurons. The antennal lobe is composed of a large number of glomeruli, i.e. 70-80 glomeruli in one AL of A. lucorum. The results of this study which provide information about the basic anatomical arrangement of the brain olfactory center of A. lucorum, are important for further investigations of chemosensory encoding mechanisms of the mirid bug.

  4. Association between tetrodotoxin resistant channels and lipid rafts regulates sensory neuron excitability.

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    Alessandro Pristerà

    Full Text Available Voltage-gated sodium channels (VGSCs play a key role in the initiation and propagation of action potentials in neurons. Na(V1.8 is a tetrodotoxin (TTX resistant VGSC expressed in nociceptors, peripheral small-diameter neurons able to detect noxious stimuli. Na(V1.8 underlies the vast majority of sodium currents during action potentials. Many studies have highlighted a key role for Na(V1.8 in inflammatory and chronic pain models. Lipid rafts are microdomains of the plasma membrane highly enriched in cholesterol and sphingolipids. Lipid rafts tune the spatial and temporal organisation of proteins and lipids on the plasma membrane. They are thought to act as platforms on the membrane where proteins and lipids can be trafficked, compartmentalised and functionally clustered. In the present study we investigated Na(V1.8 sub-cellular localisation and explored the idea that it is associated with lipid rafts in nociceptors. We found that Na(V1.8 is distributed in clusters along the axons of DRG neurons in vitro and ex vivo. We also demonstrated, by biochemical and imaging studies, that Na(V1.8 is associated with lipid rafts along the sciatic nerve ex vivo and in DRG neurons in vitro. Moreover, treatments with methyl-β-cyclodextrin (MβCD and 7-ketocholesterol (7KC led to the dissociation between rafts and Na(V1.8. By calcium imaging we demonstrated that the lack of association between rafts and Na(V1.8 correlated with impaired neuronal excitability, highlighted by a reduction in the number of neurons able to conduct mechanically- and chemically-evoked depolarisations. These findings reveal the sub-cellular localisation of Na(V1.8 in nociceptors and highlight the importance of the association between Na(V1.8 and lipid rafts in the control of nociceptor excitability.

  5. Interactions of Carbon Dioxide and Food Odours in Drosophila: Olfactory Hedonics and Sensory Neuron Properties

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    Faucher, Cécile P.; Hilker, Monika; de Bruyne, Marien

    2013-01-01

    Behavioural responses of animals to volatiles in their environment are generally dependent on context. Most natural odours are mixtures of components that can each induce different behaviours when presented on their own. We have investigated how a complex of two olfactory stimuli is evaluated by Drosophila flies in a free-flying two-trap choice assay and how these stimuli are encoded in olfactory receptor neurons. We first observed that volatiles from apple cider vinegar attracted flies while carbon dioxide (CO2) was avoided, confirming their inherent positive and negative values. In contradiction with previous results obtained from walking flies in a four-field olfactometer, in the present assay the addition of CO2 to vinegar increased rather than decreased the attractiveness of vinegar. This effect was female-specific even though males and females responded similarly to CO2 and vinegar on their own. To test whether the female-specific behavioural response to the mixture correlated with a sexual dimorphism at the peripheral level we recorded from olfactory receptor neurons stimulated with vinegar, CO2 and their combination. Responses to vinegar were obtained from three neuron classes, two of them housed with the CO2-responsive neuron in ab1 sensilla. Sensitivity of these neurons to both CO2 and vinegar per se did not differ between males and females and responses from female neurons did not change when CO2 and vinegar were presented simultaneously. We also found that CO2-sensitive neurons are particularly well adapted to respond rapidly to small concentration changes irrespective of background CO2 levels. The ability to encode temporal properties of stimulations differs considerably between CO2- and vinegar-sensitive neurons. These properties may have important implications for in-flight navigation when rapid responses to fragmented odour plumes are crucial to locate odour sources. However, the flies’ sex-specific response to the CO2-vinegar combination and the

  6. Interactions of carbon dioxide and food odours in Drosophila: olfactory hedonics and sensory neuron properties.

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    Cécile P Faucher

    Full Text Available Behavioural responses of animals to volatiles in their environment are generally dependent on context. Most natural odours are mixtures of components that can each induce different behaviours when presented on their own. We have investigated how a complex of two olfactory stimuli is evaluated by Drosophila flies in a free-flying two-trap choice assay and how these stimuli are encoded in olfactory receptor neurons. We first observed that volatiles from apple cider vinegar attracted flies while carbon dioxide (CO2 was avoided, confirming their inherent positive and negative values. In contradiction with previous results obtained from walking flies in a four-field olfactometer, in the present assay the addition of CO2 to vinegar increased rather than decreased the attractiveness of vinegar. This effect was female-specific even though males and females responded similarly to CO2 and vinegar on their own. To test whether the female-specific behavioural response to the mixture correlated with a sexual dimorphism at the peripheral level we recorded from olfactory receptor neurons stimulated with vinegar, CO2 and their combination. Responses to vinegar were obtained from three neuron classes, two of them housed with the CO2-responsive neuron in ab1 sensilla. Sensitivity of these neurons to both CO2 and vinegar per se did not differ between males and females and responses from female neurons did not change when CO2 and vinegar were presented simultaneously. We also found that CO2-sensitive neurons are particularly well adapted to respond rapidly to small concentration changes irrespective of background CO2 levels. The ability to encode temporal properties of stimulations differs considerably between CO2- and vinegar-sensitive neurons. These properties may have important implications for in-flight navigation when rapid responses to fragmented odour plumes are crucial to locate odour sources. However, the flies' sex-specific response to the CO2-vinegar

  7. TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids.

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    Nina Boiko

    Full Text Available Chemotherapy induced peripheral neuropathy (CIPN, a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1 channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.

  8. Dendritic development of Drosophila high order visual system neurons is independent of sensory experience

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    Reuter John E

    2003-06-01

    Full Text Available Abstract Background The complex and characteristic structures of dendrites are a crucial part of the neuronal architecture that underlies brain function, and as such, their development has been a focal point of recent research. It is generally believed that dendritic development is controlled by a combination of endogenous genetic mechanisms and activity-dependent mechanisms. Therefore, it is of interest to test the relative contributions of these two types of mechanisms towards the construction of specific dendritic trees. In this study, we make use of the highly complex Vertical System (VS of motion sensing neurons in the lobula plate of the Drosophila visual system to gauge the importance of visual input and synaptic activity to dendritic development. Results We find that the dendrites of VS1 neurons are unchanged in dark-reared flies as compared to control flies raised on a 12 hour light, 12 hour dark cycle. The dendrites of these flies show no differences from control in dendrite complexity, spine number, spine density, or axon complexity. Flies with genetically ablated eyes show a slight but significant reduction in the complexity and overall length of VS1 dendrites, although this effect may be due to a reduction in the overall size of the dendritic field in these flies. Conclusions Overall, our results indicate no role for visual experience in the development of VS dendrites, while spontaneous activity from photoreceptors may play at most a subtle role in the formation of fully complex dendrites in these high-order visual processing neurons.

  9. Searching for collective behavior in a large network of sensory neurons.

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    Gašper Tkačik

    2014-01-01

    Full Text Available Maximum entropy models are the least structured probability distributions that exactly reproduce a chosen set of statistics measured in an interacting network. Here we use this principle to construct probabilistic models which describe the correlated spiking activity of populations of up to 120 neurons in the salamander retina as it responds to natural movies. Already in groups as small as 10 neurons, interactions between spikes can no longer be regarded as small perturbations in an otherwise independent system; for 40 or more neurons pairwise interactions need to be supplemented by a global interaction that controls the distribution of synchrony in the population. Here we show that such "K-pairwise" models--being systematic extensions of the previously used pairwise Ising models--provide an excellent account of the data. We explore the properties of the neural vocabulary by: 1 estimating its entropy, which constrains the population's capacity to represent visual information; 2 classifying activity patterns into a small set of metastable collective modes; 3 showing that the neural codeword ensembles are extremely inhomogenous; 4 demonstrating that the state of individual neurons is highly predictable from the rest of the population, allowing the capacity for error correction.

  10. Extracellular matrix-associated gene expression in adult sensory neuron populations cultured on a laminin substrate.

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    Fudge, Neva J; Mearow, Karen M

    2013-01-30

    In our previous investigations of the role of the extracellular matrix (ECM) in promoting neurite growth we have observed that a permissive laminin (LN) substrate stimulates differential growth responses in subpopulations of mature dorsal root ganglion (DRG) neurons. DRG neurons expressing Trk and p75 receptors grow neurites on a LN substrate in the absence of neurotrophins, while isolectin B4-binding neurons (IB4+) do not display significant growth under the same conditions. We set out to determine whether there was an expression signature of the LN-induced neurite growth phenotype. Using a lectin binding protocol IB4+ neurons were isolated from dissociated DRG neurons, creating two groups - IB4+ and IB4-. A small-scale microarray approach was employed to screen the expression of a panel of ECM-associated genes following dissociation (t=0) and after 24 hr culture on LN (t=24LN). This was followed by qRT-PCR and immunocytochemistry of selected genes. The microarray screen showed that 36 of the 144 genes on the arrays were consistently expressed by the neurons. The array analyses showed that six genes had lower expression in the IB4+ neurons compared to the IB4- cells at t=0 (CTSH, Icam1, Itgβ1, Lamb1, Plat, Spp1), and one gene was expressed at higher levels in the IB4+ cells (Plaur). qRT-PCR was carried out as an independent assessment of the array results. There were discrepancies between the two methods, with qRT-PCR confirming the differences in Lamb1, Plat and Plaur, and showing decreased expression of AdamTs1, FN, and Icam in the IB4+ cells at t=0. After 24 hr culture on LN, there were no significant differences detected by qRT-PCR between the IB4+ and IB4- cells. However, both groups showed upregulation of Itgβ1 and Plaur after 24 hr on LN, the IB4+ group also had increased Plat, and the IB4- cells showed decreased Lamb1, Icam1 and AdamTs1. Further, the array screen also detected a number of genes (not subjected to qRT-PCR) expressed similarly by both

  11. Potential role of transient receptor potential channel M5 in sensing putative pheromones in mouse olfactory sensory neurons.

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    Oshimoto, Arisa; Wakabayashi, Yoshihiro; Garske, Anna; Lopez, Roberto; Rolen, Shane; Flowers, Michael; Arevalo, Nicole; Restrepo, Diego

    2013-01-01

    Based on pharmacological studies of chemosensory transduction in transient receptor potential channel M5 (TRPM5) knockout mice it was hypothesized that this channel is involved in transduction for a subset of putative pheromones in mouse olfactory sensory neurons (OSNs). Yet, in the same study an electroolfactogram (EOG) in the mouse olfactory epithelium showed no significant difference in the responses to pheromones (and odors) between wild type and TRPM5 knockout mice. Here we show that the number of OSNs expressing TRPM5 is increased by unilateral naris occlusion. Importantly, EOG experiments show that mice lacking TRPM5 show a decreased response in the occluded epithelia to putative pheromones as opposed to wild type mice that show no change upon unilateral naris occlusion. This evidence indicates that under decreased olfactory sensory input TRPM5 plays a role in mediating putative pheromone transduction. Furthermore, we demonstrate that cyclic nucleotide gated channel A2 knockout (CNGA2-KO) mice that show substantially decreased or absent responses to odors and pheromones also have elevated levels of TRPM5 compared to wild type mice. Taken together, our evidence suggests that TRPM5 plays a role in mediating transduction for putative pheromones under conditions of reduced chemosensory input.

  12. Potential role of transient receptor potential channel M5 in sensing putative pheromones in mouse olfactory sensory neurons.

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    Arisa Oshimoto

    Full Text Available Based on pharmacological studies of chemosensory transduction in transient receptor potential channel M5 (TRPM5 knockout mice it was hypothesized that this channel is involved in transduction for a subset of putative pheromones in mouse olfactory sensory neurons (OSNs. Yet, in the same study an electroolfactogram (EOG in the mouse olfactory epithelium showed no significant difference in the responses to pheromones (and odors between wild type and TRPM5 knockout mice. Here we show that the number of OSNs expressing TRPM5 is increased by unilateral naris occlusion. Importantly, EOG experiments show that mice lacking TRPM5 show a decreased response in the occluded epithelia to putative pheromones as opposed to wild type mice that show no change upon unilateral naris occlusion. This evidence indicates that under decreased olfactory sensory input TRPM5 plays a role in mediating putative pheromone transduction. Furthermore, we demonstrate that cyclic nucleotide gated channel A2 knockout (CNGA2-KO mice that show substantially decreased or absent responses to odors and pheromones also have elevated levels of TRPM5 compared to wild type mice. Taken together, our evidence suggests that TRPM5 plays a role in mediating transduction for putative pheromones under conditions of reduced chemosensory input.

  13. Deletion of Type 3 Adenylyl Cyclase Perturbs the Postnatal Maturation of Olfactory Sensory Neurons and Olfactory Cilium Ultrastructure in Mice.

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    Zhang, Zhe; Yang, Dong; Zhang, Mengdi; Zhu, Ning; Zhou, Yanfen; Storm, Daniel R; Wang, Zhenshan

    2017-01-01

    Type 3 adenylyl cyclase (Adcy3) is localized to the cilia of olfactory sensory neurons (OSNs) and is an essential component of the olfactory cyclic adenosine monophosphate (cAMP) signaling pathway. Although the role of this enzyme in odor detection and axonal projection in OSNs was previously characterized, researchers will still have to determine its function in the maturation of postnatal OSNs and olfactory cilium ultrastructure. Previous studies on newborns showed that the anatomic structure of the main olfactory epithelium (MOE) of Adcy3 knockout mice ( Adcy3 -/- ) is indistinguishable from that of their wild-type littermates ( Adcy3 +/+ ), whereas the architecture and associated composition of MOE are relatively underdeveloped at this early age. The full effects of sensory deprivation on OSNs may not also be exhibited in such age. In the present study, following a comparison of postnatal OSNs in seven-, 30-, and 90-day-old Adcy3 -/- mice and wild-type controls ( Adcy 3 +/+ ), we observed that the absence of Adcy3 leads to cumulative defects in the maturation of OSNs. Upon aging, Adcy3 -/- OSNs exhibited increase in immature cells and reduction in mature cells along with elevated apoptosis levels. The density and ultrastructure of Adcy3 -/- cilia were also disrupted in mice upon aging. Collectively, our results reveal an indispensable role of Adcy3 in postnatal maturation of OSNs and maintenance of olfactory cilium ultrastructure in mice through adulthood.

  14. Selective silencing of Na(V)1.7 decreases excitability and conduction in vagal sensory neurons.

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    Muroi, Yukiko; Ru, Fei; Kollarik, Marian; Canning, Brendan J; Hughes, Stephen A; Walsh, Stacey; Sigg, Martin; Carr, Michael J; Undem, Bradley J

    2011-12-01

    There has been much information learned in recent years about voltage gated sodium channel (Na(V)) subtypes in somatosensory pain signalling, but much less is known about the role of specific sodium channel subtypes in the vagal sensory system. In this study, we developed a technique using adeno-associated viruses (AAVs) to directly introduce shRNA against Na(V)1.7 subtype gene into the vagal sensory ganglia of guinea pigs in vivo. Na(V)1.7 gene expression in nodose ganglia was effectively and selectively reduced without influencing the expression of other sodium channel subtype genes including Na(V)1.1, 1.2, 1.3 1.6, 1.8, or 1.9. Using a whole cell patch-clamp technique, this effect on Na(V)1.7 gene expression coincided with a reduction in tetrodotoxin-sensitive sodium current, a requirement for much larger depolarizing stimulus to initiate action potentials, and reduction in repetitive action potential discharge. Extracellular recordings in the isolated vagus nerve revealed that the conduction of action potentials in sensory A- and C-fibres in many neurons was effectively abolished after Na(V)1.7 shRNA introduction. Moreover, bilateral Na(V)1.7 shRNA injected animals survived for several months and the vagal reflex behaviour, exemplified by citric acid-induced coughing, was significantly suppressed. These data indicate that selectively silencing Na(V)1.7 ion channel expression leads to a substantial decrease in neural excitability and conduction block in vagal afferent nerves.

  15. ß-catenin, a transcription factor activated by canonical Wnt signaling, is expressed in sensory neurons of calves latently infected with bovine herpesvirus 1

    Science.gov (United States)

    Like many a-herpesvirinae subfamily members, bovine herpes virus 1 (BoHV-1) expresses an abundant transcript in latently infected sensory neurons: the latency-related (LR) RNA. LR-RNA encodes a protein (ORF2) that inhibits apoptosis, interacts with Notch family members, interferes with Notch mediate...

  16. Red ginseng extract blocks histamine-dependent itch by inhibition of H1R/TRPV1 pathway in sensory neurons

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    Yongwoo Jang

    2015-07-01

    Conclusion: The current study found for the first time that RGE effectively blocks histamine-induced itch in peripheral sensory neurons. We believe that the current results will provide an insight on itch transmission and will be helpful in understanding how RGE exerts its antipruritic effects.

  17. Identification of Chloride Channels CLCN3 and CLCN5 Mediating the Excitatory Cl− Currents Activated by Sphingosine-1-Phosphate in Sensory Neurons

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    Yanmei Qi

    2018-02-01

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid involved in numerous physiological and pathophysiological processes. We have previously reported a S1P-induced nocifensive response in mice by excitation of sensory neurons via activation of an excitatory chloride current. The underlying molecular mechanism for the S1P-induced chloride conductance remains elusive. In the present study, we identified two CLCN voltage-gated chloride channels, CLCN3 and CLCN5, which mediated a S1P-induced excitatory Cl− current in sensory neurons by combining RNA-seq, adenovirus-based gene silencing and whole-cell electrophysiological voltage-clamp recordings. Downregulation of CLCN3 and CLCN5 channels by adenovirus-mediated delivery of shRNA dramatically reduced S1P-induced Cl− current and membrane depolarization in sensory neurons. The mechanism of S1P-induced activation of the chloride current involved Rho GTPase but not Rho-associated protein kinase. Although S1P-induced potentiation of TRPV1-mediated ionic currents also involved Rho-dependent process, the lack of correlation of the S1P-activated Cl− current and the potentiation of TRPV1 by S1P suggests that CLCN3 and CLCN5 are necessary components for S1P-induced excitatory Cl− currents but not for the amplification of TRPV1-mediated currents in sensory neurons. This study provides a novel mechanistic insight into the importance of bioactive sphingolipids in nociception.

  18. Nimesulide inhibits protein kinase C epsilon and substance P in sensory neurons – comparison with paracetamol

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    Vellani V

    2011-06-01

    Full Text Available Vittorio Vellani1, Silvia Franchi2, Massimiliano Prandini1, Sarah Moretti2, Giorgia Pavesi1, Chiara Giacomoni3, Paola Sacerdote21Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Modena, Italy; 2Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Italy; 3Dipartimento di Economia e Tecnologia, Università degli Studi della Repubblica di San Marino, Montegiardino, Repubblica di San MarinoAbstract: In this paper we describe new actions of nimesulide and paracetamol in cultured peripheral neurons isolated from rat dorsal root ganglia (DRG. Both drugs were able to decrease in a dose-dependent fashion the number of cultured DRG neurons showing translocation of protein kinase C epsilon (PKCε caused by exposure to 1 µM bradykinin or 100 nM thrombin. In addition, the level of substance P (SP released by DRG neurons and the level of preprotachykinin mRNA expression were measured in basal conditions and after 70 minutes or 36 hours of stimulation with nerve growth factor (NGF or with an inflammatory soup containing bradykinin, thrombin, endothelin-1, and KCl. Nimesulide (10 µM significantly decreased the mRNA levels of the SP precursor preprotachykinin in basal and in stimulated conditions, and decreased the amount of SP released in the medium during stimulation of neurons with NGF or with the inflammatory soup. The effects of paracetamol (10 µM on such response was lower. Nimesulide completely inhibited the release of prostaglandin E2 (PGE2 from DRG neurons, either basal or induced by NGF and by inflammatory soup, while paracetamol decreased PGE2 release only partially. Our data demonstrate, for the first time, a direct effect of two drugs largely used as analgesics on DRG neurons. The present results suggest that PKCε might be a target for the effect of nimesulide and paracetamol, while inhibition of SP synthesis and release is clearly more relevant for nimesulide than for

  19. Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen

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    Vittorio Vellani

    2017-01-01

    Full Text Available Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKCε translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs. We found that gabapentin significantly reduced PKCε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen, a very commonly used analgesic drug, also produces inhibition of PKCε. We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

  20. Second-order input to the medial amygdala from olfactory sensory neurons expressing the transduction channel TRPM5.

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    Thompson, John A; Salcedo, Ernesto; Restrepo, Diego; Finger, Thomas E

    2012-06-01

    Recent anatomical tracing experiments in rodents have established that a subset of mitral cells in the main olfactory bulb (MOB) projects directly to the medial amygdala (MeA), traditionally considered a target of the accessory olfactory bulb. Neurons that project from the MOB to the MeA also show activation in response to conspecific (opposite sex) volatile urine exposure, establishing a direct role of the MOB in semiochemical processing. In addition, olfactory sensory neurons (OSNs) that express the transient receptor potential M5 (TRPM5) channel innervate a subset of glomeruli that respond to putative semiochemical stimuli. In this study, we examined whether the subset of glomeruli targeted by TRPM5-expressing OSNs is innervated by the population of mitral cells that projects to the MeA. We injected the retrograde tracer cholera toxin B (CTB) into the MeA of mice in which the TRPM5 promoter drives green fluorescent protein (GFP). We found overlapping clusters of CTB-labeled mitral cell dendritic branches (CTB(+) ) in TRPM5-GFP(+) glomeruli at significantly greater frequency than expected by chance. Despite the significant degree of colocalization, some amygdalopetal mitral cells extended dendrites to non-TRPM5-GFP glomeruli and vice versa, suggesting that, although significant overlapping glomerular innervation is observed between these two features, it is not absolute. Copyright © 2011 Wiley Periodicals, Inc.

  1. SECOND ORDER INPUT TO THE MEDIAL AMYGDALA FROM OLFACTORY SENSORY NEURONS EXPRESSING THE TRANSDUCTION CHANNEL TRPM5

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    Thompson, John A.; Salcedo, Ernesto; Restrepo, Diego; Finger, Thomas E.

    2013-01-01

    Recent anatomical tracing experiments in rodents have established that a subset of mitral cells in the main olfactory bulb (MOB) project directly to the medial amygdala (MeA) traditionally considered a target of the accessory olfactory bulb. Importantly, neurons that project from the MOB to the MeA also show activation in response to conspecific (opposite sex) volatile urine exposure, establishing a direct role of the MOB in semiochemical processing. In addition, olfactory sensory neurons (OSN) that express the transient receptor potential M5 (TRPM5) channel innervate a subset of glomeruli that respond to putative semiochemical stimuli. In this study, we examined whether the subset of glomeruli targeted by TRPM5 expressing OSNs are innervated by the population of mitral cells that project to the MeA. We injected the retrograde tracer cholera toxin B (CTB) into the MeA of mice in which the TRPM5 promoter drives green fluorescent protein (GFP). We found overlapping clusters of CTB-labeled mitral cell dendritic branches (CTB (+)) in TRPM5-GFP positive (TRPM5-GFP (+)) glomeruli at significantly greater frequency than expected by chance. Despite the significant degree of co-localization, some amygdalopetal mitral cells extended dendrites to non-TRPM5-GFP glomeruli and vice versa, suggesting that although significant overlapping glomerular innervation is observed between these two features, it is not absolute. PMID:22120520

  2. Bridging the gap between theories of sensory cue integration and the physiology of multisensory neurons

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    Fetsch, Christopher R.

    2013-01-01

    The richness of perceptual experience, as well as its usefulness for guiding behavior, depends upon the synthesis of information across multiple senses. Recent decades have witnessed a surge in our understanding of how the brain combines sensory signals, or cues. Much of this research has been guided by one of two distinct approaches, one driven primarily by neurophysiological observations, the other guided by principles of mathematical psychology and psychophysics. Conflicting results and interpretations have contributed to a conceptual gap between psychophysical and physiological accounts of cue integration, but recent studies of visual-vestibular cue integration have narrowed this gap considerably. PMID:23686172

  3. Shifts in sensory neuron identity parallel differences in pheromone preference in the European corn borer

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    Fotini A Koutroumpa

    2014-10-01

    Full Text Available Pheromone communication relies on highly specific signals sent and received between members of the same species. However, how pheromone specificity is determined in moth olfactory circuits remains unknown. Here we provide the first glimpse into the mechanism that generates this specificity in Ostrinia nubilalis. In Ostrinia nubilalis it was found that a single locus causes strain-specific, diametrically opposed preferences for a 2-component pheromone blend. Previously we found pheromone preference to be correlated with the strain and hybrid-specific relative antennal response to both pheromone components. This led to the current study, in which we detail the underlying mechanism of this differential response, through chemotopically mapping of the pheromone detection circuit in the antenna. We determined that both strains and their hybrids have swapped the neuronal identity of the pheromone-sensitive neurons co-housed within a single sensillum. Furthermore, neurons that mediate behavioral antagonism surprisingly co-express up to five pheromone receptors, mirroring the concordantly broad tuning to heterospecific pheromones. This appears as possible evolutionary adaptation that could prevent cross attraction to a range of heterospecific signals, while keeping the pheromone detection system to its simplest tripartite setup.

  4. Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

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    Jones, Clinton

    2013-01-01

    α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts. PMID:25278776

  5. Ciliary neurotrophic factor activates NF-κB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents.

    Science.gov (United States)

    Saleh, Ali; Roy Chowdhury, Subir K; Smith, Darrell R; Balakrishnan, Savitha; Tessler, Lori; Martens, Corina; Morrow, Dwane; Schartner, Emily; Frizzi, Katie E; Calcutt, Nigel A; Fernyhough, Paul

    2013-02-01

    Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory neuron survival and axon regeneration and prevents axonal dwindling, nerve conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we tested the hypothesis that CNTF protects sensory neuron function during diabetes through normalization of impaired mitochondrial bioenergetics. In addition, we investigated whether the NF-κB signal transduction pathway was mobilized by CNTF. Neurite outgrowth of sensory neurons derived from streptozotocin (STZ)-induced diabetic rats was reduced compared to neurons from control rats and exposure to CNTF for 24 h enhanced neurite outgrowth. CNTF also activated NF-κB, as assessed by Western blotting for the NF-κB p50 subunit and reporter assays for NF-κB promoter activity. Conversely, blockade of NF-κB signaling using SN50 peptide inhibited CNTF-mediated neurite outgrowth. Studies in mice with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented functional indices of peripheral neuropathy along with deficiencies in dorsal root ganglion (DRG) NF-κB p50 expression and DNA binding activity. DRG neurons derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen consumption rate and associated spare respiratory capacity that were corrected by exposure to CNTF for 24 h in an NF-κB-dependent manner. We propose that the ability of CNTF to enhance axon regeneration and protect peripheral nerve from structural and functional indices of diabetic peripheral neuropathy is associated with targeting of mitochondrial function, in part via NF-κB activation, and improvement of cellular bioenergetics. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Geometric and functional architecture of visceral sensory microcircuitry.

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    Negishi, Yoshikatsu; Kawai, Yoshinori

    2011-03-01

    Is microcircuit wiring designed deterministically or probabilistically? Does geometric architecture predict functional dynamics of a given neuronal microcircuit? These questions were addressed in the visceral sensory microcircuit of the caudal nucleus of the tractus solitarius (NTS), which is generally thought to be homogeneous rather than laminar in cytoarchitecture. Using in situ hybridization histochemistry and whole-cell patch clamp recordings followed by neuronal reconstruction with biocytin filling, anatomical and functional organization of NTS microcircuitry was quantified to determine associative relationships. Morphologic and chemical features of NTS neurons displayed different patterns of process arborization and sub-nuclear localization according to neuronal types: smaller cells featured presynaptic local axons and GABAergic cells were aggregated specifically within the ventral NTS. The results suggested both a laminar organization and a spatial heterogeneity of NTS microcircuit connectivity. Geometric analysis of pre- and postsynaptic axodendritic arbor overlap of reconstructed neurons (according to parent somal distance) confirmed a heterogeneity of microcircuit connectivity that could underlie differential functional dynamics along the dorsoventral axis. Functional dynamics in terms of spontaneous and evoked postsynaptic current patterns behaved in a strongly location-specific manner according to the geometric dimension, suggesting a spatial laminar segregation of neuronal populations: a dorsal group of high excitation and a ventral group of balanced excitation and inhibition. Recurrent polysynaptic activity was also noted in a subpopulation of the ventral group. Such geometric and functional laminar organization seems to provide the NTS microcircuit with both reverberation capability and a differentiated projection system for appropriate computation of visceral sensory information.

  7. Neuronal correlates of a virtual-reality-based passive sensory P300 network.

    Directory of Open Access Journals (Sweden)

    Chun-Chuan Chen

    Full Text Available P300, a positive event-related potential (ERP evoked at around 300 ms after stimulus, can be elicited using an active or passive oddball paradigm. Active P300 requires a person's intentional response, whereas passive P300 does not require an intentional response. Passive P300 has been used in incommunicative patients for consciousness detection and brain computer interface. Active and passive P300 differ in amplitude, but not in latency or scalp distribution. However, no study has addressed the mechanism underlying the production of passive P300. In particular, it remains unclear whether the passive P300 shares an identical active P300 generating network architecture when no response is required. This study aims to explore the hierarchical network of passive sensory P300 production using dynamic causal modelling (DCM for ERP and a novel virtual reality (VR-based passive oddball paradigm. Moreover, we investigated the causal relationship of this passive P300 network and the changes in connection strength to address the possible functional roles. A classical ERP analysis was performed to verify that the proposed VR-based game can reliably elicit passive P300. The DCM results suggested that the passive and active P300 share the same parietal-frontal neural network for attentional control and, underlying the passive network, the feed-forward modulation is stronger than the feed-back one. The functional role of this forward modulation may indicate the delivery of sensory information, automatic detection of differences, and stimulus-driven attentional processes involved in performing this passive task. To our best knowledge, this is the first study to address the passive P300 network. The results of this study may provide a reference for future clinical studies on addressing the network alternations under pathological states of incommunicative patients. However, caution is required when comparing patients' analytic results with this study. For example

  8. Neuronal correlates of a virtual-reality-based passive sensory P300 network.

    Science.gov (United States)

    Chen, Chun-Chuan; Syue, Kai-Syun; Li, Kai-Chiun; Yeh, Shih-Ching

    2014-01-01

    P300, a positive event-related potential (ERP) evoked at around 300 ms after stimulus, can be elicited using an active or passive oddball paradigm. Active P300 requires a person's intentional response, whereas passive P300 does not require an intentional response. Passive P300 has been used in incommunicative patients for consciousness detection and brain computer interface. Active and passive P300 differ in amplitude, but not in latency or scalp distribution. However, no study has addressed the mechanism underlying the production of passive P300. In particular, it remains unclear whether the passive P300 shares an identical active P300 generating network architecture when no response is required. This study aims to explore the hierarchical network of passive sensory P300 production using dynamic causal modelling (DCM) for ERP and a novel virtual reality (VR)-based passive oddball paradigm. Moreover, we investigated the causal relationship of this passive P300 network and the changes in connection strength to address the possible functional roles. A classical ERP analysis was performed to verify that the proposed VR-based game can reliably elicit passive P300. The DCM results suggested that the passive and active P300 share the same parietal-frontal neural network for attentional control and, underlying the passive network, the feed-forward modulation is stronger than the feed-back one. The functional role of this forward modulation may indicate the delivery of sensory information, automatic detection of differences, and stimulus-driven attentional processes involved in performing this passive task. To our best knowledge, this is the first study to address the passive P300 network. The results of this study may provide a reference for future clinical studies on addressing the network alternations under pathological states of incommunicative patients. However, caution is required when comparing patients' analytic results with this study. For example, the task

  9. Conceptual Network Model From Sensory Neurons to Astrocytes of the Human Nervous System.

    Science.gov (United States)

    Yang, Yiqun; Yeo, Chai Kiat

    2015-07-01

    From a single-cell animal like paramecium to vertebrates like ape, the nervous system plays an important role in responding to the variations of the environment. Compared to animals, the nervous system in the human body possesses more intricate organization and utility. The nervous system anatomy has been understood progressively, yet the explanation at the cell level regarding complete information transmission is still lacking. Along the signal pathway toward the brain, an external stimulus first activates action potentials in the sensing neuron and these electric pulses transmit along the spinal nerve or cranial nerve to the neurons in the brain. Second, calcium elevation is triggered in the branch of astrocyte at the tripartite synapse. Third, the local calcium wave expands to the entire territory of the astrocyte. Finally, the calcium wave propagates to the neighboring astrocyte via gap junction channel. In our study, we integrate the existing mathematical model and biological experiments in each step of the signal transduction to establish a conceptual network model for the human nervous system. The network is composed of four layers and the communication protocols of each layer could be adapted to entities with different characterizations. We verify our simulation results against the available biological experiments and mathematical models and provide a test case of the integrated network. As the production of conscious episode in the human nervous system is still under intense research, our model serves as a useful tool to facilitate, complement and verify current and future study in human cognition.

  10. Excitability parameters and sensitivity to anemone toxin ATX-II in rat small diameter primary sensory neurones discriminated by Griffonia simplicifolia isolectin IB4.

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    Snape, Alistair; Pittaway, James F; Baker, Mark D

    2010-01-01

    Sensory neurone subtypes (ATX-II might also discriminate neurones and report that 1 microm has negligible or small effects on action potentials in IB4 +ve, but dramatically increased action potential duration in IB4 ve, neurones. The toxin did not act on tetrodotoxin-resistant (TTX-r) Na(V)1.8 currents; discrimination was based on tetrodotoxin-sensitive (TTX-s) Na(+) channel expression. We also explored the effects of varying the holding potential on current threshold, and the effect of repetitive activation on action currents in IB4 +ve and ve neurones. IB4 +ve neurones became more excitable with depolarization over the range 100 to 20 mV, but IB4 ve neurones exhibited peak excitability near 55 mV, and were inexcitable at 20 mV. Eliciting action potentials at 2 Hz, we found that peak inward action current in IB4 +ve neurones was reduced, whereas changes in the current amplitude were negligible in most IB4 ve neurones. Our findings are consistent with relatively toxin-insensitive channels including Na(V)1.7 being expressed in IB4 +ve neurones, whereas toxin sensitivity indicates that IB4 ve neurones may express Na(V)1.1 or Na(V)1.2, or both. The retention of excitability at low membrane potentials, and the responses to repetitive stimulation are explained by the known preferential expression of Na(V)1.8 in IB4 +ve neurones, and the reduction in action current in IB4 +ve neurones with repetitive stimulation supports a novel hypothesis explaining the slowing of conduction velocity in C-fibres by the build-up of Na(+) channel inactivation.

  11. Irrelevant sensory stimuli interfere with working memory storage: evidence from a computational model of prefrontal neurons.

    Science.gov (United States)

    Bancroft, Tyler D; Hockley, William E; Servos, Philip

    2013-03-01

    The encoding of irrelevant stimuli into the memory store has previously been suggested as a mechanism of interference in working memory (e.g., Lange & Oberauer, Memory, 13, 333-339, 2005; Nairne, Memory & Cognition, 18, 251-269, 1990). Recently, Bancroft and Servos (Experimental Brain Research, 208, 529-532, 2011) used a tactile working memory task to provide experimental evidence that irrelevant stimuli were, in fact, encoded into working memory. In the present study, we replicated Bancroft and Servos's experimental findings using a biologically based computational model of prefrontal neurons, providing a neurocomputational model of overwriting in working memory. Furthermore, our modeling results show that inhibition acts to protect the contents of working memory, and they suggest a need for further experimental research into the capacity of vibrotactile working memory.

  12. Comparison of classifiers for decoding sensory and cognitive information from prefrontal neuronal populations.

    Directory of Open Access Journals (Sweden)

    Elaine Astrand

    Full Text Available Decoding neuronal information is important in neuroscience, both as a basic means to understand how neuronal activity is related to cerebral function and as a processing stage in driving neuroprosthetic effectors. Here, we compare the readout performance of six commonly used classifiers at decoding two different variables encoded by the spiking activity of the non-human primate frontal eye fields (FEF: the spatial position of a visual cue, and the instructed orientation of the animal's attention. While the first variable is exogenously driven by the environment, the second variable corresponds to the interpretation of the instruction conveyed by the cue; it is endogenously driven and corresponds to the output of internal cognitive operations performed on the visual attributes of the cue. These two variables were decoded using either a regularized optimal linear estimator in its explicit formulation, an optimal linear artificial neural network estimator, a non-linear artificial neural network estimator, a non-linear naïve Bayesian estimator, a non-linear Reservoir recurrent network classifier or a non-linear Support Vector Machine classifier. Our results suggest that endogenous information such as the orientation of attention can be decoded from the FEF with the same accuracy as exogenous visual information. All classifiers did not behave equally in the face of population size and heterogeneity, the available training and testing trials, the subject's behavior and the temporal structure of the variable of interest. In most situations, the regularized optimal linear estimator and the non-linear Support Vector Machine classifiers outperformed the other tested decoders.

  13. Immunohistochemical localization of two types of choline acetyltransferase in neurons and sensory cells of the octopus arm.

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    Sakaue, Yuko; Bellier, Jean-Pierre; Kimura, Shin; D'Este, Loredana; Takeuchi, Yoshihiro; Kimura, Hiroshi

    2014-01-01

    Cholinergic structures in the arm of the cephalopod Octopus vulgaris were studied by immunohistochemistry using specific antisera for two types (common and peripheral) of acetylcholine synthetic enzyme choline acetyltransferase (ChAT): antiserum raised against the rat common type ChAT (cChAT), which is cross-reactive with molluscan cChAT, and antiserum raised against the rat peripheral type ChAT (pChAT), which has been used to delineate peripheral cholinergic structures in vertebrates, but not previously in invertebrates. Western blot analysis of octopus extracts revealed a single pChAT-positive band, suggesting that pChAT antiserum is cross-reactive with an octopus counterpart of rat pChAT. In immunohistochemistry, only neuronal structures of the octopus arm were stained by cChAT and pChAT antisera, although the pattern of distribution clearly differed between the two antisera. cChAT-positive varicose nerve fibers were observed in both the cerebrobrachial tract and neuropil of the axial nerve cord, while pChAT-positive varicose fibers were detected only in the neuropil of the axial nerve cord. After epitope retrieval, pChAT-positive neuronal cells and their processes became visible in all ganglia of the arm, including the axial and intramuscular nerve cords, and in ganglia of suckers. Moreover, pChAT-positive structures also became detectable in nerve fibers connecting the different ganglia, in smooth nerve fibers among muscle layers and dermal connective tissues, and in sensory cells of the suckers. These results suggest that the octopus arm has two types of cholinergic nerves: cChAT-positive nerves from brain ganglia and pChAT-positive nerves that are intrinsic to the arm.

  14. Expression of a Sensory Neuron Membrane Protein SNMP2 in Olfactory Sensilla of Codling Moth Cydia pomonella (Lepidoptera: Tortricidae).

    Science.gov (United States)

    Huang, Xinglong; Liu, Lu; Fang, Yiqing; Feng, Jinian

    2016-08-01

    In insects, sensory neuron membrane proteins (SNMPs) are critical peripheral olfactory proteins and highly promote the sensitivity of pheromone detection. In this study, we cloned an SNMP transcript (CpomSNMP2, GenBank KU302714) from the antennae of the codling moth Cydia pomonella (L.) Its open reading frame is 1,575 bp and it encodes a protein with 524 amino acids. CpomSNMP2 contains two putative transmembrane domains and has a large extracellular loop. Phylogenetic analysis showed that CpomSNMP2 is clustered into the group of previously characterized lepidopteron SNMP2s. Expression levels of CpomSNMP2 were significantly higher in antennae of both males and females than in tissues from the thoraxes, abdomens, legs, and wings. CpomSNMP2 was distributed in sensilla trichodea of both males and females, but only in sensilla chaetica of males. This study provides evidence for olfactory roles of CpomSNMP2 in this moth. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Nuclear Localization of the C1 Factor (Host Cell Factor) in Sensory Neurons Correlates with Reactivation of Herpes Simplex Virus from Latency

    Science.gov (United States)

    Kristie, Thomas M.; Vogel, Jodi L.; Sears, Amy E.

    1999-02-01

    After a primary infection, herpes simplex virus is maintained in a latent state in neurons of sensory ganglia until complex stimuli reactivate viral lytic replication. Although the mechanisms governing reactivation from the latent state remain unknown, the regulated expression of the viral immediate early genes represents a critical point in this process. These genes are controlled by transcription enhancer complexes whose assembly requires and is coordinated by the cellular C1 factor (host cell factor). In contrast to other tissues, the C1 factor is not detected in the nuclei of sensory neurons. Experimental conditions that induce the reactivation of herpes simplex virus in mouse model systems result in rapid nuclear localization of the protein, indicating that the C1 factor is sequestered in these cells until reactivation signals induce a redistribution of the protein. The regulated localization suggests that C1 is a critical switch determinant of the viral lytic-latent cycle.

  16. Prolactin potentiates the activity of acid-sensing ion channels in female rat primary sensory neurons.

    Science.gov (United States)

    Liu, Ting-Ting; Qu, Zu-Wei; Ren, Cuixia; Gan, Xiong; Qiu, Chun-Yu; Hu, Wang-Ping

    2016-04-01

    Prolactin (PRL) is a polypeptide hormone produced and released from the pituitary and extrapituitary tissues. It regulates activity of nociceptors and causes hyperalgesia in pain conditions, but little is known the molecular mechanism. We report here that PRL can exert a potentiating effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons. First, PRL dose-dependently increased the amplitude of ASIC currents with an EC50 of (5.89 ± 0.28) × 10(-8) M. PRL potentiation of ASIC currents was also pH dependent. Second, PRL potentiation of ASIC currents was blocked by Δ1-9-G129R-hPRL, a PRL receptor antagonist, and removed by intracellular dialysis of either protein kinase C inhibitor GF109203X, protein interacting with C-kinase 1(PICK1) inhibitor FSC-231, or PI3K inhibitor AS605240. Third, PRL altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Four, PRL exacerbated nociceptive responses to injection of acetic acid in female rats. Finally, PRL displayed a stronger effect on ASIC mediated-currents and nociceptive behavior in intact female rats than OVX female and male rats and thus modulation of PRL may be gender-dependent. These results suggest that PRL up-regulates the activity of ASICs and enhances ASIC mediated nociceptive responses in female rats, which reveal a novel peripheral mechanism underlying PRL involvement in hyperalgesia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Failure of action potential propagation in sensory neurons: mechanisms and loss of afferent filtering in C-type units after painful nerve injury.

    Science.gov (United States)

    Gemes, Geza; Koopmeiners, Andrew; Rigaud, Marcel; Lirk, Philipp; Sapunar, Damir; Bangaru, Madhavi Latha; Vilceanu, Daniel; Garrison, Sheldon R; Ljubkovic, Marko; Mueller, Samantha J; Stucky, Cheryl L; Hogan, Quinn H

    2013-02-15

    The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of 20 APs in a train could successfully transit the T-junction (following frequency) was lowest in C-type units, followed by A-type units with inflected descending limbs of the AP, and highest in A-type units without inflections. In C-type units, following frequency was slower than the rate at which AP trains could be produced in either dorsal root axonal segments or in the soma alone, indicating that the T-junction is a site that acts as a low-pass filter for AP propagation. Following frequency was slower for a train of 20 APs than for two, indicating that a cumulative process leads to propagation failure. Propagation failure was accompanied by diminished somatic membrane input resistance, and was enhanced when Ca(2+)-sensitive K(+) currents were augmented or when Ca(2+)-sensitive Cl(-) currents were blocked. After peripheral nerve injury, following frequencies were increased in axotomized C-type neurons and decreased in axotomized non-inflected A-type neurons. These findings reveal that the T-junction in sensory neurons is a regulator of afferent impulse traffic. Diminished filtering of AP trains at the T-junction of C-type neurons with axotomized peripheral processes could enhance the transmission of activity that is ectopically triggered in a neuroma or the neuronal soma, possibly contributing to pain generation.

  18. Processing of sub- and supra-second intervals in the primate brain results from the calibration of neuronal oscillators via sensory, motor, and feedback processes

    Science.gov (United States)

    Gupta, Daya S.

    2014-01-01

    The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of physical time within neuronal circuits is necessary. I propose that time dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators include the pacemaker neurons, tonic inputs, and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by “neural temporal unit,” defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a) feedback processes, (b) input of time intervals resulting from rhythmic external sensory stimulation, and (c) synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators, and the presence of modular connections prevent a complete loss of interval timing functions of the brain. PMID:25136321

  19. Processing of sub- and supra-second intervals in the primate brain results from the calibration of neuronal oscillators via sensory, motor and feedback processes

    Directory of Open Access Journals (Sweden)

    Daya Shankar Gupta

    2014-08-01

    Full Text Available The processing of time intervals in the sub- to supra-second range by the brain is critical for the interaction of primates with their surroundings in activities, such as foraging and hunting. For an accurate processing of time intervals by the brain, representation of the physical time within neuronal circuits is necessary. I propose that time-dimension of the physical surrounding is represented in the brain by different types of neuronal oscillators, generating spikes or spike bursts at regular intervals. The proposed oscillators include the pacemaker neurons, tonic inputs and synchronized excitation and inhibition of inter-connected neurons. Oscillators, which are built inside various circuits of brain, help to form modular clocks, processing time intervals or other temporal characteristics specific to functions of a circuit. Relative or absolute duration is represented within neuronal oscillators by ‘neural temporal unit’, defined as the interval between regularly occurring spikes or spike bursts. Oscillator output is processed to produce changes in activities of neurons, named frequency modulator neuron, wired within a separate module, represented by the rate of change in frequency, and frequency of activities, proposed to encode time intervals. Inbuilt oscillators are calibrated by (a feedback processes (b input of time intervals resulting from rhythmic external sensory stimulation and (c synchronous effects of feedback processes and evoked sensory activity. A single active clock is proposed per circuit, which is calibrated by one or more mechanisms. Multiple calibration mechanisms, inbuilt oscillators and the presence of modular connections prevent a complete loss of interval timing functions of the brain.

  20. FM1-43 is a permeant blocker of mechanosensitive ion channels in sensory neurons and inhibits behavioural responses to mechanical stimuli

    Directory of Open Access Journals (Sweden)

    Drew Liam J

    2007-01-01

    Full Text Available Abstract The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca2+. The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in culture mediate mechanosensation in the intact animal. These data give further insight into the mechanosensitive ion channels expressed by somatosensory neurons and suggest FM dyes are an interesting tool for studying them.

  1. Cholinergic microvillous cells in the mouse main olfactory epithelium and effect of acetylcholine on olfactory sensory neurons and supporting cells.

    Science.gov (United States)

    Ogura, Tatsuya; Szebenyi, Steven A; Krosnowski, Kurt; Sathyanesan, Aaron; Jackson, Jacqueline; Lin, Weihong

    2011-09-01

    The mammalian olfactory epithelium is made up of ciliated olfactory sensory neurons (OSNs), supporting cells, basal cells, and microvillous cells. Previously, we reported that a population of nonneuronal microvillous cells expresses transient receptor potential channel M5 (TRPM5). Using transgenic mice and immunocytochemical labeling, we identify that these cells are cholinergic, expressing the signature markers of choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter. This result suggests that acetylcholine (ACh) can be synthesized and released locally to modulate activities of neighboring supporting cells and OSNs. In Ca(2+) imaging experiments, ACh induced increases in intracellular Ca(2+) levels in 78% of isolated supporting cells tested in a concentration-dependent manner. Atropine, a muscarinic ACh receptor (mAChR) antagonist suppressed the ACh responses. In contrast, ACh did not induce or potentiate Ca(2+) increases in OSNs. Instead ACh suppressed the Ca(2+) increases induced by the adenylyl cyclase activator forskolin in some OSNs. Supporting these results, we found differential expression of mAChR subtypes in supporting cells and OSNs using subtype-specific antibodies against M(1) through M(5) mAChRs. Furthermore, we found that various chemicals, bacterial lysate, and cold saline induced Ca(2+) increases in TRPM5/ChAT-expressing microvillous cells. Taken together, our data suggest that TRPM5/ChAT-expressing microvillous cells react to certain chemical or thermal stimuli and release ACh to modulate activities of neighboring supporting cells and OSNs via mAChRs. Our studies reveal an intrinsic and potentially potent mechanism linking external stimulation to cholinergic modulation of activities in the olfactory epithelium.

  2. Coupling of exocytosis and endocytosis at the presynaptic active zone.

    Science.gov (United States)

    Maritzen, Tanja; Haucke, Volker

    2018-02-01

    Brain function depends on the ability of neurons to communicate with each other via the regulated exocytosis of neurotransmitter-containing synaptic vesicles (SVs) at specialized presynaptic release sites termed active zones (AZs). The presynaptic AZ comprises an assembly of large multidomain proteins that link the machinery for vesicle fusion to sites of voltage-dependent Ca 2+ entry. Following SV fusion at AZ release sites SV membranes are retrieved by compensatory endocytosis, and SVs are reformed. Recent data suggest that Ca 2+ -triggered SV exocytosis at AZs and endocytic retrieval of SVs may be functionally and physically linked. Here we discuss the evidence supporting such exo-endocytic coupling as well as possible modes and mechanisms that may underlie coupling of exocytosis and endocytosis at and around AZs in presynaptic nerve terminals. As components of the exo-endocytic machinery at synapses have been linked to neurological and neuropsychiatric disorders, understanding the mechanisms that couple exocytosis and endocytosis at AZs may be of importance for developing novel therapies to treat these diseases. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  3. Axonal and presynaptic RNAs are locally transcribed in glial cells.

    Science.gov (United States)

    Giuditta, Antonio; Chun, Jong Tai; Eyman, Maria; Cefaliello, Carolina; Bruno, Anna Paola; Crispino, Marianna

    2007-01-01

    In the last few years, the long-standing opinion that axonal and presynaptic proteins are exclusively derived from the neuron cell body has been substantially modified by the demonstration that active systems of protein synthesis are present in axons and nerve terminals. These observations have raised the issue of the cellular origin of the involved RNAs, which has been generally attributed to the neuron soma. However, data gathered in a number of model systems indicated that axonal RNAs are synthesized in the surrounding glial cells. More recent experiments on the perfused squid giant axon have definitively proved that axoplasmic RNAs are transcribed in periaxonal glia. Their delivery to the axon occurs by a modulatory mechanism based on the release of neurotransmitters from the stimulated axon and on their binding to glial receptors. In additional experiments on squid optic lobe synaptosomes, presynaptic RNA has been also shown to be synthesized locally, presumably in nearby glia. Together with a wealth of literature data, these observations indicate that axons and nerve terminals are endowed with a local system of gene expression that supports the maintenance and plasticity of these neuronal domains.

  4. Acetylsalicylic acid-induced changes in the chemical coding of extrinsic sensory neurons supplying the prepyloric area of the porcine stomach.

    Science.gov (United States)

    Rytel, L; Calka, J

    2016-03-23

    Acetylsalicylic acid is a popular drug that is commonly used to treat fever and inflammation, but which can also negativity affect the mucosal layer of the stomach, although knowledge concerning its influence on gastric innervation is very scarce. Thus, the aim of the present study was to study the influence of prolonged acetylsalicylic acid supplementation on the extrinsic primary sensory neurons supplying the porcine stomach prepyloric region. Fast Blue (FB) was injected into the above-mentioned region of the stomach. Acetylsalicylic acid was then given orally to the experimental gilts from the seventh day after FB injection to the 27th day of the experiment. After euthanasia, the nodose ganglia (NG) and dorsal root ganglia (DRG) were collected. Sections of these ganglia were processed for routine double-labelling immunofluorescence technique for substance P (SP), calcitonine gene related peptide (CGRP), galanin (GAL), neuronal isoform of nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Under physiological conditions within the nodose ganglia, the percentage of the FB-labeled neurons immunoreactive to particular substances ranged between 17.9 ± 2.7% (VIP-like immunoreactive (LI) neurons in the right NG) and 60.4 ± 1.7% (SP-LI cells within the left NG). Acetylsalicylic acid supplementation caused a considerable increase in the expression of all active substances studied within both left and right NG and the percentage of neurons positive to particular substances fluctuated from 47.2 ± 3.6% (GAL-LI neurons in the right NG) to 67.2 ± 2.0% (cells immunoreactive to SP in the left NG). All studied substances were also observed in DRG neurons supplying the prepyloric region of the stomach, but the number of immunoreactive neurons was too small to conduct a statistical analysis. The obtained results show that ASA may influence chemical coding of the sensory neurons supplying the porcine stomach, but the exact mechanisms of this action still

  5. RIM genes differentially contribute to organizing presynaptic release sites.

    Science.gov (United States)

    Kaeser, Pascal S; Deng, Lunbin; Fan, Mingming; Südhof, Thomas C

    2012-07-17

    Tight coupling of Ca(2+) channels to the presynaptic active zone is critical for fast synchronous neurotransmitter release. RIMs are multidomain proteins that tether Ca(2+) channels to active zones, dock and prime synaptic vesicles for release, and mediate presynaptic plasticity. Here, we use conditional knockout mice targeting all RIM isoforms expressed by the Rims1 and Rims2 genes to examine the contributions and mechanism of action of different RIMs in neurotransmitter release. We show that acute single deletions of each Rims gene decreased release and impaired vesicle priming but did not alter the extracellular Ca(2+)-responsiveness of release (which for Rims gene mutants is a measure of presynaptic Ca(2+) influx). Moreover, single deletions did not affect the synchronization of release (which depends on the close proximity of Ca(2+) channels to release sites). In contrast, deletion of both Rims genes severely impaired the Ca(2+) responsiveness and synchronization of release. RIM proteins may act on Ca(2+) channels in two modes: They tether Ca(2+) channels to active zones, and they directly modulate Ca(2+)-channel inactivation. The first mechanism is essential for localizing presynaptic Ca(2+) influx to nerve terminals, but the role of the second mechanism remains unknown. Strikingly, we find that although the RIM2 C(2)B domain by itself significantly decreased Ca(2+)-channel inactivation in transfected HEK293 cells, it did not rescue any aspect of the RIM knockout phenotype in cultured neurons. Thus, RIMs primarily act in release as physical Ca(2+)-channel tethers and not as Ca(2+)-channel modulators. Different RIM proteins compensate for each other in recruiting Ca(2+) channels to active zones, but contribute independently and incrementally to vesicle priming.

  6. Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function

    Directory of Open Access Journals (Sweden)

    Alvarez Alejandra R

    2009-11-01

    Full Text Available Abstract Background The Wnt signaling pathway regulates several fundamental developmental processes and recently has been shown to be involved in different aspects of synaptic differentiation and plasticity. Some Wnt signaling components are localized at central synapses, and it is thus possible that this pathway could be activated at the synapse. Results We examined the distribution of the Wnt receptor Frizzled-1 in cultured hippocampal neurons and determined that this receptor is located at synaptic contacts co-localizing with presynaptic proteins. Frizzled-1 was found in functional synapses detected with FM1-43 staining and in synaptic terminals from adult rat brain. Interestingly, overexpression of Frizzled-1 increased the number of clusters of Bassoon, a component of the active zone, while treatment with the extracellular cysteine-rich domain (CRD of Frizzled-1 decreased Bassoon clustering, suggesting a role for this receptor in presynaptic differentiation. Consistent with this, treatment with the Frizzled-1 ligand Wnt-3a induced presynaptic protein clustering and increased functional presynaptic recycling sites, and these effects were prevented by co-treatment with the CRD of Frizzled-1. Moreover, in synaptically mature neurons Wnt-3a was able to modulate the kinetics of neurotransmitter release. Conclusion Our results indicate that the activation of the Wnt pathway through Frizzled-1 occurs at the presynaptic level, and suggest that the synaptic effects of the Wnt signaling pathway could be modulated by local activation through synaptic Frizzled receptors.

  7. Activation of nuclear factor-kappa B via endogenous tumor necrosis factor alpha regulates survival of axotomized adult sensory neurons

    NARCIS (Netherlands)

    Fernyhough, P; Smith, DR; Schapansky, J; Van Der Ploeg, R; Gardiner, NJ; Tweed, CW; Kontos, A; Freeman, L; Purves-Tyson, TD; Glazner, GW

    2005-01-01

    Embryonic dorsal root ganglion (DRG) neurons die after axonal damage in vivo, and cultured embryonic DRG neurons require exogenous neurotrophic factors that activate the neuroprotective transcription factor nuclear factor-kappaB(NF-kappaB) for survival. In contrast, adult DRG neurons survive

  8. Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam

    Science.gov (United States)

    Song, Yuanquan; Ori-McKenney, Kassandra M.; Zheng, Yi; Han, Chun; Jan, Lily Yeh; Jan, Yuh Nung

    2012-01-01

    Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. Here we report that, like the axons of mammalian sensory neurons, the axons of certain Drosophila dendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNA bantam but is facilitated by cell-autonomous activation of the Akt pathway. Our study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN–Akt pathway that is also important for axon regeneration. We thus established an important new model system—the fly da neuron regeneration model that resembles the mammalian injury model—with which to study and gain novel insights into the regeneration machinery. PMID:22759636

  9. Neuro-fuzzy decoding of sensory information from ensembles of simultaneously recorded dorsal root ganglion neurons for functional electrical stimulation applications.

    Science.gov (United States)

    Rigosa, J; Weber, D J; Prochazka, A; Stein, R B; Micera, S

    2011-08-01

    Functional electrical stimulation (FES) is used to improve motor function after injury to the central nervous system. Some FES systems use artificial sensors to switch between finite control states. To optimize FES control of the complex behavior of the musculo-skeletal system in activities of daily life, it is highly desirable to implement feedback control. In theory, sensory neural signals could provide the required control signals. Recent studies have demonstrated the feasibility of deriving limb-state estimates from the firing rates of primary afferent neurons recorded in dorsal root ganglia (DRG). These studies used multiple linear regression (MLR) methods to generate estimates of limb position and velocity based on a weighted sum of firing rates in an ensemble of simultaneously recorded DRG neurons. The aim of this study was to test whether the use of a neuro-fuzzy (NF) algorithm (the generalized dynamic fuzzy neural networks (GD-FNN)) could improve the performance, robustness and ability to generalize from training to test sets compared to the MLR technique. NF and MLR decoding methods were applied to ensemble DRG recordings obtained during passive and active limb movements in anesthetized and freely moving cats. The GD-FNN model provided more accurate estimates of limb state and generalized better to novel movement patterns. Future efforts will focus on implementing these neural recording and decoding methods in real time to provide closed-loop control of FES using the information extracted from sensory neurons.

  10. Rho-independent stimulation of axon outgrowth and activation of the ERK and Akt signaling pathways by C3 transferase in sensory neurons

    Directory of Open Access Journals (Sweden)

    Maria eAuer

    2012-10-01

    Full Text Available Peripheral nerve injury triggers the activation of RhoA in spinal motor and peripheral sensory neurons. RhoA activates a number of effector proteins including the Rho-associated kinase, ROCK, which targets the cytoskeleton and leads to inhibition of neurite outgrowth. Blockade of the Rho/ROCK pathway by pharmacological means improves axon regeneration after experimental injury. C3bot transferase, an exoenzyme produced by Clostridium botulinum, inactivates RhoA by ADP-ribosylation. Up to now it was not investigated thoroughly whether C3bot exerts positive effects on peripheral axon regeneration as well. In the present study, recombinant membrane permeable C3bot produced a small, but significant, axon outgrowth effect on peripheral sensory neurons dissociated from adult dorsal root ganglia of the rat. Neuronal overexpression of C3, however, did not enhance axonal growth. Moreover, transfection of plasmids encoding dominant negative RhoA or RhoA specific shRNAs failed to increase axonal growth. Furthermore, we show that the C3bot mutant, C3E174Q, which lacks RhoA inhibitory activity, still stimulates axonal growth. When analyzing possible signaling mechanisms we found that ERK (extracellular signal-regulated kinase and Akt are activated by C3bot and ERK is induced by the C3E174Q mutant. Upregulation of kinase activities by C3bot occurs significantly faster than inactivation of RhoA indicating a RhoA-independent pathway of action by C3bot. The induction of ERK signaling by C3bot was detected in embryonic hippocampal neurons, too. Taken together, although RhoA plays a central role for inhibition of axon outgrowth by myelin-derived inhibitors, it does not interfere with axonal growth of sensory neurons on a permissive substrate in vitro. C3bot blocks neuronal RhoA activity, but its positive effects on axon elongation and branching appear to be mediated by Rho independent mechanisms involving activation of axon growth promoting ERK and Akt kinases.

  11. A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

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    Yulia A. Sidorova

    2017-06-01

    Full Text Available Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF and artemin (ARTN, as these GDNF family ligands (GFLs show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003; Wang et al., 2008, 2014. As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics. This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.

  12. Artificial Induction of Associative Olfactory Memory by Optogenetic and Thermogenetic Activation of Olfactory Sensory Neurons and Octopaminergic Neurons in Drosophila Larvae.

    Science.gov (United States)

    Honda, Takato; Lee, Chi-Yu; Honjo, Ken; Furukubo-Tokunaga, Katsuo

    2016-01-01

    The larval brain of Drosophila melanogaster provides an excellent system for the study of the neurocircuitry mechanism of memory. Recent development of neurogenetic techniques in fruit flies enables manipulations of neuronal activities in freely behaving animals. This protocol describes detailed steps for artificial induction of olfactory associative memory in Drosophila larvae. In this protocol, the natural reward signal is substituted by thermogenetic activation of octopaminergic neurons in the brain. In parallel, the odor signal is substituted by optogenetic activation of a specific class of olfactory receptor neurons. Association of reward and odor stimuli is achieved with the concomitant application of blue light and heat that leads to activation of both sets of neurons in living transgenic larvae. Given its operational simplicity and robustness, this method could be utilized to further our knowledge on the neurocircuitry mechanism of memory in the fly brain.

  13. Neuronal responses to tactile stimuli and tactile sensations evoked by microstimulation in the human thalamic principal somatic sensory nucleus (ventral caudal).

    Science.gov (United States)

    Schmid, Anne-Christine; Chien, Jui-Hong; Greenspan, Joel D; Garonzik, Ira; Weiss, Nirit; Ohara, Shinji; Lenz, Frederick Arthur

    2016-06-01

    The normal organization and plasticity of the cutaneous core of the thalamic principal somatosensory nucleus (ventral caudal, Vc) have been studied by single-neuron recordings and microstimulation in patients undergoing awake stereotactic operations for essential tremor (ET) without apparent somatic sensory abnormality and in patients with dystonia or chronic pain secondary to major nervous system injury. In patients with ET, most Vc neurons responded to one of the four stimuli, each of which optimally activates one mechanoreceptor type. Sensations evoked by microstimulation were similar to those evoked by the optimal stimulus only among rapidly adapting neurons. In patients with ET, Vc was highly segmented somatotopically, and vibration, movement, pressure, and sharp sensations were usually evoked by microstimulation at separate sites in Vc. In patients with conditions including spinal cord transection, amputation, or dystonia, RFs were mismatched with projected fields more commonly than in patients with ET. The representation of the border of the anesthetic area (e.g., stump) or of the dystonic limb was much larger than that of the same part of the body in patients with ET. This review describes the organization and reorganization of human Vc neuronal activity in nervous system injury and dystonia and then proposes basic mechanisms. Copyright © 2016 the American Physiological Society.

  14. Effect of ionizing radiation in sensory ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.

    Science.gov (United States)

    Casafont, Iñigo; Palanca, Ana; Lafarga, Vanesa; Berciano, Maria T; Lafarga, Miguel

    2011-10-01

    Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0-G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.

  15. The presynaptic microtubule cytoskeleton in physiological and pathological conditions: lessons from Fragile X Syndrome and Hereditary Spastic Paraplegias

    Directory of Open Access Journals (Sweden)

    Felipe Bodaleo

    2016-07-01

    Full Text Available The capacity of the nervous system to generate neuronal networks relies on the establishment and maintenance of synaptic contacts. Synapses are composed of functionally different presynaptic and postsynaptic compartments. An appropriate synaptic architecture is required to provide the structural basis that supports synaptic transmission, a process involving changes in cytoskeletal dynamics. Actin microfilaments are the main cytoskeletal components present at both presynaptic and postsynaptic terminals in glutamatergic synapses. However, in the last few years it has been demonstrated that microtubules (MTs transiently invade dendritic spines, promoting their maturation. Nevertheless, the presence and functions of MTs at the presynaptic site are still a matter of debate. Early electron microscopy (EM studies revealed that MTs are present in the presynaptic terminals of the central nervous system (CNS where they interact with synaptic vesicles (SVs and reach the active zone. These observations have been reproduced by several EM protocols; however, there is empirical heterogeneity in detecting presynaptic MTs, since they appear to be both labile and unstable. Moreover, increasing evidence derived from studies in the fruit fly neuromuscular junction proposes different roles for MTs in regulating presynaptic function in physiological and pathological conditions. In this review, we summarize the main findings that support the presence and roles of MTs at presynaptic terminals, integrating descriptive and biochemical analyses, and studies performed in invertebrate genetic models.

  16. Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

    Science.gov (United States)

    Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

    2017-07-01

    Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

  17. Cellular mechanisms for presynaptic inhibition of sensory afferents

    DEFF Research Database (Denmark)

    Perrier, Jean-Francois Marie; delgado-lezama, rodolfo; Christensen, Rasmus Kordt

    (DRP) by stimulating one dorsal root and recording another one. In the presence of a low concentration of tetrodotoxin (100nM) nerve impulses are abolished centrally but remain in nociceptive afferents. Under these conditions, a DRP generated by a non-spiking microcircuit remained. In the presence...... with a 2-photon microscope. Stimulation of primary afferents evoked a transient increase in calcium concentration in a subset of cells. The response disappeared after addition of CNQX. This showed that primary afferents activate astrocytes. In a thin slice preparation, we recorded astrocytes with the whole...

  18. A CLCA regulatory protein present in the chemosensory cilia of olfactory sensory neurons induces a Ca2+-activated Cl-current when transfected into HEK293.

    Science.gov (United States)

    Mura, Casilda V; Delgado, Ricardo; Delgado, María Graciela; Restrepo, Diego; Bacigalupo, Juan

    2017-08-11

    CLCA is a family of metalloproteases that regulate Ca 2+ -activated Cl - fluxes in epithelial tissues. In HEK293 cells, CLCA1 promotes membrane expression of an endogenous Anoctamin 1 (ANO1, also termed TMEM16A)-dependent Ca 2+ -activated Cl - current. Motif architecture similarity with CLCA2, 3 and 4 suggested that they have similar functions. We previously detected the isoform CLCA4L in rat olfactory sensory neurons, where Anoctamin 2 is the principal chemotransduction Ca 2+ -activated Cl - channel. We explored the possibility that this protein plays a role in odor transduction. We cloned and expressed CLCA4L from rat olfactory epithelium in HEK293 cells. In the transfected HEK293 cells we measured a Cl - -selective Ca 2+ -activated current, blocked by niflumic acid, not present in the non-transfected cells. Thus, CLCA4L mimics the CLCA1 current on its ability to induce the ANO1-dependent Ca 2+ -activated Cl - current endogenous to these cells. By immunocytochemistry, a CLCA protein, presumably CLCA4L, was detected in the cilia of olfactory sensory neurons co-expressing with ANO2. These findings suggests that a CLCA isoform, namely CLCA4L, expressed in OSN cilia, might have a regulatory function over the ANO2-dependent Ca 2+ -activated Cl - channel involved in odor transduction.

  19. Repeated touch and needle-prick stimulation in the neonatal period increases the baseline mechanical sensitivity and postinjury hypersensitivity of adult spinal sensory neurons.

    Science.gov (United States)

    van den Hoogen, Nynke J; Patijn, Jacob; Tibboel, Dick; Joosten, Bert A; Fitzgerald, Maria; Kwok, Charlie H T

    2018-03-08

    Noxious stimulation at critical stages of development has long-term consequences on somatosensory processing in later life, but it is not known whether this developmental plasticity is restricted to nociceptive pathways. Here, we investigate the effect of repeated neonatal noxious or innocuous hind paw stimulation on adult spinal dorsal horn cutaneous mechanical sensitivity. Neonatal Sprague-Dawley rats of both sexes received 4 unilateral left hind paw needle pricks (NPs, n = 13) or 4 tactile (cotton swab touch) stimuli, per day (TC, n = 11) for the first 7 days of life. Control pups were left undisturbed (n = 17). When adult (6-8 weeks), lumbar wide-dynamic-range neuron activity in laminae III-V was recorded using in vivo extracellular single-unit electrophysiology. Spike activity evoked by cutaneous dynamic tactile (brush), pinch and punctate (von Frey hair) stimulation, and plantar receptive field areas were recorded, at baseline and 2 and 5 days after left plantar hind paw incision. Baseline brush receptive fields, von Frey hair, and pinch sensitivity were significantly enhanced in adult NP and TC animals compared with undisturbed controls, although effects were greatest in NP rats. After incision, injury sensitivity of adult wide-dynamic-range neurons to both noxious and dynamic tactile hypersensitivity was significantly greater in NP animals compared with TC and undisturbed controls. We conclude that both repeated touch and needle-prick stimulation in the neonatal period can alter adult spinal sensory neuron sensitivity to both innocuous and noxious mechanical stimulation. Thus, spinal sensory circuits underlying touch and pain processing are shaped by a range of early-life somatosensory experiences.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  20. Presynaptic mechanisms of L-DOPA-induced dyskinesia: the findings, the debate, the therapeutic implications.

    Directory of Open Access Journals (Sweden)

    M Angela eCenci

    2014-12-01

    Full Text Available The dopamine precursor L-DOPA has been the most effective treatment for Parkinson´s disease (PD for over 40 years. However, the response to this treatment changes during the progression of PD, and most patients develop dyskinesias (abnormal involuntary movements and motor fluctuations within a few years of L-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal dopamine transmission. Several presynaptic mechanisms converge to generate large dopamine swings in the brain concomitant with the peaks-and-troughs of plasma L-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in dopamine transmission depend on deficiency/dysfunction of the dopamine transporter, aberrant release of dopamine from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from dopamine play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of L-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

  1. Local synthesis of axonal and presynaptic RNA in squid model systems.

    Science.gov (United States)

    Eyman, Maria; Cefaliello, Carolina; Ferrara, Eugenia; De Stefano, Rosanna; Lavina, Zeno Scotto; Crispino, Marianna; Squillace, Angela; van Minnen, Jan; Kaplan, Barry B; Giuditta, Antonio

    2007-01-01

    The presence of active systems of protein synthesis in axons and nerve endings raises the question of the cellular origin of the corresponding RNAs. Our present experiments demonstrate that, besides a possible derivation from neuronal cell bodies, axoplasmic RNAs originate in periaxonal glial cells and presynaptic RNAs derive from nearby cells, presumably glial cells. Indeed, in perfused squid giant axons, delivery of newly synthesized RNA to the axon perfusate is strongly stimulated by axonal depolarization or agonists of glial glutamate and acetylcholine receptors. Likewise, incubation of squid optic lobe slices with [3H]uridine leads to a marked accumulation of [3H]RNA in the large synaptosomes derived from the nerve terminals of retinal photoreceptor neurons. As the cell bodies of these neurons lie outside the optic lobe, the data demonstrate that presynaptic RNA is locally synthesized, presumably by perisynaptic glial cells. Overall, our results support the view that axons and presynaptic regions are endowed with local systems of gene expression which may prove essential for the maintenance and plasticity of these extrasomatic neuronal domains.

  2. Degeneracy in the regulation of short-term plasticity and synaptic filtering by presynaptic mechanisms.

    Science.gov (United States)

    Mukunda, Chinmayee L; Narayanan, Rishikesh

    2017-04-15

    We develop a new biophysically rooted, physiologically constrained conductance-based synaptic model to mechanistically account for short-term facilitation and depression, respectively through residual calcium and transmitter depletion kinetics. We address the specific question of how presynaptic components (including voltage-gated ion channels, pumps, buffers and release-handling mechanisms) and interactions among them define synaptic filtering and short-term plasticity profiles. Employing global sensitivity analyses (GSAs), we show that near-identical synaptic filters and short-term plasticity profiles could emerge from disparate presynaptic parametric combinations with weak pairwise correlations. Using virtual knockout models, a technique to address the question of channel-specific contributions within the GSA framework, we unveil the differential and variable impact of each ion channel on synaptic physiology. Our conclusions strengthen the argument that parametric and interactional complexity in biological systems should not be viewed from the limited curse-of-dimensionality standpoint, but from the evolutionarily advantageous perspective of providing functional robustness through degeneracy. Information processing in neurons is known to emerge as a gestalt of pre- and post-synaptic filtering. However, the impact of presynaptic mechanisms on synaptic filters has not been quantitatively assessed. Here, we developed a biophysically rooted, conductance-based model synapse that was endowed with six different voltage-gated ion channels, calcium pumps, calcium buffer and neurotransmitter-replenishment mechanisms in the presynaptic terminal. We tuned our model to match the short-term plasticity profile and band-pass structure of Schaffer collateral synapses, and performed sensitivity analyses to demonstrate that presynaptic voltage-gated ion channels regulated synaptic filters through changes in excitability and associated calcium influx. These sensitivity analyses

  3. SNAP-25, a known presynaptic protein with emerging postsynaptic functions.

    Directory of Open Access Journals (Sweden)

    Flavia eAntonucci

    2016-03-01

    Full Text Available A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD, schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different synaptopathies. The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions.

  4. Energy Requirements of Odor Transduction in the Chemosensory Cilia of Olfactory Sensory Neurons Rely on Oxidative Phosphorylation and Glycolytic Processing of Extracellular Glucose.

    Science.gov (United States)

    Villar, Pablo S; Delgado, Ricardo; Vergara, Cecilia; Reyes, Juan G; Bacigalupo, Juan

    2017-06-07

    The mechanisms that power the physiological events occurring in cilia, flagella, and microvilli are of fundamental importance for the functions of these important and ubicuous organelles. The olfactory epithelium is mostly populated by ciliated olfactory sensory neurons (OSNs) and surrounding sustentacular cells (SCs) with apical microvilli. The only OSN dendrite extends to the surface forming a knob projecting several chemosensory cilia of ∼50 × 0.2 μm, devoid of inner membranes embedded in a mucus layer. Upon odorant binding, odor receptors couple to G-protein activating adenylyl cyclase, producing cAMP. cAMP opens cyclic nucleotide-gated channels allowing a Ca 2+ influx that opens Ca 2+ -activated Cl - channels, generating the receptor potential. Many enzymes are activated in chemotransduction to hydrolyze ATP. The knob contains approximately two mitochondria; assuming that the cilia ATP is 1 mm and diffuses along it at ∼10 μm in 500 ms, ATP from the knob mitochondria may not fulfill the demands of transduction over the full length of the cilium, which suggests an additional ATP source. We measured millimolar glucose in rat mucus; we detected glucose transporter GLUT3 in rat and toad ( Caudiverbera caudiverbera ) OSN cilia, SC microvilli, and glycolytic enzymes in rat cilia. We also found that the cilia and knob can incorporate and accumulate 2-deoxyglucose (glucose analog), but not when blocking GLUT. Glucose removal and the inhibition of glycolysis or oxidative phospholylation impaired the odor response. This evidence strongly suggests that glycolysis in the cilia and knob oxidative phosphorylation together fuel chemotransduction. SIGNIFICANCE STATEMENT How processes occurring in cilia and flagella are powered is a matter of general interest. Substantial progress has been made in unraveling the sensory transduction mechanisms, commonly occurring in such structures; however, the energy sources powering them have been scarcely explored. Accessibility to

  5. Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels.

    Science.gov (United States)

    Salzer, Isabella; Gantumur, Enkhbileg; Yousuf, Arsalan; Boehm, Stefan

    2016-11-01

    Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Presynaptic calcium signalling in cerebellar mossy fibres

    DEFF Research Database (Denmark)

    Thomsen, Louiza Bohn; Jörntell, Henrik; Midtgaard, Jens

    2010-01-01

    affected burst firing in mossy fibres; this paired-pulse depression was reduced by GABA B antagonists. While our results indicated that a presynaptic rosette electrophysiologically functioned as a unit, topical GABA application showed that calcium signals in the branches of complex rosettes could......Whole-cell recordings were obtained from mossy fibre terminals in adult turtles in order to characterize the basic membrane properties. Calcium imaging of presynaptic calcium signals was carried out in order to analyse calcium dynamics and presynaptic GABA B inhibition. A tetrodotoxin (TTX......)-sensitive fast Na(+) spike faithfully followed repetitive depolarizing pulses with little change in spike duration or amplitude, while a strong outward rectification dominated responses to long-lasting depolarizations. High-threshold calcium spikes were uncovered following addition of potassium channel blockers...

  7. A developmental approach of imitation to study the emergence of mirror neurons in a sensory-motor controller

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    Gaussier Philippe

    2011-12-01

    Full Text Available Mirror neurons have often been considered as the explanation of how primates can imitate. In this paper, we show that a simple neural network architecture that learns visuo-motor associations can be enough to let low level imitation emerge without a priori mirror neurons. Adding sequence learning mechanisms and action inhibition allows to perform deferred imitation of gestures demonstrated visually or by body manipulation. With the building of a cognitive map giving the capability of learning plans, we can study in our model the emergence of both low level and high level resonances highlighted by Rizzolatti et al.

  8. Presynaptic Ionotropic Receptors Controlling and Modulating the Rules for Spike Timing-Dependent Plasticity

    Directory of Open Access Journals (Sweden)

    Matthijs B. Verhoog

    2011-01-01

    Full Text Available Throughout life, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. In line with predictions made by Hebb, synapse strength can be modified depending on the millisecond timing of action potential firing (STDP. The sign of synaptic plasticity depends on the spike order of presynaptic and postsynaptic neurons. Ionotropic neurotransmitter receptors, such as NMDA receptors and nicotinic acetylcholine receptors, are intimately involved in setting the rules for synaptic strengthening and weakening. In addition, timing rules for STDP within synapses are not fixed. They can be altered by activation of ionotropic receptors located at, or close to, synapses. Here, we will highlight studies that uncovered how network actions control and modulate timing rules for STDP by activating presynaptic ionotropic receptors. Furthermore, we will discuss how interaction between different types of ionotropic receptors may create “timing” windows during which particular timing rules lead to synaptic changes.

  9. Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

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    Tillu Dipti V

    2012-01-01

    Full Text Available Abstract Background Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. Results To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6 is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment. Conclusions These results highlight the importance of signaling

  10. Exocytosis: using amperometry to study presynaptic mechanisms of neurotoxicity

    NARCIS (Netherlands)

    Westerink, R.H.S.

    2004-01-01

    The development of carbon fiber microelectrode amperometry enabled detailed investigation of the presynaptic response at the single cell level with single vesicle resolution. Consequently, amperometry allowed for detailed studies into the presynaptic mechanisms underlying neurotoxicity. This review

  11. Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system.

    Science.gov (United States)

    McGovern, Alice E; Driessen, Alexandria K; Simmons, David G; Powell, Joseph; Davis-Poynter, Nicholas; Farrell, Michael J; Mazzone, Stuart B

    2015-05-06

    Sensory nerves innervating the mucosa of the airways monitor the local environment for the presence of irritant stimuli and, when activated, provide input to the nucleus of the solitary tract (Sol) and paratrigeminal nucleus (Pa5) in the medulla to drive a variety of protective behaviors. Accompanying these behaviors are perceivable sensations that, particularly for stimuli in the proximal end of the airways, can be discrete and localizable. Airway sensations likely reflect the ascending airway sensory circuitry relayed via the Sol and Pa5, which terminates broadly throughout the CNS. However, the relative contribution of the Sol and Pa5 to these ascending pathways is not known. In the present study, we developed and characterized a novel conditional anterograde transneuronal viral tracing system based on the H129 strain of herpes simplex virus 1 and used this system in rats along with conventional neuroanatomical tracing with cholera toxin B to identify subcircuits in the brainstem and forebrain that are in receipt of relayed airway sensory inputs via the Sol and Pa5. We show that both the Pa5 and proximal airways disproportionately receive afferent terminals arising from the jugular (rather than nodose) vagal ganglia and the output of the Pa5 is predominately directed toward the ventrobasal thalamus. We propose the existence of a somatosensory-like pathway from the proximal airways involving jugular ganglia afferents, the Pa5, and the somatosensory thalamus and suggest that this pathway forms the anatomical framework for sensations arising from the proximal airway mucosa. Copyright © 2015 the authors 0270-6474/15/357041-15$15.00/0.

  12. Multilayer perceptron classification of unknown volatile chemicals from the firing rates of insect olfactory sensory neurons and its application to biosensor design.

    Science.gov (United States)

    Bachtiar, Luqman R; Unsworth, Charles P; Newcomb, Richard D; Crampin, Edmund J

    2013-01-01

    In this letter, we use the firing rates from an array of olfactory sensory neurons (OSNs) of the fruit fly, Drosophila melanogaster, to train an artificial neural network (ANN) to distinguish different chemical classes of volatile odorants. Bootstrapping is implemented for the optimized networks, providing an accurate estimate of a network's predicted values. Initially a simple linear predictor was used to assess the complexity of the data and was found to provide low prediction performance. A nonlinear ANN in the form of a single multilayer perceptron (MLP) was also used, providing a significant increase in prediction performance. The effect of the number of hidden layers and hidden neurons of the MLP was investigated and found to be effective in enhancing network performance with both a single and a double hidden layer investigated separately. A hybrid array of MLPs was investigated and compared against the single MLP architecture. The hybrid MLPs were found to classify all vectors of the validation set, presenting the highest degree of prediction accuracy. Adjustment of the number of hidden neurons was investigated, providing further performance gain. In addition, noise injection was investigated, proving successful for certain network designs. It was found that the best-performing MLP was that of the double-hidden-layer hybrid MLP network without the use of noise injection. Furthermore, the level of performance was examined when different numbers of OSNs used were varied from the maximum of 24 to only 5 OSNs. Finally, the ideal OSNs were identified that optimized network performance. The results obtained from this study provide strong evidence of the usefulness of ANNs in the field of olfaction for the future realization of a signal processing back end for an artificial olfactory biosensor.

  13. C. elegans bicd-1, homolog of the Drosophila dynein accessory factor Bicaudal D, regulates the branching of PVD sensory neuron dendrites.

    Science.gov (United States)

    Aguirre-Chen, Cristina; Bülow, Hannes E; Kaprielian, Zaven

    2011-02-01

    The establishment of cell type-specific dendritic arborization patterns is a key phase in the assembly of neuronal circuitry that facilitates the integration and processing of synaptic and sensory input. Although studies in Drosophila and vertebrate systems have identified a variety of factors that regulate dendrite branch formation, the molecular mechanisms that control this process remain poorly defined. Here, we introduce the use of the Caenorhabditis elegans PVD neurons, a pair of putative nociceptors that elaborate complex dendritic arbors, as a tractable model for conducting high-throughput RNAi screens aimed at identifying key regulators of dendritic branch formation. By carrying out two separate RNAi screens, a small-scale candidate-based screen and a large-scale screen of the ~3000 genes on chromosome IV, we retrieved 11 genes that either promote or suppress the formation of PVD-associated dendrites. We present a detailed functional characterization of one of the genes, bicd-1, which encodes a microtubule-associated protein previously shown to modulate the transport of mRNAs and organelles in a variety of organisms. Specifically, we describe a novel role for bicd-1 in regulating dendrite branch formation and show that bicd-1 is likely to be expressed, and primarily required, in PVD neurons to control dendritic branching. We also present evidence that bicd-1 operates in a conserved pathway with dhc-1 and unc-116, components of the dynein minus-end-directed and kinesin-1 plus-end-directed microtubule-based motor complexes, respectively, and interacts genetically with the repulsive guidance receptor unc-5.

  14. Sea-anemone toxin ATX-II elicits A-fiber-dependent pain and enhances resurgent and persistent sodium currents in large sensory neurons

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    Klinger Alexandra B

    2012-09-01

    Full Text Available Abstract Background Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD. One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium currents. It is long known that toxins from Anemonia sulcata, such as ATX-II, slow fast inactivation and skin contact for example during diving leads to various symptoms such as pain and itch. Here, we investigated if ATX-II induces resurgent currents in sensory neurons of the dorsal root ganglion (DRGs and how this may translate into human sensations. Results In large A-fiber related DRGs ATX-II (5 nM enhances persistent and resurgent sodium currents, but failed to do so in small C-fiber linked DRGs when investigated using the whole-cell patch-clamp technique. Resurgent currents are thought to depend on the presence of the sodium channel β4-subunit. Using RT-qPCR experiments, we show that small DRGs express significantly less β4 mRNA than large sensory neurons. With the β4-C-terminus peptide in the pipette solution, it was possible to evoke resurgent currents in small DRGs and in Nav1.7 or Nav1.6 expressing HEK293/N1E115 cells, which were enhanced by the presence of extracellular ATX-II. When injected into the skin of healthy volunteers, ATX-II induces painful and itch-like sensations which were abolished by mechanical nerve block. Increase in superficial blood flow of the skin, measured by Laser doppler imaging is limited to the injection site, so no axon reflex erythema as a correlate for C-fiber activation was detected. Conclusion ATX-II enhances persistent and resurgent sodium currents in large diameter DRGs, whereas small DRGs depend on the addition of β4-peptide to the pipette recording solution for ATX-II to affect resurgent currents. Mechanical A-fiber blockade abolishes all ATX-II effects in human skin (e.g. painful and itch

  15. Sea-anemone toxin ATX-II elicits A-fiber-dependent pain and enhances resurgent and persistent sodium currents in large sensory neurons.

    Science.gov (United States)

    Klinger, Alexandra B; Eberhardt, Mirjam; Link, Andrea S; Namer, Barbara; Kutsche, Lisa K; Schuy, E Theresa; Sittl, Ruth; Hoffmann, Tali; Alzheimer, Christian; Huth, Tobias; Carr, Richard W; Lampert, Angelika

    2012-09-15

    Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD). One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium currents. It is long known that toxins from Anemonia sulcata, such as ATX-II, slow fast inactivation and skin contact for example during diving leads to various symptoms such as pain and itch. Here, we investigated if ATX-II induces resurgent currents in sensory neurons of the dorsal root ganglion (DRGs) and how this may translate into human sensations. In large A-fiber related DRGs ATX-II (5 nM) enhances persistent and resurgent sodium currents, but failed to do so in small C-fiber linked DRGs when investigated using the whole-cell patch-clamp technique. Resurgent currents are thought to depend on the presence of the sodium channel β4-subunit. Using RT-qPCR experiments, we show that small DRGs express significantly less β4 mRNA than large sensory neurons. With the β4-C-terminus peptide in the pipette solution, it was possible to evoke resurgent currents in small DRGs and in Nav1.7 or Nav1.6 expressing HEK293/N1E115 cells, which were enhanced by the presence of extracellular ATX-II. When injected into the skin of healthy volunteers, ATX-II induces painful and itch-like sensations which were abolished by mechanical nerve block. Increase in superficial blood flow of the skin, measured by Laser doppler imaging is limited to the injection site, so no axon reflex erythema as a correlate for C-fiber activation was detected. ATX-II enhances persistent and resurgent sodium currents in large diameter DRGs, whereas small DRGs depend on the addition of β4-peptide to the pipette recording solution for ATX-II to affect resurgent currents. Mechanical A-fiber blockade abolishes all ATX-II effects in human skin (e.g. painful and itch-like paraesthesias), suggesting that it mediates its effects mainly

  16. Presynaptic molecular determinants of quantal size

    Directory of Open Access Journals (Sweden)

    Shigeo eTakamori

    2016-02-01

    Full Text Available The quantal hypothesis for the release of neurotransmitters at the chemical synapse has gained wide acceptance since it was first worked out at the motor endplate in frog skeletal muscle in the 1950s. Considering the morphological identification of synaptic vesicles at the nerve terminals that appeared to be homogeneous in size, the hypothesis proposed that signal transduction at synapses is mediated by the release of neurotransmitters packed in synaptic vesicles that are individually uniform in size; the amount of transmitter in a synaptic vesicle is called a quantum. Although quantal size – the amplitude of the postsynaptic response elicited by the release of neurotransmitters from a single vesicle – clearly depends on the number and sensitivity of the postsynaptic receptors, accumulating evidence has also indicated that the amount of neurotransmitters stored in synaptic vesicles can be altered by various presynaptic factors. Here, I provide an overview of the concepts and underlying presynaptic molecular underpinnings that may regulate quantal size.

  17. Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity

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    Agnes Thalhammer

    2017-07-01

    Full Text Available Alternative splicing of pre-mRNAs is prominent in the mammalian brain, where it is thought to expand proteome diversity. For example, alternative splicing of voltage-gated Ca2+ channel (VGCC α1 subunits can generate thousands of isoforms with differential properties and expression patterns. However, the impact of this molecular diversity on brain function, particularly on synaptic transmission, which crucially depends on VGCCs, is unclear. Here, we investigate how two major splice isoforms of P/Q-type VGCCs (Cav2.1[EFa/b] regulate presynaptic plasticity in hippocampal neurons. We find that the efficacy of P/Q-type VGCC isoforms in supporting synaptic transmission is markedly different, with Cav2.1[EFa] promoting synaptic depression and Cav2.1[EFb] synaptic facilitation. Following a reduction in network activity, hippocampal neurons upregulate selectively Cav2.1[EFa], the isoform exhibiting the higher synaptic efficacy, thus effectively supporting presynaptic homeostatic plasticity. Therefore, the balance between VGCC splice variants at the synapse is a key factor in controlling neurotransmitter release and presynaptic plasticity.

  18. Monitoring single-synapse glutamate release and presynaptic calcium concentration in organised brain tissue.

    Science.gov (United States)

    Jensen, Thomas P; Zheng, Kaiyu; Tyurikova, Olga; Reynolds, James P; Rusakov, Dmitri A

    2017-06-01

    Brain function relies in large part on Ca 2+ -dependent release of the excitatory neurotransmitter glutamate from neuronal axons. Establishing the causal relationship between presynaptic Ca 2+ dynamics and probabilistic glutamate release is therefore a fundamental quest across neurosciences. Its progress, however, has hitherto depended primarily on the exploration of either cultured nerve cells or giant central synapses accessible to direct experimental probing in situ. Here we show that combining patch-clamp with time-resolved imaging of Ca 2+ -sensitive fluorescence lifetime of Oregon Green BAPTA-1 (Tornado-FLIM) enables readout of single spike-evoked presynaptic Ca 2+ concentration dynamics, with nanomolar sensitivity, in individual neuronal axons in acute brain slices. In parallel, intensity Tornado imaging of a locally expressed extracellular optical glutamate sensor iGluSnFr provides direct monitoring of single-quantum, single-synapse glutamate releases in situ. These two methods pave the way for simultaneous registration of presynaptic Ca 2+ dynamics and transmitter release in an intact brain at the level of individual synapses. Copyright © 2017. Published by Elsevier Ltd.

  19. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

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    Katharine L. Dobson

    2015-01-01

    Full Text Available In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

  20. Presynaptic adenosine receptor-mediated regulation of diverse thalamocortical short-term plasticity in the mouse whisker pathway

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    Giovanni eFerrati

    2016-02-01

    Full Text Available Short-term synaptic plasticity (STP sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In driver thalamocortical (TC synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors, modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release.

  1. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway.

    Science.gov (United States)

    Quiroz, César; Luján, Rafael; Uchigashima, Motokazu; Simoes, Ana Patrícia; Lerner, Talia N; Borycz, Janusz; Kachroo, Anil; Canas, Paula M; Orru, Marco; Schwarzschild, Michael A; Rosin, Diane L; Kreitzer, Anatol C; Cunha, Rodrigo A; Watanabe, Masahiko; Ferré, Sergi

    2009-11-18

    Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  2. Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

    Directory of Open Access Journals (Sweden)

    César Quiroz

    2009-01-01

    Full Text Available Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  3. The presynaptic machinery at the synapse of C. elegans.

    Science.gov (United States)

    Calahorro, Fernando; Izquierdo, Patricia G

    2018-03-12

    Synapses are specialized contact sites that mediate information flow between neurons and their targets. Important physical interactions across the synapse are mediated by synaptic adhesion molecules. These adhesions regulate formation of synapses during development and play a role during mature synaptic function. Importantly, genes regulating synaptogenesis and axon regeneration are conserved across the animal phyla. Genetic screens in the nematode Caenorhabditis elegans have identified a number of molecules required for synapse patterning and assembly. C. elegans is able to survive even with its neuronal function severely compromised. This is in comparison with Drosophila and mice where increased complexity makes them less tolerant to impaired function. Although this fact may reflect differences in the function of the homologous proteins in the synapses between these organisms, the most likely interpretation is that many of these components are equally important, but not absolutely essential, for synaptic transmission to support the relatively undemanding life style of laboratory maintained C. elegans. Here, we review research on the major group of synaptic proteins, involved in the presynaptic machinery in C. elegans, showing a strong conservation between higher organisms and highlight how C. elegans can be used as an informative tool for dissecting synaptic components, based on a simple nervous system organization.

  4. Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

    Science.gov (United States)

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-01-01

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

  5. Effect of superficial radial nerve stimulation on the activity of nigro-striatal dopaminergic neurons in the cat: role of cutaneous sensory input

    International Nuclear Information System (INIS)

    Nieoullon, A.; Dusticier, N.

    1982-01-01

    The release of 3 H-dopamine (DA) continuously synthesized from 3 H-thyrosine was measured in the caudate nucleus (CN) and in the substantia nigra (SN) in both sides of the brain during electrical stimulation of the superficial radial nerve in cats lightly anaesthetized with halothane. Use of appropriate electrophysiologically controlled stimulation led to selective activation of low threshold afferent fibers whereas high stimulation activated all cutaneous afferents. Results showed that low threshold fiber activation induced a decreased dopaminergic activity in CN contralateral to nerve stimulation and a concomitant increase in dopaminergic activity on the ipsilateral side. Stimulation of group I and threshold stimulation of group II afferent fibers induced changes in the release of 3 H-DA mainly on the contralateral CN and SN and in the ipsilateral CN. High stimulation was followed by a general increase of the neurotransmitter release in the four structures. This shows that the nigro-striatal dopaminergic neurons are mainly-if not exclusively-controlled by cutaneous sensory inputs. This control, non-specific when high threshold cutaneous fibers are also activated. Such activations could contribute to restablish sufficient release of DA when the dopaminergic function is impaired as in Parkinson's disease. (Author)

  6. 17β-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception.

    Science.gov (United States)

    Qu, Zu-Wei; Liu, Ting-Ting; Ren, Cuixia; Gan, Xiong; Qiu, Chun-Yu; Ren, Ping; Rao, Zhiguo; Hu, Wang-Ping

    2015-12-01

    Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17β-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.

  7. Quantal analysis reveals a functional correlation between presynaptic and postsynaptic efficacy in excitatory connections from rat neocortex.

    Science.gov (United States)

    Hardingham, Neil R; Read, Jenny C A; Trevelyan, Andrew J; Nelson, J Charmaine; Jack, J Julian B; Bannister, Neil J

    2010-01-27

    At many central synapses, the presynaptic bouton and postsynaptic density are structurally correlated. However, it is unknown whether this correlation extends to the functional properties of the synapses. To investigate this, we made recordings from synaptically coupled pairs of pyramidal neurons in rat visual cortex. The mean peak amplitude of EPSPs recorded from pairs of L2/3 neurons ranged between 40 microV and 2.9 mV. EPSP rise times were consistent with the majority of the synapses being located on basal dendrites; this was confirmed by full anatomical reconstructions of a subset of connected pairs. Over a third of the connections could be described using a quantal model that assumed simple binomial statistics. Release probability (P(r)) and quantal size (Q), as measured at the somatic recording site, showed considerable heterogeneity between connections. However, across the population of connections, values of P(r) and Q for individual connections were positively correlated with one another. This correlation also held for inputs to layer 5 pyramidal neurons from both layer 2/3 and neighboring layer 5 pyramidal neurons, suggesting that during development of cortical connections presynaptic and postsynaptic strengths are dependently scaled. For 2/3 to 2/3 connections, mean EPSP amplitude was correlated with both Q and P(r) values but uncorrelated with N, the number of functional release sites mediating the connection. The efficacy of a cortical connection is thus set by coordinated presynaptic and postsynaptic strength.

  8. Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx

    OpenAIRE

    Qian, Jing; Saggau, Peter

    1997-01-01

    Modulation of presynaptic voltage-dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura-2. Stimulation-evoked presynaptic calcium transients ([Capre]t) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied.Activation of muscarinic receptors inhibited [Capre]t, thereb...

  9. Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila

    Science.gov (United States)

    Nässel, Dick R.

    2018-01-01

    It has been known for more than 40 years that individual neurons can produce more than one neurotransmitter and that neuropeptides often are colocalized with small molecule neurotransmitters (SMNs). Over the years much progress has been made in understanding the functional consequences of cotransmission in the nervous system of mammals. There are also some excellent invertebrate models that have revealed roles of coexpressed neuropeptides and SMNs in increasing complexity, flexibility, and dynamics in neuronal signaling. However, for the fly Drosophila there are surprisingly few functional studies on cotransmission, although there is ample evidence for colocalization of neuroactive compounds in neurons of the CNS, based both on traditional techniques and novel single cell transcriptome analysis. With the hope to trigger interest in initiating cotransmission studies, this review summarizes what is known about Drosophila neurons and neuronal circuits where different neuropeptides and SMNs are colocalized. Coexistence of neuroactive substances has been recorded in different neuron types such as neuroendocrine cells, interneurons, sensory cells and motor neurons. Some of the circuits highlighted here are well established in the analysis of learning and memory, circadian clock networks regulating rhythmic activity and sleep, as well as neurons and neuroendocrine cells regulating olfaction, nociception, feeding, metabolic homeostasis, diuretic functions, reproduction, and developmental processes. One emerging trait is the broad role of short neuropeptide F in cotransmission and presynaptic facilitation in a number of different neuronal circuits. This review also discusses the functional relevance of coexisting peptides in the intestine. Based on recent single cell transcriptomics data, it is likely that the neuronal systems discussed in this review are just a fraction of the total set of circuits where cotransmission occurs in Drosophila. Thus, a systematic search for

  10. Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila

    Directory of Open Access Journals (Sweden)

    Dick R. Nässel

    2018-03-01

    Full Text Available It has been known for more than 40 years that individual neurons can produce more than one neurotransmitter and that neuropeptides often are colocalized with small molecule neurotransmitters (SMNs. Over the years much progress has been made in understanding the functional consequences of cotransmission in the nervous system of mammals. There are also some excellent invertebrate models that have revealed roles of coexpressed neuropeptides and SMNs in increasing complexity, flexibility, and dynamics in neuronal signaling. However, for the fly Drosophila there are surprisingly few functional studies on cotransmission, although there is ample evidence for colocalization of neuroactive compounds in neurons of the CNS, based both on traditional techniques and novel single cell transcriptome analysis. With the hope to trigger interest in initiating cotransmission studies, this review summarizes what is known about Drosophila neurons and neuronal circuits where different neuropeptides and SMNs are colocalized. Coexistence of neuroactive substances has been recorded in different neuron types such as neuroendocrine cells, interneurons, sensory cells and motor neurons. Some of the circuits highlighted here are well established in the analysis of learning and memory, circadian clock networks regulating rhythmic activity and sleep, as well as neurons and neuroendocrine cells regulating olfaction, nociception, feeding, metabolic homeostasis, diuretic functions, reproduction, and developmental processes. One emerging trait is the broad role of short neuropeptide F in cotransmission and presynaptic facilitation in a number of different neuronal circuits. This review also discusses the functional relevance of coexisting peptides in the intestine. Based on recent single cell transcriptomics data, it is likely that the neuronal systems discussed in this review are just a fraction of the total set of circuits where cotransmission occurs in Drosophila. Thus, a

  11. Octopamine regulates antennal sensory neurons via daytime-dependent changes in cAMP and IP3 levels in the hawkmoth Manduca sexta.

    Directory of Open Access Journals (Sweden)

    Thomas Schendzielorz

    Full Text Available The biogenic amine octopamine (OA mediates reward signals in olfactory learning and memory as well as circadian rhythms of sleep and activity. In the crepuscular hawkmoth Manduca sexta, OA changed pheromone detection thresholds daytime-dependently, suggesting that OA confers circadian control of olfactory transduction. Thus, with enzyme-linked immunosorbent assays we searched hawkmoth antennae for daytime-dependent changes in the concentration of OA and its respective second messengers. Antennal stimulation with OA raised cAMP- and IP3 levels. Furthermore, antennae expressed daytime-dependent changes in the concentration of OA, with maxima at Zeitgebertime (ZT 20 when moths were active and also maximal concentrations of cAMP occurred. Maximal IP3 levels at ZT 18 and 23 correlated with maximal flight activity of male moths, while minimal IP3 levels at dusk correlated with peaks of feeding activity. Half maximal effective concentration (EC50 for activation of the OA-receptor decreased during the moth's activity phase suggesting daytime-dependent changes in OA receptor sensitivity. With an antiserum against tyramine, the precursor of OA, two centrifugal neurons were detected projecting out into the sensory cell layer of the antenna, possibly mediating more rapid stimulus-dependent OA actions. Indeed, in fast kinetic assays OA receptor stimulation increased cAMP concentrations within 50 msec. Thus, we hypothesize that fast, stimulus-dependent centrifugal control of OA-release in the antenna occurs. Additional slow systemic OA actions might be based upon circadian release of OA into the hemolymph mediating circadian rhythms of antennal second messenger levels. The resulting rhythms of odor sensitivity are suggested to underlie circadian rhythms in odor-mediated behavior.

  12. Chemostimuli for guanylyl cyclase-D-expressing olfactory sensory neurons promote the acquisition of preferences for foods adulterated with the rodenticide warfarin

    Directory of Open Access Journals (Sweden)

    Kevin Robert Kelliher

    2015-07-01

    Full Text Available Many animals have the ability to acquire food preferences from conspecifics via social signals. For example, the coincident detection of a food odor by canonical olfactory sensory neurons (OSNs and agonists of the specialized OSNs expressing the receptor guanylyl cyclase GC-D (GC-D+ OSNs will promote a preference in recipient rodents for similarly odored foods. It has been hypothesized that these preferences are acquired and maintained regardless of the palatability or quality of the food. We assessed whether mice could acquire and maintain preferences for food that had been adulterated with the anticoagulant rodenticide warfarin. After olfactory investigation of a saline droplet containing either cocoa (2%, w/w or cinnamon (1%, w/w along with a GC-D+ OSN-specific chemostimulus (either of the guanylin-family peptides uroguanylin and guanylin; 1–50 nM, C57BL/6J mice exhibited robust preferences for unadulterated food containing the demonstrated odor. The peptide-dependent preference was observed even when the food contained warfarin (0.025% w/w. Repeated ingestion of warfarin-containing food over four days did not disrupt the preference, even though mice were not re-exposed to the peptide stimulus. Surprisingly, mice continued to prefer warfarin-adulterated food containing the demonstrated odor when presented with a choice of warfarin-free food containing a novel odor. Our results indicate that olfactory-mediated food preferences can be acquired and maintained for warfarin-containing foods and suggest that guanylin peptides may be effective stimuli for promoting the ingestion of foods or other edibles with low palatability or potential toxicity.

  13. Action potential broadening in a presynaptic channelopathy

    Science.gov (United States)

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-07-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  14. Local synthesis of nuclear-encoded mitochondrial proteins in the presynaptic nerve terminal.

    Science.gov (United States)

    Gioio, A E; Eyman, M; Zhang, H; Lavina, Z S; Giuditta, A; Kaplan, B B

    2001-06-01

    One of the central tenets in neuroscience has been that the protein constituents of distal compartments of the neuron (e.g., the axon and nerve terminal) are synthesized in the nerve cell body and are subsequently transported to their ultimate sites of function. In contrast to this postulate, we have established previously that a heterogeneous population of mRNAs and biologically active polyribosomes exist in the giant axon and presynaptic nerve terminals of the photoreceptor neurons in squid. We report that these mRNA populations contain mRNAs for nuclear-encoded mitochondrial proteins to include: cytochrome oxidase subunit 17, propionyl-CoA carboxylase (EC 6.4.1.3), dihydrolipoamide dehydrogenase (EC 1.8.1.4), and coenzyme Q subunit 7. The mRNA for heat shock protein 70, a chaperone protein known to be involved in the import of proteins into mitochondria, has also been identified. Electrophoretic gel analysis of newly synthesized proteins in the synaptosomal fraction isolated from the squid optic lobe revealed that the large presynaptic terminals of the photoreceptor neuron contain a cytoplasmic protein synthetic system. Importantly, a significant amount of the cycloheximide resistant proteins locally synthesized in the terminal becomes associated with mitochondria. PCR analysis of RNA from synaptosomal polysomes establishes that COX17 and CoQ7 mRNAs are being actively translated. Taken together, these findings indicate that proteins required for the maintenance of mitochondrial function are synthesized locally in the presynaptic nerve terminal, and call attention to the intimacy of the relationship between the terminal and its energy generating system. J. Neurosci. Res. 64:447-453, 2001. Published 2001 Wiley-Liss, Inc.

  15. Optogenetic probing and manipulation of the calyx-type presynaptic terminal in the embryonic chick ciliary ganglion.

    Science.gov (United States)

    Egawa, Ryo; Hososhima, Shoko; Hou, Xubin; Katow, Hidetaka; Ishizuka, Toru; Nakamura, Harukazu; Yawo, Hiromu

    2013-01-01

    The calyx-type synapse of chick ciliary ganglion (CG) has been intensively studied for decades as a model system for the synaptic development, morphology and physiology. Despite recent advances in optogenetics probing and/or manipulation of the elementary steps of the transmitter release such as membrane depolarization and Ca(2+) elevation, the current gene-manipulating methods are not suitable for targeting specifically the calyx-type presynaptic terminals. Here, we evaluated a method for manipulating the molecular and functional organization of the presynaptic terminals of this model synapse. We transfected progenitors of the Edinger-Westphal (EW) nucleus neurons with an EGFP expression vector by in ovo electroporation at embryonic day 2 (E2) and examined the CG at E8-14. We found that dozens of the calyx-type presynaptic terminals and axons were selectively labeled with EGFP fluorescence. When a Brainbow construct containing the membrane-tethered fluorescent proteins m-CFP, m-YFP and m-RFP, was introduced together with a Cre expression construct, the color coding of each presynaptic axon facilitated discrimination among inter-tangled projections, particularly during the developmental re-organization period of synaptic connections. With the simultaneous expression of one of the chimeric variants of channelrhodopsins, channelrhodopsin-fast receiver (ChRFR), and R-GECO1, a red-shifted fluorescent Ca(2+)-sensor, the Ca(2+) elevation was optically measured under direct photostimulation of the presynaptic terminal. Although this optically evoked Ca(2+) elevation was mostly dependent on the action potential, a significant component remained even in the absence of extracellular Ca(2+). It is suggested that the photo-activation of ChRFR facilitated the release of Ca(2+) from intracellular Ca(2+) stores directly or indirectly. The above system, by facilitating the molecular study of the calyx-type presynaptic terminal, would provide an experimental platform for unveiling

  16. Optogenetic probing and manipulation of the calyx-type presynaptic terminal in the embryonic chick ciliary ganglion.

    Directory of Open Access Journals (Sweden)

    Ryo Egawa

    Full Text Available The calyx-type synapse of chick ciliary ganglion (CG has been intensively studied for decades as a model system for the synaptic development, morphology and physiology. Despite recent advances in optogenetics probing and/or manipulation of the elementary steps of the transmitter release such as membrane depolarization and Ca(2+ elevation, the current gene-manipulating methods are not suitable for targeting specifically the calyx-type presynaptic terminals. Here, we evaluated a method for manipulating the molecular and functional organization of the presynaptic terminals of this model synapse. We transfected progenitors of the Edinger-Westphal (EW nucleus neurons with an EGFP expression vector by in ovo electroporation at embryonic day 2 (E2 and examined the CG at E8-14. We found that dozens of the calyx-type presynaptic terminals and axons were selectively labeled with EGFP fluorescence. When a Brainbow construct containing the membrane-tethered fluorescent proteins m-CFP, m-YFP and m-RFP, was introduced together with a Cre expression construct, the color coding of each presynaptic axon facilitated discrimination among inter-tangled projections, particularly during the developmental re-organization period of synaptic connections. With the simultaneous expression of one of the chimeric variants of channelrhodopsins, channelrhodopsin-fast receiver (ChRFR, and R-GECO1, a red-shifted fluorescent Ca(2+-sensor, the Ca(2+ elevation was optically measured under direct photostimulation of the presynaptic terminal. Although this optically evoked Ca(2+ elevation was mostly dependent on the action potential, a significant component remained even in the absence of extracellular Ca(2+. It is suggested that the photo-activation of ChRFR facilitated the release of Ca(2+ from intracellular Ca(2+ stores directly or indirectly. The above system, by facilitating the molecular study of the calyx-type presynaptic terminal, would provide an experimental platform for

  17. Cervical vagus nerve stimulation augments spontaneous discharge in second- and higher-order sensory neurons in the rat nucleus of the solitary tract.

    Science.gov (United States)

    Beaumont, Eric; Campbell, Regenia P; Andresen, Michael C; Scofield, Stephanie; Singh, Krishna; Libbus, Imad; KenKnight, Bruce H; Snyder, Logan; Cantrell, Nathan

    2017-08-01

    Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insensitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. NEW & NOTEWORTHY Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents

  18. A single GABAergic neuron mediates feedback of odor-evoked signals in the mushroom body of larval Drosophila

    Directory of Open Access Journals (Sweden)

    Liria Monica Masuda-Nakagawa

    2014-04-01

    Full Text Available Inhibition has a central role in defining the selectivity of the responses of higher order neurons to sensory stimuli. However, the circuit mechanisms of regulation of these responses by inhibitory neurons are still unclear. In Drosophila, the mushroom bodies (MBs are necessary for olfactory memory, and by implication for the selectivity of learned responses to specific odors. To understand the circuitry of inhibition in the calyx (the input dendritic region of the MBs, and its relationship with MB excitatory activity, we used the simple anatomy of the Drosophila larval olfactory system to identify any inhibitory inputs that could contribute to the selectivity of MB odor responses. We found that a single neuron accounts for all detectable GABA innervation in the calyx of the MBs, and that this neuron has presynaptic terminals in the calyx and postsynaptic branches in the MB lobes (output axonal area. We call this neuron the larval anterior paired lateral (APL neuron, because of its similarity to the previously described adult APL neuron. Reconstitution of GFP partners (GRASP suggests that the larval APL makes extensive contacts with the MB intrinsic neurons, Kenyon Cells (KCs, but few contacts with incoming projection neurons. Using calcium imaging of neuronal activity in live larvae, we show that the larval APL responds to odors, in a mannner that requires output from KCs. Our data suggest that the larval APL is the sole GABAergic neuron that innervates the MB input region and carries inhibitory feedback from the MB output region, consistent with a role in modulating the olfactory selectivity of MB neurons.

  19. PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

    Science.gov (United States)

    España, Rodrigo A.; Jones, Sara R.

    2013-01-01

    The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

  20. Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a.

    Science.gov (United States)

    Wang, Tong; Martin, Sally; Papadopulos, Andreas; Harper, Callista B; Mavlyutov, Timur A; Niranjan, Dhevahi; Glass, Nick R; Cooper-White, Justin J; Sibarita, Jean-Baptiste; Choquet, Daniel; Davletov, Bazbek; Meunier, Frédéric A

    2015-04-15

    Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity. Copyright © 2015 the authors 0270-6474/15/356179-16$15.00/0.

  1. Presynaptic control of group Ia afferents in relation to acquisition of a visuo-motor skill in healthy humans

    DEFF Research Database (Denmark)

    Perez, Monica A.; Lungholt, Bjarke K.S.; Nielsen, Jens Bo

    2005-01-01

    Sensory information continuously converges on the spinal cord during a variety of motor behaviours. Here, we examined presynaptic control of group Ia afferents in relation to acquisition of a novel motor skill. We tested whether repetition of two motor tasks with different degrees of difficulty...... of the monosynaptic Ia facilitation of the soleus H-reflex evoked by femoral nerve stimulation. The D1 inhibition was increased and the femoral nerve facilitation was decreased following the visuo-motor skill task, suggesting an increase in presynaptic inhibition of Ia afferents. No changes were observed...... in the disynaptic reciprocal Ia inhibition. Somatosensory evoked potentials (SEPs) evoked by stimulation of the tibial nerve (TN) were also unchanged, suggesting that transmission in ascending pathways was unaltered following the visuo-motor skill task. Together these observations suggest that a selective...

  2. Protein synthesis in presynaptic endings from squid brain: modulation by calcium ions.

    Science.gov (United States)

    Benech, J C; Crispino, M; Kaplan, B B; Giuditta, A

    1999-03-15

    Previous biochemical, autoradiographic, and ultrastructural data have shown that, in the synaptosomal fraction of the squid optic lobe, protein synthesis is largely due to the presynaptic terminals of the retinal photoreceptor neurons (Crispino et al. [1993a] Mol. Cell. Neurosci. 4:366-374; Crispino et al. [1993b] J. Neurochem. 61:1144-1146; Crispino et al. [1997] J. Neurosci. 17:7694-7702). We now report that this process is close to its maximum at the basal concentration of cytosolic Ca++, and is markedly inhibited when the concentration of this ion is either decreased or increased. This conclusion is supported by the results of experiments with: 1) compounds known to increase the level of cytosolic Ca++, such as A23187, ionomycin, thapsigargin, and caffeine; 2) compounds sequestering cytosolic calcium ions such as BAPTA-AM; and 3) agents that block the role of Ca++ as second messenger, such as TFP and W7, which inhibit calmodulin, and calphostin, which inhibits protein kinase C. We conclude that variations in the level of cytosolic Ca++ induced in presynaptic terminals by neuronal activity may contribute to the modulation of the local synthesis of protein.

  3. Presynaptic GABAB Receptors Regulate Hippocampal Synapses during Associative Learning in Behaving Mice.

    Directory of Open Access Journals (Sweden)

    M Teresa Jurado-Parras

    Full Text Available GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the central nervous system. Pharmacological activation of GABAB receptors regulates neurotransmission and neuronal excitability at pre- and postsynaptic sites. Electrophysiological activation of GABAB receptors in brain slices generally requires strong stimulus intensities. This raises the question as to whether behavioral stimuli are strong enough to activate GABAB receptors. Here we show that GABAB1a-/- mice, which constitutively lack presynaptic GABAB receptors at glutamatergic synapses, are impaired in their ability to acquire an operant learning task. In vivo recordings during the operant conditioning reveal a deficit in learning-dependent increases in synaptic strength at CA3-CA1 synapses. Moreover, GABAB1a-/- mice fail to synchronize neuronal activity in the CA1 area during the acquisition process. Our results support that activation of presynaptic hippocampal GABAB receptors is important for acquisition of a learning task and for learning-associated synaptic changes and network dynamics.

  4. Changes in presynaptic release, but not reuptake, of bioamines induced by long-term antidepressant treatment

    International Nuclear Information System (INIS)

    Dolzhenko, A.T.; Komissarov, I.V.

    1986-01-01

    This paper describes an investigation into the effect of long-term administration of antidepressants on neuronal uptake of NA and 5-HT and on their release, induced by electrical stimulation, in rat brain slices. The effects of the test substances on neuronal uptake of 14 C-NA and 3 H-5-HT by the slices was investigated. Values of IC 50 and EC 2 were found and compared in the experiments and control. The inhibitory effect of clonidine (10 -4 M) and of 5-HT (10 -5 M) on presynaptic release of 14 C-NA and 3 H-5-HT also was studied in brain slices from intact rats and rats treated for two weeks with antidepressants

  5. Contribution of large-sized primary sensory neuronal sensitization to mechanical allodynia by upregulation of hyperpolarization-activated cyclic nucleotide gated channels via cyclooxygenase 1 cascade.

    Science.gov (United States)

    Sun, Wei; Yang, Fei; Wang, Yan; Fu, Han; Yang, Yan; Li, Chun-Li; Wang, Xiao-Liang; Lin, Qing; Chen, Jun

    2017-02-01

    Under physiological state, small- and medium-sized dorsal root ganglia (DRG) neurons are believed to mediate nociceptive behavioral responses to painful stimuli. However, recently it has been found that a number of large-sized neurons are also involved in nociceptive transmission under neuropathic conditions. Nonetheless, the underlying mechanisms that large-sized DRG neurons mediate nociception are poorly understood. In the present study, the role of large-sized neurons in bee venom (BV)-induced mechanical allodynia and the underlying mechanisms were investigated. Behaviorally, it was found that mechanical allodynia was still evoked by BV injection in rats in which the transient receptor potential vanilloid 1-positive DRG neurons were chemically deleted. Electrophysiologically, in vitro patch clamp recordings of large-sized neurons showed hyperexcitability in these neurons. Interestingly, the firing pattern of these neurons was changed from phasic to tonic under BV-inflamed state. It has been suggested that hyperpolarization-activated cyclic nucleotide gated channels (HCN) expressed in large-sized DRG neurons contribute importantly to repeatedly firing. So we examined the roles of HCNs in BV-induced mechanical allodynia. Consistent with the overexpression of HCN1/2 detected by immunofluorescence, HCNs-mediated hyperpolarization activated cation current (I h ) was significantly increased in the BV treated samples. Pharmacological experiments demonstrated that the hyperexcitability and upregulation of I h in large-sized neurons were mediated by cyclooxygenase-1 (COX-1)-prostaglandin E2 pathway. This is evident by the fact that the COX-1 inhibitor significantly attenuated the BV-induced mechanical allodynia. These results suggest that BV can excite the large-sized DRG neurons at least in part by increasing I h through activation of COX-1. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. A POSTSYNAPTIC ROLE FOR SHORT-TERM NEURONAL FACILITATION IN DENDRITIC SPINES

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    Sunggu Yang

    2016-09-01

    Full Text Available Synaptic plasticity is a fundamental component of information processing in the brain. Presynaptic facilitation in response to repetitive stimuli, often referred to as paired-pulse facilitation (PPF, is a dominant form of short-term synaptic plasticity. Recently, an additional cellular mechanism for short-term facilitation (short-term postsynaptic plasticity has been proposed. While a dendritic mechanism was described in hippocampus, its expression has not yet been demonstrated at the levels of the spine. Furthermore, it is unknown whether the mechanism can be expressed in other brain regions, such as sensory cortex. Here, we demonstrated that a postsynaptic response can be facilitated by prior spine excitation in both hippocampal and cortical neurons, using 3D digital holography and two-photon calcium imaging. The coordinated action of pre- and post-synaptic plasticity may provide a more thorough account of information processing in the brain.

  7. Reduced sensory stimulation alters the molecular make-up of glutamatergic hair cell synapses in the developing cochlea.

    Science.gov (United States)

    Barclay, M; Constable, R; James, N R; Thorne, P R; Montgomery, J M

    2016-06-14

    Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. Auditory brainstem responses at P15 and P21 showed a 40-50-dB increase in thresholds for frequencies 8-32kHz in the dislocated ear relative to the control ear. Immunohistochemistry and confocal microscopy were subsequently used to examine the effect of this attenuation of sound stimulation on the expression of RIBEYE, which comprises the presynaptic ribbons, Shank-1, a postsynaptic scaffolding protein, and the GluA2/3 and 4 subunits of postsynaptic AMPA receptors. Our results show that dislocation did not alter the number of pre- or postsynaptic protein puncta. However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. A Computational Model Based on Multi-Regional Calcium Imaging Represents the Spatio-Temporal Dynamics in a Caenorhabditis elegans Sensory Neuron.

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    Masahiro Kuramochi

    Full Text Available Due to the huge number of neuronal cells in the brain and their complex circuit formation, computer simulation of neuronal activity is indispensable to understanding whole brain dynamics. Recently, various computational models have been developed based on whole-brain calcium imaging data. However, these analyses monitor only the activity of neuronal cell bodies and treat the cells as point unit. This point-neuron model is inexpensive in computational costs, but the model is unrealistically simplistic at representing intact neural activities in the brain. Here, we describe a novel three-unit Ordinary Differential Equation (ODE model based on the neuronal responses derived from a Caenorhabditis elegans salt-sensing neuron. We recorded calcium responses in three regions of the ASER neuron using a simple downstep of NaCl concentration. Our simple ODE model generated from a single recording can adequately reproduce and predict the temporal responses of each part of the neuron to various types of NaCl concentration changes. Our strategy which combines a simple recording data and an ODE mathematical model may be extended to realistically understand whole brain dynamics by computational simulation.

  9. The structure and function of presynaptic endosomes

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    Jähne, Sebastian, E-mail: sebastian.jaehne1@stud.uni-goettingen.de [Department of Neuro- and Sensory Physiology, University of Göttingen Medical Center, Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, Humboldtallee 23, 37073 Göttingen (Germany); International Max Planck Research School for Neurosciences, 37077 Göttingen (Germany); Rizzoli, Silvio O. [Department of Neuro- and Sensory Physiology, University of Göttingen Medical Center, Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, Humboldtallee 23, 37073 Göttingen (Germany); Helm, Martin S., E-mail: martin.helm@med.uni-goettingen.de [Department of Neuro- and Sensory Physiology, University of Göttingen Medical Center, Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, Humboldtallee 23, 37073 Göttingen (Germany); International Max Planck Research School for Molecular Biology, 37077 Göttingen (Germany)

    2015-07-15

    The function of endosomes and of endosome-like structures in the presynaptic compartment is still controversial. This is in part due to the absence of a consensus on definitions and markers for these compartments. Synaptic endosomes are sometimes seen as stable organelles, permanently present in the synapse. Alternatively, they are seen as short-lived intermediates in synaptic vesicle recycling, arising from the endocytosis of large vesicles from the plasma membrane, or from homotypic fusion of small vesicles. In addition, the potential function of the endosome is largely unknown in the synapse. Some groups have proposed that the endosome is involved in the sorting of synaptic vesicle proteins, albeit others have produced data that deny this possibility. In this review, we present the existing evidence for synaptic endosomes, we discuss their potential functions, and we highlight frequent technical pitfalls in the analysis of this elusive compartment. We also sketch a roadmap to definitely determine the role of synaptic endosomes for the synaptic vesicle cycle. Finally, we propose a common definition of synaptic endosome-like structures.

  10. Stereoselectivity of presynaptic autoreceptors modulating dopamine release

    International Nuclear Information System (INIS)

    Arbilla, S.; Langer, S.Z.

    1981-01-01

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [ 3 H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01-1μM enhanced the electrically evoked release of [ 3 H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.1-1 μM) but not to (R)-butaclamol (0.1-10μM) enhanced the field-stimulated release of [ 3 H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1μM) of the stimulated release of [ 3 H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [ 3 H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective. (Auth.)

  11. Pancreatic and snake venom presynaptically active phospholipases A2 inhibit nicotinic acetylcholine receptors.

    Science.gov (United States)

    Vulfius, Catherine A; Kasheverov, Igor E; Kryukova, Elena V; Spirova, Ekaterina N; Shelukhina, Irina V; Starkov, Vladislav G; Andreeva, Tatyana V; Faure, Grazyna; Zouridakis, Marios; Tsetlin, Victor I; Utkin, Yuri N

    2017-01-01

    Phospholipases A2 (PLA2s) are enzymes found throughout the animal kingdom. They hydrolyze phospholipids in the sn-2 position producing lysophospholipids and unsaturated fatty acids, agents that can damage membranes. PLA2s from snake venoms have numerous toxic effects, not all of which can be explained by phospholipid hydrolysis, and each enzyme has a specific effect. We have earlier demonstrated the capability of several snake venom PLA2s with different enzymatic, cytotoxic, anticoagulant and antiproliferative properties, to decrease acetylcholine-induced currents in Lymnaea stagnalis neurons, and to compete with α-bungarotoxin for binding to nicotinic acetylcholine receptors (nAChRs) and acetylcholine binding protein. Since nAChRs are implicated in postsynaptic and presynaptic activities, in this work we probe those PLA2s known to have strong presynaptic effects, namely β-bungarotoxin from Bungarus multicinctus and crotoxin from Crotalus durissus terrificus. We also wished to explore whether mammalian PLA2s interact with nAChRs, and have examined non-toxic PLA2 from porcine pancreas. It was found that porcine pancreatic PLA2 and presynaptic β-bungarotoxin blocked currents mediated by nAChRs in Lymnaea neurons with IC50s of 2.5 and 4.8 μM, respectively. Crotoxin competed with radioactive α-bungarotoxin for binding to Torpedo and human α7 nAChRs and to the acetylcholine binding protein. Pancreatic PLA2 interacted similarly with these targets; moreover, it inhibited radioactive α-bungarotoxin binding to the water-soluble extracellular domain of human α9 nAChR, and blocked acetylcholine induced currents in human α9α10 nAChRs heterologously expressed in Xenopus oocytes. These and our earlier results show that all snake PLA2s, including presynaptically active crotoxin and β-bungarotoxin, as well as mammalian pancreatic PLA2, interact with nAChRs. The data obtained suggest that this interaction may be a general property of all PLA2s, which should be proved by

  12. Pancreatic and snake venom presynaptically active phospholipases A2 inhibit nicotinic acetylcholine receptors.

    Directory of Open Access Journals (Sweden)

    Catherine A Vulfius

    Full Text Available Phospholipases A2 (PLA2s are enzymes found throughout the animal kingdom. They hydrolyze phospholipids in the sn-2 position producing lysophospholipids and unsaturated fatty acids, agents that can damage membranes. PLA2s from snake venoms have numerous toxic effects, not all of which can be explained by phospholipid hydrolysis, and each enzyme has a specific effect. We have earlier demonstrated the capability of several snake venom PLA2s with different enzymatic, cytotoxic, anticoagulant and antiproliferative properties, to decrease acetylcholine-induced currents in Lymnaea stagnalis neurons, and to compete with α-bungarotoxin for binding to nicotinic acetylcholine receptors (nAChRs and acetylcholine binding protein. Since nAChRs are implicated in postsynaptic and presynaptic activities, in this work we probe those PLA2s known to have strong presynaptic effects, namely β-bungarotoxin from Bungarus multicinctus and crotoxin from Crotalus durissus terrificus. We also wished to explore whether mammalian PLA2s interact with nAChRs, and have examined non-toxic PLA2 from porcine pancreas. It was found that porcine pancreatic PLA2 and presynaptic β-bungarotoxin blocked currents mediated by nAChRs in Lymnaea neurons with IC50s of 2.5 and 4.8 μM, respectively. Crotoxin competed with radioactive α-bungarotoxin for binding to Torpedo and human α7 nAChRs and to the acetylcholine binding protein. Pancreatic PLA2 interacted similarly with these targets; moreover, it inhibited radioactive α-bungarotoxin binding to the water-soluble extracellular domain of human α9 nAChR, and blocked acetylcholine induced currents in human α9α10 nAChRs heterologously expressed in Xenopus oocytes. These and our earlier results show that all snake PLA2s, including presynaptically active crotoxin and β-bungarotoxin, as well as mammalian pancreatic PLA2, interact with nAChRs. The data obtained suggest that this interaction may be a general property of all PLA2s, which

  13. The mechanism of functional up-regulation of P2X3 receptors of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine type 1 (FHM-1.

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    Swathi K Hullugundi

    Full Text Available A knock-in (KI mouse model of FHM-1 expressing the R192Q missense mutation of the Cacna1a gene coding for the α1 subunit of CaV2.1 channels shows, at the level of the trigeminal ganglion, selective functional up-regulation of ATP -gated P2X3 receptors of sensory neurons that convey nociceptive signals to the brainstem. Why P2X3 receptors are constitutively more responsive, however, remains unclear as their membrane expression and TRPV1 nociceptor activity are the same as in wildtype (WT neurons. Using primary cultures of WT or KI trigeminal ganglia, we investigated whether soluble compounds that may contribute to initiating (or maintaining migraine attacks, such as TNFα, CGRP, and BDNF, might be responsible for increasing P2X3 receptor responses. Exogenous application of TNFα potentiated P2X3 receptor-mediated currents of WT but not of KI neurons, most of which expressed both the P2X3 receptor and the TNFα receptor TNFR2. However, sustained TNFα neutralization failed to change WT or KI P2X3 receptor currents. This suggests that endogenous TNFα does not regulate P2X3 receptor responses. Nonetheless, on cultures made from both genotypes, exogenous TNFα enhanced TRPV1 receptor-mediated currents expressed by a few neurons, suggesting transient amplification of TRPV1 nociceptor responses. CGRP increased P2X3 receptor currents only in WT cultures, although prolonged CGRP receptor antagonism or BDNF neutralization reduced KI currents to WT levels. Our data suggest that, in KI trigeminal ganglion cultures, constitutive up-regulation of P2X3 receptors probably is already maximal and is apparently contributed by basal CGRP and BDNF levels, thereby rendering these neurons more responsive to extracellular ATP.

  14. Differential dynamic processing of afferent signals in frog tonic and phasic second-order vestibular neurons.

    Science.gov (United States)

    Pfanzelt, Sandra; Rössert, Christian; Rohregger, Martin; Glasauer, Stefan; Moore, Lee E; Straka, Hans

    2008-10-08

    The sensory-motor transformation of the large dynamic spectrum of head-motion-related signals occurs in separate vestibulo-ocular pathways. Synaptic responses of tonic and phasic second-order vestibular neurons were recorded in isolated frog brains after stimulation of individual labyrinthine nerve branches with trains of single electrical pulses. The timing of the single pulses was adapted from spike discharge patterns of frog semicircular canal nerve afferents during sinusoidal head rotation. Because each electrical pulse evoked a single spike in afferent fibers, the resulting sequences with sinusoidally modulated intervals and peak frequencies up to 100 Hz allowed studying the processing of presynaptic afferent inputs with in vivo characteristics in second-order vestibular neurons recorded in vitro in an isolated whole brain. Variation of pulse-train parameters showed that the postsynaptic compound response dynamics differ in the two types of frog vestibular neurons. In tonic neurons, subthreshold compound responses and evoked discharge patterns exhibited relatively linear dynamics and were generally aligned with pulse frequency modulation. In contrast, compound responses of phasic neurons were asymmetric with large leads of subthreshold response peaks and evoked spike discharge relative to stimulus waveform. These nonlinearities were caused by the particular intrinsic properties of phasic vestibular neurons and were facilitated by GABAergic and glycinergic inhibitory inputs from tonic type vestibular interneurons and by cerebellar circuits. Coadapted intrinsic filter and emerging network properties thus form dynamically different neuronal elements that provide the appropriate cellular basis for a parallel processing of linear, tonic, and nonlinear phasic vestibulo-ocular response components in central vestibular neurons.

  15. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3–36), and glucagon-like peptide-1 in rats

    Science.gov (United States)

    Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-01-01

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3–36) [PYY-(3–36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg−1·min−1), PYY-(3–36) (5, 17, 50 pmol·kg−1·min−1), or GLP-1 (17, 50 pmol·kg−1·min−1). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg−1·min−1 reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3–36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3–36) at 5, 17, and 50 pmol·kg−1·min−1 reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg−1·min−1 reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3–36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia. PMID:25117406

  16. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats.

    Science.gov (United States)

    Reidelberger, Roger; Haver, Alvin; Anders, Krista; Apenteng, Bettye

    2014-10-15

    Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.

  17. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

    OpenAIRE

    Crain, S M; Shen, K F

    1995-01-01

    Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the ...

  18. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    Science.gov (United States)

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  19. Pre-synaptic control of remote fear extinction in the neocortex

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    Gisella eVetere

    2012-06-01

    Full Text Available Consolidation of remote memory enhances immediate early genes induction (IEGs, augments the expression of the presynaptic growth associated protein 43 (GAP-43, and increases the density and size of dendritic spines in anterior cingulate (aCC and infra-limbic (ILC cortices. Remote memory extinction, however, does not uniformly alter consolidation-induced structural changes. In the aCC, the density, but not the size, of spines is reset to pseudo-conditioning levels while novel thin spines are formed in the ILC. Whether IEGs and GAP-43 also undergo region-specific changes upon remote memory extinction is undetermined. Here we confirm in the same batch of mice that c-Fos induction and GAP-43 expression are increased in both the aCC and the ILC 36 days after contextual fear conditioning. We then show that, in both regions, remote memory extinction is associated with decrease of c-Fos induction but no change in GAP-43 expression thus revealing similar, although protein-specific, pre-synaptic adaptations in aCC and ILC neurons. These observations, in addition to our previous report of region-specific post-synaptic structural changes, disclose a complex pattern of extinction-driven neocortical alterations suitable to support erasure or reinstatement of fear according to the environment demand.

  20. Fibroblast growth factor type 1 receptor stimulation of T-type Ca2+channels in sensory neurons requires the phosphatidylinositol 3-kinase and protein kinase A pathways, independently of Akt.

    Science.gov (United States)

    Si, Weibing; Zhang, Yuan; Chen, Kun; Hu, Dan; Qian, Zhiyuan; Gong, Shan; Li, Hua; Hao, Yuefeng; Tao, Jin

    2018-01-31

    Fibroblast growth factor-23 (FGF-23) secreted by osteocytes is known as a circulating factor that is essential for phosphate homeostasis. Recent studies have implicated FGF-23 in the nociceptive signalling of peripheral sensory neurons. However, the relevant mechanisms underlying this effect are not known. In this study, we determine the role of FGF-23 in regulating T-type Ca 2+ channels (T-type channels) in small-diameter dorsal root ganglion (DRG) neurons in mice. Our results show that FGF-23 increases T-type channel currents in a concentration-dependent manner. This FGF-23-induced response was dependent on FGF type 1 receptor (FGFR1) and was accompanied by a depolarizing shift in the steady-state inactivation curve. Pretreatment of neurons with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 prevented the FGF-23-mediated T-type channel response. Analysis of phospho-Akt (p-Akt) revealed that FGF-23 significantly activated Akt, but Akt inhibition did not affect the FGF-23-induced T-type channel current increase. The cell-permeable protein kinase A (PKA) inhibitor KT-5720 pretreatment and intracellular application of PKI 6-22 both abolished the stimulatory effects of FGF-23 on T-type channels, but inhibition of PKC had no effect. In summary, these findings indicate that FGF-23 stimulates T-type channel activity via activation of FGFR1, which is coupled to the PI3K-dependent PKA signalling cascade in small DRG neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit

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    Sara J. Hawkins

    2017-11-01

    Full Text Available Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks.

  2. Presynaptic Adenosine Receptor-Mediated Regulation of Diverse Thalamocortical Short-Term Plasticity in the Mouse Whisker Pathway

    Science.gov (United States)

    Ferrati, Giovanni; Martini, Francisco J.; Maravall, Miguel

    2016-01-01

    Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In “driver” thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release. PMID:26941610

  3. Hierarchical sparse coding in the sensory system of Caenorhabditis elegans.

    Science.gov (United States)

    Zaslaver, Alon; Liani, Idan; Shtangel, Oshrat; Ginzburg, Shira; Yee, Lisa; Sternberg, Paul W

    2015-01-27

    Animals with compact sensory systems face an encoding problem where a small number of sensory neurons are required to encode information about its surrounding complex environment. Using Caenorhabditis elegans worms as a model, we ask how chemical stimuli are encoded by a small and highly connected sensory system. We first generated a comprehensive library of transgenic worms where each animal expresses a genetically encoded calcium indicator in individual sensory neurons. This library includes the vast majority of the sensory system in C. elegans. Imaging from individual sensory neurons while subjecting the worms to various stimuli allowed us to compile a comprehensive functional map of the sensory system at single neuron resolution. The functional map reveals that despite the dense wiring, chemosensory neurons represent the environment using sparse codes. Moreover, although anatomically closely connected, chemo- and mechano-sensory neurons are functionally segregated. In addition, the code is hierarchical, where few neurons participate in encoding multiple cues, whereas other sensory neurons are stimulus specific. This encoding strategy may have evolved to mitigate the constraints of a compact sensory system.

  4. Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury

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    Costigan Michael

    2008-12-01

    Full Text Available Abstract Background The role of the neurotrophin regulated polypeptide, VGF, has been investigated in a rat spared injury model of neuropathic pain. This peptide has been shown to be associated with synaptic strengthening and learning in the hippocampus and while it is known that VGFmRNA is upregulated in dorsal root ganglia following peripheral nerve injury, the role of this VGF peptide in neuropathic pain has yet to be investigated. Results Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol to naïve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses. Conclusion VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in naïve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain.

  5. The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism

    International Nuclear Information System (INIS)

    Booij, J.; Speelman, J.DE.; Horstink, M. W.I.M.; Wolters, E.C.

    2001-01-01

    [ 123 I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several ''presynaptic parkinsonian'' syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [ 123 I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with ''presynaptic parkinsonism'' from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [ 123 I]FP-CIT SPET. Using [ 123 I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [ 123 I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases

  6. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

    Science.gov (United States)

    Crain, S M; Shen, K F

    1995-11-07

    Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

  7. Positron emission tomography studies of neuronal activity patterns during sensory and cognitive stimulations in Alzheimer`s disease. A study of cortical attention sites in man

    Energy Technology Data Exchange (ETDEWEB)

    Johannsen, Peter

    1997-12-31

    This Ph.D.-thesis describes different subtypes of attention, models for the organization of attention, and the attention deficits in Alzheimer`s disease. The experimental part of the study is based on studies of sustained and divided attention to two different sensory modalities; a visual checkerboard stimulation reversing at 7 Hz, and a 110 Hz vibrotactile stimulation of the right hand in a group of healthy elderly subjects (n = 16) age-matched with a group of patients with mild to moderate Alzheimer`s disease (n = 16). The cortical activations during the attention tasks have been mapped using O-15-water and positron emission tomography (PET) measurements of regional cerebral blood flow (rCBF) during rest and during performance of an attention task. After anatomical standardization and averaging over subjects, activation foci were assessed by a t-statistical evaluation of the differences of rCBF maps acquired before and during the execution of the attention tasks. The rCBF deficits in the Alzheimer patients were compared to rCBF pattern in the healthy elderly and assessed statistically on a voxel-by-voxel basis, revealing a distinct and localized pattern of rCBF deficits extending from the hippocampal area along the longitudinal fascicle to the temporo-parietal cortices with further deficits in the frontal regions. The resting rCBF deficits are distributed with the same pattern as described in neuropathological studies of lesions in Alzheimer`s disease. In the healthy elderly, both sustained and divided attention elicited activation of the right inferior parietal lobule (Brodmann Area 19/40) and the right middle frontal gyrus (Brodmann Area 46). Divided attention favored activation of the right middle frontal gyrus and sustained attention activation of the right inferior parietal lobule. Both the frontal and the parietal attention sites were active during attention to both the visual and the vibrotactile stimuli. These results support a network hypothesis of

  8. Positron emission tomography studies of neuronal activity patterns during sensory and cognitive stimulations in Alzheimer's disease. A study of cortical attention sites in man

    International Nuclear Information System (INIS)

    Johannsen, Peter

    1997-01-01

    This Ph.D.-thesis describes different subtypes of attention, models for the organization of attention, and the attention deficits in Alzheimer's disease. The experimental part of the study is based on studies of sustained and divided attention to two different sensory modalities; a visual checkerboard stimulation reversing at 7 Hz, and a 110 Hz vibrotactile stimulation of the right hand in a group of healthy elderly subjects (n = 16) age-matched with a group of patients with mild to moderate Alzheimer's disease (n = 16). The cortical activations during the attention tasks have been mapped using O-15-water and positron emission tomography (PET) measurements of regional cerebral blood flow (rCBF) during rest and during performance of an attention task. After anatomical standardization and averaging over subjects, activation foci were assessed by a t-statistical evaluation of the differences of rCBF maps acquired before and during the execution of the attention tasks. The rCBF deficits in the Alzheimer patients were compared to rCBF pattern in the healthy elderly and assessed statistically on a voxel-by-voxel basis, revealing a distinct and localized pattern of rCBF deficits extending from the hippocampal area along the longitudinal fascicle to the temporo-parietal cortices with further deficits in the frontal regions. The resting rCBF deficits are distributed with the same pattern as described in neuropathological studies of lesions in Alzheimer's disease. In the healthy elderly, both sustained and divided attention elicited activation of the right inferior parietal lobule (Brodmann Area 19/40) and the right middle frontal gyrus (Brodmann Area 46). Divided attention favored activation of the right middle frontal gyrus and sustained attention activation of the right inferior parietal lobule. Both the frontal and the parietal attention sites were active during attention to both the visual and the vibrotactile stimuli. These results support a network hypothesis of

  9. The Role of Cysteine String Protein α Phosphorylation at Serine 10 and 34 by Protein Kinase Cγ for Presynaptic Maintenance.

    Science.gov (United States)

    Shirafuji, Toshihiko; Ueyama, Takehiko; Adachi, Naoko; Yoshino, Ken-Ichi; Sotomaru, Yusuke; Uwada, Junsuke; Kaneoka, Azumi; Ueda, Taro; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

    2018-01-10

    Protein kinase Cγ (PKCγ) knock-out (KO) animals exhibit symptoms of Parkinson's disease (PD), including dopaminergic neuronal loss in the substantia nigra. However, the PKCγ substrates responsible for the survival of dopaminergic neurons in vivo have not yet been elucidated. Previously, we found 10 potent substrates in the striatum of PKCγ-KO mice. Here, we focused on cysteine string protein α (CSPα), a protein from the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles. We found that in cultured cells, PKCγ phosphorylates CSPα at serine (Ser) 10 and Ser34. Additionally, apoptosis was found to have been enhanced by the overexpression of a phosphorylation-null mutant of CSPα, CSPα(S10A/S34A). Compared with wild-type (WT) CSPα, the CSPα(S10A/S34A) mutant had a weaker interaction with HSP70. However, in sharp contrast, a phosphomimetic CSPα(S10D/S34D) mutant, compared with WT CSPα, had a stronger interaction with HSP70. In addition, total levels of synaptosomal-associated protein (SNAP) 25, a main downstream target of the HSC70/HSP70 chaperone complex, were found to have decreased by the CSPα(S10A/S34A) mutant through increased ubiquitination of SNAP25 in PC12 cells. In the striatum of 2-year-old male PKCγ-KO mice, decreased phosphorylation levels of CSPα and decreased SNAP25 protein levels were observed. These findings indicate the phosphorylation of CSPα by PKCγ may protect the presynaptic terminal from neurodegeneration. The PKCγ-CSPα-HSC70/HSP70-SNAP25 axis, because of its role in protecting the presynaptic terminal, may provide a new therapeutic target for the treatment of PD. SIGNIFICANCE STATEMENT Cysteine string protein α (CSPα) is a protein belonging to the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles, which maintain the presynaptic terminal. However, the function of CSPα phosphorylation by protein kinase C (PKC) for neuronal cell survival remains unclear. The experiments

  10. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    Science.gov (United States)

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  11. Mapping sensory circuits by anterograde trans-synaptic transfer of recombinant rabies virus

    Science.gov (United States)

    Zampieri, Niccolò; Jessell, Thomas M.; Murray, Andrew J.

    2014-01-01

    Summary Primary sensory neurons convey information from the external world to relay circuits within the central nervous system (CNS), but the identity and organization of the neurons that process incoming sensory information remains sketchy. Within the CNS viral tracing techniques that rely on retrograde trans-synaptic transfer provide a powerful tool for delineating circuit organization. Viral tracing of the circuits engaged by primary sensory neurons has, however, been hampered by the absence of a genetically tractable anterograde transfer system. In this study we demonstrate that rabies virus can infect sensory neurons in the somatosensory system, is subject to anterograde trans-synaptic transfer from primary sensory to spinal target neurons, and can delineate output connectivity with third-order neurons. Anterograde trans-synaptic transfer is a feature shared by other classes of primary sensory neurons, permitting the identification and potentially the manipulation of neural circuits processing sensory feedback within the mammalian CNS. PMID:24486087

  12. A multi-ingredient dietary supplement abolishes large-scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice.

    Science.gov (United States)

    Lemon, J A; Aksenov, V; Samigullina, R; Aksenov, S; Rodgers, W H; Rollo, C D; Boreham, D R

    2016-06-01

    Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer's disease and likely explains their striking age-related cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382-404, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Sepsis causes presynaptic histamine H3 and alpha2-adrenergic dysfunction in canine myocardium.

    Science.gov (United States)

    Cheng, Zao-Qin; Bose, Deepak; Jacobs, Han; Light, R Bruce; Mink, Steven N

    2002-11-01

    Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level. In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect. We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma. We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

  14. Presynaptic Active Zone Density during Development and Synaptic Plasticity.

    Science.gov (United States)

    Clarke, Gwenaëlle L; Chen, Jie; Nishimune, Hiroshi

    2012-01-01

    Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density) during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs), the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS), active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  15. Presynaptic active zone density during development and synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Gwenaëlle L Clarke

    2012-02-01

    Full Text Available Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs, the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS, active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  16. Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

    Science.gov (United States)

    Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

    2017-12-01

    Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

  17. An electrophysiological study of sound sensitive neurons in the 'primitive ear' of acheta domesticus.

    Science.gov (United States)

    Counter, S A

    1976-01-01

    Crickets have two types of mechanisms for the reception of environmental sounds: (1)the tympanal organs in the two forelegs and (2) the freely articulated setal receptors on the abdominal ceri. The cereal setal receptors have hitherto received much less experimental attention as decoders of biologically significant sounds than have the tympano-receptors. In the present study the cereal auditory system of Acheta domesticus was examined electrophysiologically to determine its auditory frequency sensitivity, the tuning characteristics of individual units, and the synchronization between nerve impulses and stimulus frequency. Both pre- and postsynaptic units were examined in the fifth abdominal ganglion; several of the observed response patterns were compared with those of homologous cereal sensory neurons in Periplaneta americana. The results show that (1) A. domesticus possesses an elaborate array of cereal receptors which are highly sensitive to sounds, (2) the cereal setal receptors are more sensitive and numerous in the cricket than in the cockroach, and (3) the cereal auditory system can decode stimulus information by narrow tuning in individual cells and by synchronous discharge patterns; firing frequencies range up to 300 Hz in presynaptic sensory units and 60 Hz in the postsynaptic giants. The response patterns were related to the structure of the receptor and the behavioural adaptations of the insect.

  18. The effects of stimulation of substantia innominata and sensory receiving areas of the forebrain upon the activity of neurons within the amygdala of the anesthetized cat.

    Science.gov (United States)

    Femano, P A; Edinger, H M; Siegel, A

    1983-06-13

    The present study investigated the response characteristics of individual neurons in the amygdala following stimulation of the substantia innominata (SI), and compared these responses with those elicited by stimulation of insular and temporal polar cortices and the lateral olfactory tract (LOT). Recordings were made from single units within the medial, central, basal, and lateral amygdaloid nuclei of anesthetized, male cats. Stimulating electrodes were located in the SI, LOT, and sylvian cortex (SG). Unit responses were classified as either excitation or inhibition. Excitatory responses were further divided into fixed latency excitation (FLE) and variable latency excitation (VLE) based on the variability of the onset latency of the response. The majority of responses to SI stimulation were of the FLE type, implying a direct orthodromic, monosynaptic activation of amygdaloid units. Proportionally more FLE responses were recorded laterally, especially in the magnocellular basal nucleus, compared to VLE responses which were more common in the medial and central nuclei. SI stimulation consistently affected the activity of many more units than did SG or LOT stimulation. The onset latencies of the population of cells exhibiting excitatory responses elicited by SI stimulation were distributed bimodally, and this may reflect a dual projection pathway of amygdaloid afferents from this basal forebrain region. This correlates with anatomical descriptions indicating that SI projections to amygdala pass via the ventral amygdalofugal pathway as well as in the stria terminalis. Excitatory onset latencies of responses to SI stimulation were the shortest in the lateral and magnocellular basal nuclei and the longest in the parvocellular basal nucleus. Amygdaloid units exhibited convergent input from the stimulus sites. A clear topographical distribution of units was not demonstrated. The data suggests that units receiving a convergent input were rarely driven monosynaptically by

  19. In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

    Science.gov (United States)

    Tomlinson, Susan E; Tan, S Veronica; Burke, David; Labrum, Robyn W; Haworth, Andrea; Gibbons, Vaneesha S; Sweeney, Mary G; Griggs, Robert C; Kullmann, Dimitri M; Bostock, Hugh; Hanna, Michael G

    2016-02-01

    Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

  20. Acupuncture Points and Their Relationship with Multireceptive Fields of Neurons

    OpenAIRE

    Salvador Quiroz-González; Sergio Torres-Castillo; Rosa Estela López-Gómez; Ismael Jiménez Estrada

    2017-01-01

    In Traditional Chinese Medicine, acupuncture points (APs) have been emphasized as key elements that generate the therapeutic effects of acupuncture. At the spinal cord or supraspinal level, sensory neurons located in the dorsal horn receive an extensive supply of sensory information from skin and muscle receptors through peripheral afferent nerves. The stimulated skin area that influences the activity of a spinal sensory neuron is known as the peripheral receptive field (RF) of that neuron. B...

  1. Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

    Directory of Open Access Journals (Sweden)

    Alexander F. Jeans

    2017-10-01

    Full Text Available Voltage-dependent Ca2+ channels (VGCC represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

  2. Sensory modulation disorders in childhood epilepsy.

    Science.gov (United States)

    van Campen, Jolien S; Jansen, Floor E; Kleinrensink, Nienke J; Joëls, Marian; Braun, Kees Pj; Bruining, Hilgo

    2015-01-01

    Altered sensory sensitivity is generally linked to seizure-susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders. We used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4-17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire). Sensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory "sensitivity," "sensory avoidance," and "poor registration" but not "sensory seeking." Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder. Sensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy.

  3. Sensory changes in pediatric patients with spinal muscular atrophy: an electrophysiologic study

    Directory of Open Access Journals (Sweden)

    Hussien E Sultan

    2016-01-01

    Conclusion Sensory neuron and/or axonal affection have been demonstrated in the studied series of pediatric SMA patients suggesting that the pathological changes in SMA may also involve the sensory system.

  4. Does human presynaptic striatal dopamine function predict social conformity?

    Science.gov (United States)

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  5. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease.

    Science.gov (United States)

    Gomez-Arboledas, Angela; Davila, Jose C; Sanchez-Mejias, Elisabeth; Navarro, Victoria; Nuñez-Diaz, Cristina; Sanchez-Varo, Raquel; Sanchez-Mico, Maria Virtudes; Trujillo-Estrada, Laura; Fernandez-Valenzuela, Juan Jose; Vizuete, Marisa; Comella, Joan X; Galea, Elena; Vitorica, Javier; Gutierrez, Antonia

    2018-03-01

    Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components of intermediate filaments, is a common feature in brains of Alzheimer's patients. Reactive astrocytes are found in close association with neuritic plaques; however, the precise role of these glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical techniques and light and electron microscopy, we report that plaque-associated reactive astrocytes enwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursor protein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparently not engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% of amyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophic neurites was low, around 7% of total dystrophies around plaques at both ages. This fact, along with the accumulation of dystrophic neurites during disease course, suggests that the efficiency of the astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surrounding and engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer's patients by confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytes might contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impaired neural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limiting the amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytes may represent a potential therapy in Alzheimer's disease. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

  6. Sensory-evoked perturbations of locomotor activity by sparse sensory input: a computational study.

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    Bui, Tuan V; Brownstone, Robert M

    2015-04-01

    Sensory inputs from muscle, cutaneous, and joint afferents project to the spinal cord, where they are able to affect ongoing locomotor activity. Activation of sensory input can initiate or prolong bouts of locomotor activity depending on the identity of the sensory afferent activated and the timing of the activation within the locomotor cycle. However, the mechanisms by which afferent activity modifies locomotor rhythm and the distribution of sensory afferents to the spinal locomotor networks have not been determined. Considering the many sources of sensory inputs to the spinal cord, determining this distribution would provide insights into how sensory inputs are integrated to adjust ongoing locomotor activity. We asked whether a sparsely distributed set of sensory inputs could modify ongoing locomotor activity. To address this question, several computational models of locomotor central pattern generators (CPGs) that were mechanistically diverse and generated locomotor-like rhythmic activity were developed. We show that sensory inputs restricted to a small subset of the network neurons can perturb locomotor activity in the same manner as seen experimentally. Furthermore, we show that an architecture with sparse sensory input improves the capacity to gate sensory information by selectively modulating sensory channels. These data demonstrate that sensory input to rhythm-generating networks need not be extensively distributed. Copyright © 2015 the American Physiological Society.

  7. Peripheral control of the gain of a central synaptic connection between antagonistic motor neurones in the locust

    Science.gov (United States)

    Jellema; Heitler

    1996-01-01

    The metathoracic fast extensor tibiae (FETi) motor neurone of locusts is unusual amongst insect motor neurones because it makes output connections within the central nervous system as well as in the periphery. It makes excitatory chemical synaptic connections to most if not all of the antagonist flexor tibiae motor neurones. The gain of the FETi-flexor connection is dependent on the peripheral conditions at the time of the FETi spike. This dependency has two aspects. First, sensory input resulting from the extensor muscle contraction can sum with the central excitatory postsynaptic potential (EPSP) to augment its falling phase if the tibia is restrained in the flexed position (initiating a tension-dependent reflex) or is free to extend (initiating a movement-dependent resistance reflex). This effect is thus due to simple postsynaptic summation of the central EPSP with peripheral sensory input. Second, the static tibial position at the time of the FETi spike can change the amplitude of the central EPSP, in the absence of any extensor muscle contraction. The EPSP can be up to 30 % greater in amplitude if FETi spikes with the tibia held flexed rather than extended. The primary sense organ mediating this effect is the femoral chordotonal organ. Evidence is presented suggesting that the mechanism underlying this change in gain may be specifically localised to the FETi-flexor connection, rather than being due to general position-dependent sensory feedback summing with the EPSP. The change in the amplitude of the central EPSP is probably not caused by general postsynaptic summation with tonic sensory input, since a diminution in the amplitude of the central EPSP caused by tibial extension is often accompanied by overall tonic excitation of the flexor motor neurone. Small but significant changes in the peak amplitude of the FETi spike have a positive correlation with changes in the EPSP amplitude, suggesting a likely presynaptic component to the mechanism of gain control

  8. Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

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    Andreia F.R. Batista

    2017-09-01

    Full Text Available Localized protein synthesis is a mechanism for developing axons to react acutely and in a spatially restricted manner to extracellular signals. As such, it is important for many aspects of axonal development, but its role in the formation of presynapses remains poorly understood. We found that the induced assembly of presynaptic terminals required local protein synthesis. Newly synthesized proteins were detectable at nascent presynapses within 15 min of inducing synapse formation in isolated axons. The transcript for the t-SNARE protein SNAP25, which is required for the fusion of synaptic vesicles with the plasma membrane, was recruited to presynaptic sites and locally translated. Inhibition of intra-axonal SNAP25 synthesis affected the clustering of SNAP25 and other presynaptic proteins and interfered with the release of synaptic vesicles from presynaptic sites. This study reveals a critical role for the axonal synthesis of SNAP25 in the assembly of presynaptic terminals.

  9. Active polysomes are present in the large presynaptic endings of the synaptosomal fraction from squid brain.

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    Crispino, M; Kaplan, B B; Martin, R; Alvarez, J; Chun, J T; Benech, J C; Giuditta, A

    1997-10-15

    Previous data have suggested that the large nerve terminals present in the synaptosomal fraction from squid optic lobe are capable of protein synthesis (Crispino et al., 1993a,b). We have further examined this issue by comparing the translation products of synaptosomal and microsomal polysomes. Both preparations programmed an active process of translation, which was completely abolished by their previous treatment with EDTA. After immunoabsorption of the newly synthesized neurofilament (NF) proteins, the labeling ratio of the 60 and 70 kDa NF proteins was found to differ, in agreement with comparable differences obtained with intact synaptosomes. These observations indicate that the set of mRNAs translated by synaptosomes differs from that translated by nerve cell bodies. Hence, because NF proteins are neuron-specific, they support the view that the active synaptosomal polysomes are mostly localized in the large nerve terminals that represent the most abundant neuronal component of the fraction. This hypothesis was confirmed (1) by electron spectroscopic data demonstrating the presence of ribosomes and polysomes within the large nerve endings of the synaptosomal fraction, as well as in the carrot-like nerve endings of the retinal photoreceptors that constitute the only large terminals in the optic lobe, and (2) by light and high resolution autoradiography of synaptosomal samples incubated with [3H]leucine, showing that most labeled proteins are associated with the large nerve endings. This response was abolished by cycloheximide. Taken together, the data provide the first unequivocal demonstration that presynaptic nerve terminals are capable of protein synthesis.

  10. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

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    Melanie Laßek

    2016-04-01

    Full Text Available The hallmarks of Alzheimer's disease (AD are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.

  11. Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord.

    Science.gov (United States)

    Xie, Jing-Dun; Chen, Shao-Rui; Chen, Hong; Pan, Hui-Lin

    2017-09-01

    Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-d-aspartate receptors (NMDARs) at the spinal cord level are critically involved in the synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment with bortezomib, a proteasome inhibitor, affects the NMDAR activity of spinal dorsal horn neurons. Systemic treatment with bortezomib in rats did not significantly affect postsynaptic NMDAR currents elicited by puff application of NMDA directly to dorsal horn neurons. Bortezomib treatment markedly increased the baseline frequency of miniature excitatory postsynaptic currents (EPSCs), which was completely normalized by the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5). AP5 also reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation in bortezomib-treated, but not vehicle-treated, rats. Furthermore, inhibition of protein kinase C (PKC) with chelerythrine fully reversed the increased frequency of miniature EPSCs and the amplitude of evoked EPSCs in bortezomib-treated rats. Intrathecal injection of AP5 and chelerythrine both profoundly attenuated mechanical allodynia and hyperalgesia induced by systemic treatment with bortezomib. In addition, treatment with bortezomib induced striking membrane translocation of PKC-βII, PKC-δ, and PKC-ε in the dorsal root ganglion. Our findings indicate that bortezomib treatment potentiates nociceptive input from primary afferent nerves via PKC-mediated tonic activation of presynaptic NMDARs. Targeting presynaptic NMDARs and PKC at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.

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    Shi-Bing Wong

    Full Text Available Peroxisomal proliferator-activated receptor gamma (PPARγ is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA receptor-mediated temporal lobe epilepsy (TLE. We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.

  13. Spinal Cord Excitability and Sprint Performance Are Enhanced by Sensory Stimulation During Cycling.

    Science.gov (United States)

    Pearcey, Gregory E P; Noble, Steven A; Munro, Bridget; Zehr, E Paul

    2017-01-01

    Spinal cord excitability, as assessed by modulation of Hoffmann (H-) reflexes, is reduced with fatiguing isometric contractions. Furthermore, spinal cord excitability is reduced during non-fatiguing arm and leg cycling. Presynaptic inhibition of Ia terminals is believed to contribute to this suppression of spinal cord excitability. Electrical stimulation to cutaneous nerves reduces Ia presynaptic inhibition, which facilitates spinal cord excitability, and this facilitation is present during arm cycling. Although it has been suggested that reducing presynaptic inhibition may prolong fatiguing contractions, it is unknown whether sensory stimulation can alter the effects of fatiguing exercise on performance or spinal cord excitability. Thus, the aim of this experiment was to determine if sensory stimulation can interfere with fatigue-related suppression of spinal cord excitability, and alter fatigue rates during cycling sprints. Thirteen participants randomly performed three experimental sessions that included: unloaded cycling with sensory stimulation ( CONTROL + STIM ), sprints with sensory stimulation ( SPRINT + STIM ) and sprints without stimulation ( SPRINT ). Seven participants also performed a fourth session ( CONTROL ), which consisted of unloaded cycling. During SPRINT and SPRINT + STIM, participants performed seven, 10 s cycling sprints interleaved with 3 min rest. For CONTROL and CONTROL + STIM , participants performed unloaded cycling for ~30 min. During SPRINT + STIM and CONTROL + STIM , participants received patterned sensory stimulation to nerves of the right foot. H-reflexes and M-waves of the right soleus were evoked by stimulation of the tibial nerve at multiple time points throughout exercise. Sensory stimulation facilitated soleus H-reflexes during unloaded cycling, whereas sprints suppressed soleus H-reflexes. While receiving sensory stimulation, there was less suppression of soleus H-reflexes and slowed reduction in average power output, compared

  14. Spinal Cord Excitability and Sprint Performance Are Enhanced by Sensory Stimulation During Cycling

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    Gregory E. P. Pearcey

    2017-12-01

    Full Text Available Spinal cord excitability, as assessed by modulation of Hoffmann (H- reflexes, is reduced with fatiguing isometric contractions. Furthermore, spinal cord excitability is reduced during non-fatiguing arm and leg cycling. Presynaptic inhibition of Ia terminals is believed to contribute to this suppression of spinal cord excitability. Electrical stimulation to cutaneous nerves reduces Ia presynaptic inhibition, which facilitates spinal cord excitability, and this facilitation is present during arm cycling. Although it has been suggested that reducing presynaptic inhibition may prolong fatiguing contractions, it is unknown whether sensory stimulation can alter the effects of fatiguing exercise on performance or spinal cord excitability. Thus, the aim of this experiment was to determine if sensory stimulation can interfere with fatigue-related suppression of spinal cord excitability, and alter fatigue rates during cycling sprints. Thirteen participants randomly performed three experimental sessions that included: unloaded cycling with sensory stimulation (CONTROL + STIM, sprints with sensory stimulation (SPRINT + STIM and sprints without stimulation (SPRINT. Seven participants also performed a fourth session (CONTROL, which consisted of unloaded cycling. During SPRINT and SPRINT + STIM, participants performed seven, 10 s cycling sprints interleaved with 3 min rest. For CONTROL and CONTROL + STIM, participants performed unloaded cycling for ~30 min. During SPRINT + STIM and CONTROL + STIM, participants received patterned sensory stimulation to nerves of the right foot. H-reflexes and M-waves of the right soleus were evoked by stimulation of the tibial nerve at multiple time points throughout exercise. Sensory stimulation facilitated soleus H-reflexes during unloaded cycling, whereas sprints suppressed soleus H-reflexes. While receiving sensory stimulation, there was less suppression of soleus H-reflexes and slowed reduction in average power output

  15. Whisker sensory system - from receptor to decision.

    Science.gov (United States)

    Diamond, Mathew E; Arabzadeh, Ehsan

    2013-04-01

    One of the great challenges of systems neuroscience is to understand how the neocortex transforms neuronal representations of the physical characteristics of sensory stimuli into the percepts which can guide the animal's decisions. Here we present progress made in understanding behavioral and neurophysiological aspects of a highly efficient sensory apparatus, the rat whisker system. Beginning with the 1970s discovery of "barrels" in the rat and mouse brain, one line of research has focused on unraveling the circuits that transmit information from the whiskers to the sensory cortex, together with the cellular mechanisms that underlie sensory responses. A second, more recent line of research has focused on tactile psychophysics, that is, quantification of the behavioral capacities supported by whisker sensation. The opportunity to join these two lines of investigation makes whisker-mediated sensation an exciting platform for the study of the neuronal bases of perception and decision-making. Even more appealing is the beginning-to-end prospective offered by this system: the inquiry can start at the level of the sensory receptor and conclude with the animal's choice. We argue that rats can switch between two modes of operation of the whisker sensory system: (1) generative mode and (2) receptive mode. In the generative mode, the rat moves its whiskers forward and backward to actively seek contact with objects and to palpate the object after initial contact. In the receptive mode, the rat immobilizes its whiskers to optimize the collection of signals from an object that is moving by its own power. We describe behavioral tasks that rats perform in these different modes. Next, we explore which neuronal codes in sensory cortex account for the rats' discrimination capacities. Finally, we present hypotheses for mechanisms through which "downstream" brain regions may read out the activity of sensory cortex in order to extract the significance of sensory stimuli and, ultimately

  16. Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

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    Kari A Johnson

    2016-11-01

    Full Text Available Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses, and G protein-coupled receptors (GPCRs that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, dopamine (D1- and D2-like receptors, endocannabinoids (CB1 receptors and glutamate (group II metabotropic glutamate (mGlu receptors. The focus is on recent evidence from laboratory animal models (and some evidence in humans implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on

  17. Functional characterization of neuronal pre and postsynaptic alpha 2-adrenoceptor subtypes in guinea-pig submucosal plexus.

    Science.gov (United States)

    Shen, K. Z.; Barajas-Lopez, C.; Surprenant, A.

    1990-01-01

    1. The alpha 2-adrenoceptors on cell bodies of submucosal neurones, on presynaptic cholinergic nerve terminals innervating submucosal neurones, and on presynaptic sympathetic fibres innervating submucosal arterioles were characterized in functional studies by use of subtype selective ligands. 2. Both membrane hyperpolarization and presynaptic inhibition of nicotinic excitatory synaptic potentials (e.p.s.ps) produced by UK 14304 were similarly antagonized by idazoxan, yohimbine. SKF 104078, WB 4101 and ARC-239. Antagonism was competitive and dissociation equilibrium constants were the same for both effects. 3. Vasoconstriction of submucosal arterioles in response to stimulation of the sympathetic nerves (20 Hz for 2 s) was inhibited by UK 14304 and clonidine: concentrations producing half-maximum responses were 6 nm and 10 nM respectively. Idazoxan, yohimbine, WB 4101 and SKF 104078 antagonized this action, with dissociation constants similar to those for antagonism of the postsynaptic membrane hyperpolarization and presynaptic inhibition of nicotinic e.p.s.ps. 4. Oxymetazoline was a partial agonist when membrane hyperpolarization or presynaptic inhibition of nicotinic e.p.s.ps were measured but a full agonist when presynaptic inhibition of sympathetically-mediated arteriolar vasoconstriction was measured. As an agonist, oxymetazoline produced half maximum responses at 80-120 nM; the dissociation constant for oxymetazoline as an antagonist was 130 nM. 5. Neither prazosin nor chlorpromazine (up to 30 microM) altered any of the three responses to alpha 2-adrenoceptor agonists. 6. It is concluded that alpha 2-adrenoceptors present on submucosal neuronal cell bodies, on presynaptic cholinergic nerve terminals and on presynaptic sympathetic nerve terminals are the alpha 2A subtype. However, functional characterization of this subtype differs from that provided by ligand binding studies. PMID:1982232

  18. Sensory Transduction in Caenorhabditis elegans

    Science.gov (United States)

    Brown, Austin L.; Ramot, Daniel; Goodman, Miriam B.

    The roundworm Caenorhabditis elegans has a well-defined and comparatively simple repertoire of sensory-guided behaviors, all of which rely on its ability to detect chemical, mechanical or thermal stimuli. In this chapter, we review what is known about the ion channels that mediate sensation in this remarkable model organism. Genetic screens for mutants defective in sensory-guided behaviors have identified genes encoding channel proteins, which are likely transducers of chemical, thermal, and mechanical stimuli. Such classical genetic approaches are now being coupled with molecular genetics and in vivo cellular physiology to elucidate how these channels are activated in specific sensory neurons. The ion channel superfamilies implicated in sensory transduction in C. elegans - CNG, TRP, and DEG/ENaC - are conserved across phyla and also appear to contribute to sensory transduction in other organisms, including vertebrates. What we learn about the role of these ion channels in C. elegans sensation is likely to illuminate analogous processes in other animals, including humans.

  19. Local gene expression in axons and nerve endings: the glia-neuron unit.

    Science.gov (United States)

    Giuditta, Antonio; Chun, Jong Tai; Eyman, Maria; Cefaliello, Carolina; Bruno, Anna Paola; Crispino, Marianna

    2008-04-01

    Neurons have complex and often extensively elongated processes. This unique cell morphology raises the problem of how remote neuronal territories are replenished with proteins. For a long time, axonal and presynaptic proteins were thought to be exclusively synthesized in the cell body, which delivered them to peripheral sites by axoplasmic transport. Despite this early belief, protein has been shown to be synthesized in axons and nerve terminals, substantially alleviating the trophic burden of the perikaryon. This observation raised the question of the cellular origin of the peripheral RNAs involved in protein synthesis. The synthesis of these RNAs was initially attributed to the neuron soma almost by default. However, experimental data and theoretical considerations support the alternative view that axonal and presynaptic RNAs are also transcribed in the flanking glial cells and transferred to the axon domain of mature neurons. Altogether, these data suggest that axons and nerve terminals are served by a distinct gene expression system largely independent of the neuron cell body. Such a local system would allow the neuron periphery to respond promptly to environmental stimuli. This view has the theoretical merit of extending to axons and nerve terminals the marginalized concept of a glial supply of RNA (and protein) to the neuron cell body. Most long-term plastic changes requiring de novo gene expression occur in these domains, notably in presynaptic endings, despite their intrinsic lack of transcriptional capacity. This review enlightens novel perspectives on the biology and pathobiology of the neuron by critically reviewing these issues.

  20. Effects of spinal transection on presynaptic markers for glutamatergic neurons in the rat

    International Nuclear Information System (INIS)

    Singer, H.S.; Coyle, J.T.; Frangia, J.; Price, D.L.

    1981-01-01

    To evaluate the hypothesis that glutamic acid may be the neurotransmitter of descending, excitatory supraspinal pathways, the uptake and release of L-[3H] glutamate and the levels of endogenous glutamate were measured in preparations from rat lumbar spinal cord following complete mid-thoracic transection. Following transection, the activity of the synaptosomal high-affinity glutamate uptake process was increased in both dorsal and ventral halves of lumbar cord between 1 and 14 days after transection and returned to control levels by 21 days posttransection. At 7 days, the increased activity of the uptake process for L-[3H]glutamate resulted in elevation of Vmax with no significant alteration in KT as compared to age-matched controls. Depolarization-induced release of L-[3H]glutamate from prelabeled slices did not differ significantly from control in the lesioned rat except at 21 days after lesion when the amount of tritium release was significantly greater in the transected preparations than in control. Amino acid analysis of the lumbar cord from control and transected rats indicated only a 10% decrease in the level of endogenous glutamate and no alterations in the concentration of GABA and glycine 7 days after lesion. These findings do not support the hypothesis that glutamate serves as a major excitatory neurotransmitter in supraspinal pathways innervating the lumbar cord of the rat

  1. Genetics Home Reference: hereditary sensory and autonomic neuropathy type II

    Science.gov (United States)

    ... is found in the cells of the nervous system, including sensory neurons. The mutations involved in HSAN2A result in ... Samuels M, Rouleau GA. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Invest. 2008 Jul; ...

  2. Evidence for glutamate as a neuroglial transmitter within sensory ganglia.

    Science.gov (United States)

    Kung, Ling-Hsuan; Gong, Kerui; Adedoyin, Mary; Ng, Johnson; Bhargava, Aditi; Ohara, Peter T; Jasmin, Luc

    2013-01-01

    This study examines key elements of glutamatergic transmission within sensory ganglia of the rat. We show that the soma of primary sensory neurons release glutamate when depolarized. Using acute dissociated mixed neuronal/glia cultures of dorsal root ganglia (DRG) or trigeminal ganglia and a colorimetric assay, we show that when glutamate uptake by satellite glial cells (SGCs) is inhibited, KCl stimulation leads to simultaneous increase of glutamate in the culture medium. With calcium imaging we see that the soma of primary sensory neurons and SGCs respond to AMPA, NMDA, kainate and mGluR agonists, and selective antagonists block this response. Using whole cell patch-clamp technique, inward currents were recorded from small diameter (ganglion preparation) in response to local application of the above glutamate receptor agonists. Following a chronic constriction injury (CCI) of either the inferior orbital nerve or the sciatic nerve, glutamate expression increases in the trigeminal ganglia and DRG respectively. This increase occurs in neurons of all diameters and is present in the somata of neurons with injured axons as well as in somata of neighboring uninjured neurons. These data provides additional evidence that glutamate can be released within the sensory ganglion, and that the somata of primary sensory neurons as well as SGCs express functional glutamate receptors at their surface. These findings, together with our previous gene knockdown data, suggest that glutamatergic transmission within the ganglion could impact nociceptive threshold.

  3. Presynaptic [Ca2+] and GCAPs: aspects on the structure and function of photoreceptor ribbon synapses

    Directory of Open Access Journals (Sweden)

    Frank eSchmitz

    2014-02-01

    Full Text Available Changes in intracellular calcium ions [Ca2+] play important roles in photoreceptor signalling. Consequently, intracellular [Ca2+] levels need to be tightly controlled. In the light-sensitive outer segments (OS of photoreceptors, Ca2+ regulates the activity of retinal guanylate cyclases (ret-GCs thus playing a central role in phototransduction and light-adaptation by restoring light-induced decreases in cGMP. In the synaptic terminals, changes of intracellular Ca2+ trigger various aspects of neurotransmission. Photoreceptors employ tonically active ribbon synapses that encode light-induced, graded changes of membrane potential into different rates of synaptic vesicle exocytosis. The active zones of ribbon synapses contain large electron-dense structures, synaptic ribbons, that are associated with large numbers of synaptic vesicles. Synaptic coding at ribbon synapses differs from synaptic coding at conventional (phasic synapses. Recent studies revealed new insights how synaptic ribbons are involved in this process. This review focuses on the regulation of [Ca2+] in presynaptic photoreceptor terminals and on the function of a particular Ca2+-regulated protein, the neuronal calcium sensor protein GCAP2 (guanylate cyclase-activating protein-2 in the photoreceptor ribbon synapse. GCAP2, an EF hand-containing protein plays multiple roles in the OS and in the photoreceptor synapse. In the OS, GCAP2 works as a Ca2+-sensor within a Ca2+-regulated feedback loop that adjusts cGMP levels. In the photoreceptor synapse, GCAP2 binds to RIBEYE, a component of synaptic ribbons, and mediates Ca2+-dependent plasticity at that site. Possible mechanisms are discussed.

  4. Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

    Science.gov (United States)

    Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana; Karam, Caline S; Farino, Zachary J; Sonders, Mark S; Choi, Se Joon; Grygoruk, Anna; Zhang, Yuchao; Cela, Carolina; Choi, Ben Jiwon; Flores, Jorge; Freyberg, Robin J; McCabe, Brian D; Mosharov, Eugene V; Krantz, David E; Javitch, Jonathan A; Sulzer, David; Sames, Dalibor; Rayport, Stephen; Freyberg, Zachary

    2017-08-30

    The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Presynaptic localization of histamine H3-receptors in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, K.; Mizuguchi, H.; Fukui, H.; Wada, H. (Osaka Univ. (Japan))

    1991-06-28

    The localization of histamine H3-receptors in subcellular fractions from the rat brain was examined in a (3H) (R) alpha-methylhistamine binding assay and compared with those of histamine H1- and adrenaline alpha 1- and alpha 2-receptors. Major (3H)(R) alpha-methylhistamine binding sites with increased specific activities ((3H)ligand binding vs. protein amount) were recovered from the P2 fraction by differential centrifugation. Minor (3H)(R)alpha-methylhistamine binding sites with increased specific activities were also detected in the P3 fraction. Further subfractionation of the P2 fraction by discontinuous sucrose density gradient centrifugation showed major recoveries of (3H)(R)alpha-methylhistamine binding in myelin (MYE) and synaptic plasma membrane (SPM) fractions. A further increase in specific activity was observed in the MYE fraction, but the SPM fraction showed no significant increase in specific activity. Adrenaline alpha 2-receptors, the pre-synaptic autoreceptors, in a (3H) yohimbine binding assay showed distribution patterns similar to histamine H3-receptors. On the other hand, post-synaptic histamine H1- and adrenaline alpha 1-receptors were closely localized and distributed mainly in the SPM fraction with increased specific activity. Only a negligible amount was recovered in the MYE fraction, unlike the histamine H3- and adrenaline alpha 2-receptors.

  6. Presynaptic localization of histamine H3-receptors in rat brain

    International Nuclear Information System (INIS)

    Fujimoto, K.; Mizuguchi, H.; Fukui, H.; Wada, H.

    1991-01-01

    The localization of histamine H3-receptors in subcellular fractions from the rat brain was examined in a [3H] (R) alpha-methylhistamine binding assay and compared with those of histamine H1- and adrenaline alpha 1- and alpha 2-receptors. Major [3H](R) alpha-methylhistamine binding sites with increased specific activities ([3H]ligand binding vs. protein amount) were recovered from the P2 fraction by differential centrifugation. Minor [3H](R)alpha-methylhistamine binding sites with increased specific activities were also detected in the P3 fraction. Further subfractionation of the P2 fraction by discontinuous sucrose density gradient centrifugation showed major recoveries of [3H](R)alpha-methylhistamine binding in myelin (MYE) and synaptic plasma membrane (SPM) fractions. A further increase in specific activity was observed in the MYE fraction, but the SPM fraction showed no significant increase in specific activity. Adrenaline alpha 2-receptors, the pre-synaptic autoreceptors, in a [3H] yohimbine binding assay showed distribution patterns similar to histamine H3-receptors. On the other hand, post-synaptic histamine H1- and adrenaline alpha 1-receptors were closely localized and distributed mainly in the SPM fraction with increased specific activity. Only a negligible amount was recovered in the MYE fraction, unlike the histamine H3- and adrenaline alpha 2-receptors

  7. Molecular mechanisms underlying monosynaptic sensory-motor circuit development in the spinal cord.

    Science.gov (United States)

    Imai, Fumiyasu; Yoshida, Yutaka

    2018-04-01

    Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key components of the sensory system, are located in the dorsal root ganglia and project axons both centrally to the spinal cord and peripherally to muscles and tendons, communicating peripheral information about the body to the CNS. Changes in muscle length detected by muscle spindles, and tension variations in tendons conveyed by Golgi tendon organs, are communicated to the CNS through group Ia /II, and Ib proprioceptive sensory afferents, respectively. Group Ib proprioceptive sensory neurons connect with motor neurons indirectly through spinal interneurons, whereas group Ia/II axons form both direct (monosynaptic) and indirect connections with motor neurons. Although monosynaptic sensory-motor circuits between spindle proprioceptive sensory neurons and motor neurons have been extensively studied since 1950s, the molecular mechanisms underlying their formation and upkeep have only recently begun to be understood. We will discuss our current understanding of the molecular foundation of monosynaptic circuit development and maintenance involving proprioceptive sensory neurons and motor neurons in the mammalian spinal cord. Developmental Dynamics 247:581-587, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  8. Macoilin, a conserved nervous system-specific ER membrane protein that regulates neuronal excitability.

    Directory of Open Access Journals (Sweden)

    Fausto Arellano-Carbajal

    2011-03-01

    Full Text Available Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O₂ responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca²(+ transients, at least in some neurons: in maco-1 mutants the O₂-sensing neuron PQR is unable to generate a Ca²(+ response to a rise in O₂. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O₂, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca²(+ channels, also fails to disrupt Ca²(+ responses in the PQR cell body to O₂ stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca²(+ channel α1 subunit, recapitulate the Ca²(+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or

  9. Processing of Sensory Information in the Olfactory System

    DEFF Research Database (Denmark)

    The olfactory system is an attractive model system due to the easy control of sensory input and the experimental accessibility in animal studies. The odorant signals are processed from receptor neurons to a neural network of mitral and granular cells while various types of nonlinear behaviour can...... and equation-free techniques allow for a better reproduction and understanding of recent experimental findings. Talks: Olfaction as a Model System for Sensory-Processing Neural Networks (Jens Midtgaard, University of Copenhagen, Denmark) Nonlinear Effects of Signal Transduction in Olfactory Sensory Neurons...

  10. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H

    2007-01-01

    of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal...

  11. Dopamine Modulates the Activity of Sensory Hair Cells.

    Science.gov (United States)

    Toro, Cecilia; Trapani, Josef G; Pacentine, Itallia; Maeda, Reo; Sheets, Lavinia; Mo, Weike; Nicolson, Teresa

    2015-12-16

    The senses of hearing and balance are subject to modulation by efferent signaling, including the release of dopamine (DA). How DA influences the activity of the auditory and vestibular systems and its site of action are not well understood. Here we show that dopaminergic efferent fibers innervate the acousticolateralis epithelium of the zebrafish during development but do not directly form synapses with hair cells. However, a member of the D1-like receptor family, D1b, tightly localizes to ribbon synapses in inner ear and lateral-line hair cells. To assess modulation of hair-cell activity, we reversibly activated or inhibited D1-like receptors (D1Rs) in lateral-line hair cells. In extracellular recordings from hair cells, we observed that D1R agonist SKF-38393 increased microphonic potentials, whereas D1R antagonist SCH-23390 decreased microphonic potentials. Using ratiometric calcium imaging, we found that increased D1R activity resulted in larger calcium transients in hair cells. The increase of intracellular calcium requires Cav1.3a channels, as a Cav1 calcium channel antagonist, isradipine, blocked the increase in calcium transients elicited by the agonist SKF-38393. Collectively, our results suggest that DA is released in a paracrine fashion and acts at ribbon synapses, likely enhancing the activity of presynaptic Cav1.3a channels and thereby increasing neurotransmission. The neurotransmitter dopamine acts in a paracrine fashion (diffusion over a short distance) in several tissues and bodily organs, influencing and regulating their activity. The cellular target and mechanism of the action of dopamine in mechanosensory organs, such as the inner ear and lateral-line organ, is not clearly understood. Here we demonstrate that dopamine receptors are present in sensory hair cells at synaptic sites that are required for signaling to the brain. When nearby neurons release dopamine, activation of the dopamine receptors increases the activity of these mechanosensitive

  12. Whereas Short-Term Facilitation Is Presynaptic, Intermediate-Term Facilitation Involves Both Presynaptic and Postsynaptic Protein Kinases and Protein Synthesis

    Science.gov (United States)

    Jin, Iksung; Kandel, Eric R.; Hawkins, Robert D.

    2011-01-01

    Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that…

  13. GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks.

    Science.gov (United States)

    Vertkin, Irena; Styr, Boaz; Slomowitz, Edden; Ofir, Nir; Shapira, Ilana; Berner, David; Fedorova, Tatiana; Laviv, Tal; Barak-Broner, Noa; Greitzer-Antes, Dafna; Gassmann, Martin; Bettler, Bernhard; Lotan, Ilana; Slutsky, Inna

    2015-06-23

    Stabilization of neuronal activity by homeostatic control systems is fundamental for proper functioning of neural circuits. Failure in neuronal homeostasis has been hypothesized to underlie common pathophysiological mechanisms in a variety of brain disorders. However, the key molecules regulating homeostasis in central mammalian neural circuits remain obscure. Here, we show that selective inactivation of GABAB, but not GABA(A), receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA(B) receptor (GABA(B)R) blockade or genetic deletion of the GB(1a) receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA(B)Rs mediate adaptive presynaptic enhancement to neuronal inactivity by two principle mechanisms: First, neuronal silencing promotes syntaxin-1 switch from a closed to an open conformation to accelerate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and second, it boosts spike-evoked presynaptic calcium flux. In both cases, neuronal inactivity removes tonic block imposed by the presynaptic, GB(1a)-containing receptors on syntaxin-1 opening and calcium entry to enhance probability of vesicle fusion. We identified the GB(1a) intracellular domain essential for the presynaptic homeostatic response by tuning intermolecular interactions among the receptor, syntaxin-1, and the Ca(V)2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB(1b)-containing receptors. Thus, GABA(B)Rs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA(B)R as a key regulator of population firing stability and propose that disruption of homeostatic synaptic plasticity may underlie seizure's persistence in the absence of functional GABA(B)Rs.

  14. Adaptation of velocity encoding in synaptically coupled neurons in the fly visual system.

    Science.gov (United States)

    Kalb, Julia; Egelhaaf, Martin; Kurtz, Rafael

    2008-09-10

    Although many adaptation-induced effects on neuronal response properties have been described, it is often unknown at what processing stages in the nervous system they are generated. We focused on fly visual motion-sensitive neurons to identify changes in response characteristics during prolonged visual motion stimulation. By simultaneous recordings of synaptically coupled neurons, we were able to directly compare adaptation-induced effects at two consecutive processing stages in the fly visual motion pathway. This allowed us to narrow the potential sites of adaptation effects within the visual system and to relate them to the properties of signal transfer between neurons. Motion adaptation was accompanied by a response reduction, which was somewhat stronger in postsynaptic than in presynaptic cells. We found that the linear representation of motion velocity degrades during adaptation to a white-noise velocity-modulated stimulus. This effect is caused by an increasingly nonlinear velocity representation rather than by an increase of noise and is similarly strong in presynaptic and postsynaptic neurons. In accordance with this similarity, the dynamics and the reliability of interneuronal signal transfer remained nearly constant. Thus, adaptation is mainly based on processes located in the presynaptic neuron or in more peripheral processing stages. In contrast, changes of transfer properties at the analyzed synapse or in postsynaptic spike generation contribute little to changes in velocity coding during motion adaptation.

  15. Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

    Science.gov (United States)

    Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

    2014-05-07

    Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

  16. The Descending Diencephalic Dopamine System Is Tuned to Sensory Stimuli.

    Science.gov (United States)

    Reinig, Sebastian; Driever, Wolfgang; Arrenberg, Aristides B

    2017-02-06

    The vertebrate diencephalic A11 system provides the sole dopaminergic innervation of hindbrain and spinal cord and has been implicated in modulation of locomotion and sensory processes. However, the exact contributions of sensory stimuli and motor behavior to A11 dopaminergic activity remain unclear. We recorded cellular calcium activity in four anatomically distinct posterior tubercular A11-type dopaminergic subgroups and two adjacent hypothalamic dopaminergic groups in GCaMP7a-transgenic, semi-restrained zebrafish larvae. Our analyses reveal the contributions of different sensory modalities and motor states to dopaminergic activity. Each posterior tubercular and hypothalamic subgroup showed distinct activity patterns, while activity was synchronous within individual subgroups. Caudal and dorsomedial hypothalamic dopaminergic neurons are activated following vigorous tail movements and stay active for about 10 s, revealing predominantly post-motor activity. In contrast, posterior tubercular dopaminergic neurons are predominantly sensory driven, with subgroups differentially responding to different tactile or visual sensory modalities. In the anterior subgroups, neuronal response magnitudes are tuned to tactile stimulus intensities, revealing features similar to sensory systems. We identify the lateral line system as source for this tactile tuning. In contrast, the posterior subgroup is responsive to distinct moving visual stimuli. Specifically, translational forward stimuli, which may indicate insufficient rheotaxis and drift, induce dopaminergic activity, but backward or rotational stimuli not. The activation of posterior tubercular dopaminergic neurons by sensory stimuli, and their projections onto peripheral mechanosensory systems, suggests a participation of A11-type neurons in the feedback regulation of sensory systems. Together with the adjacent hypothalamic neurons, they may serve to set basic behavioral states. Copyright © 2017 Elsevier Ltd. All rights

  17. Prospective Coding by Spiking Neurons.

    Directory of Open Access Journals (Sweden)

    Johanni Brea

    2016-06-01

    Full Text Available Animals learn to make predictions, such as associating the sound of a bell with upcoming feeding or predicting a movement that a motor command is eliciting. How predictions are realized on the neuronal level and what plasticity rule underlies their learning is not well understood. Here we propose a biologically plausible synaptic plasticity rule to learn predictions on a single neuron level on a timescale of seconds. The learning rule allows a spiking two-compartment neuron to match its current firing rate to its own expected future discounted firing rate. For instance, if an originally neutral event is repeatedly followed by an event that elevates the firing rate of a neuron, the originally neutral event will eventually also elevate the neuron's firing rate. The plasticity rule is a form of spike timing dependent plasticity in which a presynaptic spike followed by a postsynaptic spike leads to potentiation. Even if the plasticity window has a width of 20 milliseconds, associations on the time scale of seconds can be learned. We illustrate prospective coding with three examples: learning to predict a time varying input, learning to predict the next stimulus in a delayed paired-associate task and learning with a recurrent network to reproduce a temporally compressed version of a sequence. We discuss the potential role of the learning mechanism in classical trace conditioning. In the special case that the signal to be predicted encodes reward, the neuron learns to predict the discounted future reward and learning is closely related to the temporal difference learning algorithm TD(λ.

  18. Interplay between presynaptic and postsynaptic activities is required for dendritic plasticity and synaptogenesis in the supraoptic nucleus.

    Science.gov (United States)

    Chevaleyre, Vivien; Moos, Francoise C; Desarménien, Michel G

    2002-01-01

    Developing oxytocin and vasopressin (OT/AVP) supraoptic nucleus (SON) neurons positively autocontrol their electrical activity via dendritic release of their respective peptide. The effects of this autocontrol are maximum during the second postnatal week (PW2), when the dendritic arbor transiently increases and glutamatergic postsynaptic potentials appear. Here, we studied the role and interaction of dendritic OT/AVP release and glutamate release in dendritic plasticity and synaptogenesis in SON. In vivo treatment with the peptides antagonists or with an NMDA antagonist suppressed the transient increase in dendritic arbor of SON neurons at the beginning of PW2. Incubation of acute slices with these compounds decreased the dendritic arbor on a short time scale (3-8 hr) in slices of postnatal day 7 (P7) to P9 rats. Conversely, application of OT/AVP or NMDA increased dendritic branches in slices of P3-P6 rats. Their effects were inhibited by blockade of electrical activity, voltage-gated Ca2+ channels, or intracellular Ca2+ mobilization. They were also interdependent because both OT/AVP and NMDA (but not AMPA) receptor activation were required for increasing the dendritic arbor. Part of this interdependence probably results from a retrograde action of the peptides facilitating glutamate release. Finally, blocking OT/AVP receptors by in vivo treatment with the peptides antagonists during development decreased spontaneous glutamatergic synaptic activity recorded in young adults. These results show that an interplay between postsynaptic dendritic peptide release and presynaptic glutamate release is involved in the transient increase in dendritic arbor of SON neurons and indicate that OT/AVP are required for normal synaptogenesis of glutamatergic inputs in SON.

  19. RIM determines Ca2+ channel density and vesicle docking at the presynaptic active zone

    Science.gov (United States)

    Han, Yunyun; Kaeser, Pascal S.; Südhof, Thomas C.; Schneggenburger, Ralf

    2012-01-01

    At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca2+ channels close to docked vesicles. The mechanisms that enrich Ca2+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knock-out approach at a presynaptically accessible CNS synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca2+ channel density, revealing a new role of RIM proteins in Ca2+ channel targeting. Removal of RIMs also reduced the readily-releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca2+ channel - vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release: enabling a high presynaptic Ca2+ channel density, and vesicle docking at the active zone. PMID:21262468

  20. The shortest isoform of dystrophin (Dp40) interacts with a group of presynaptic proteins to form a presumptive novel complex in the mouse brain.

    Science.gov (United States)

    Tozawa, Takenori; Itoh, Kyoko; Yaoi, Takeshi; Tando, So; Umekage, Masafumi; Dai, Hongmei; Hosoi, Hajime; Fushiki, Shinji

    2012-04-01

    Duchenne muscular dystrophy (DMD) causes cognitive impairment in one third of the patients, although the underlying mechanisms remain to be elucidated. Recent studies showed that mutations in the distal part of the dystrophin gene correlate well with the cognitive impairment in DMD patients, which is attributed to Dp71. The study on the expression of the shortest isoform, Dp40, has not been possible due to the lack of an isoform specific antibody. Dp40 has the same promoter as that found in Dp71 and lacks the normal C-terminal end of Dp427. In the present study, we have raised polyclonal antibody against the N-terminal sequence common to short isoforms of dystrophin, including Dp40, and investigated the expression pattern of Dp40 in the mouse brain. Affinity chromatography with this antibody and the consecutive LC-MS/MS analysis on the interacting proteins revealed that Dp40 was abundantly expressed in synaptic vesicles and interacted with a group of presynaptic proteins, including syntaxin1A and SNAP25, which are involved in exocytosis of synaptic vesicles in neurons. We thus suggest that Dp40 may form a novel protein complex and play a crucial role in presynaptic function. Further studies on these aspects of Dp40 function might provide more insight into the molecular mechanisms of cognitive impairment found in patients with DMD.

  1. Closing the gap: long-term presynaptic plasticity in brain function and disease.

    Science.gov (United States)

    Monday, Hannah R; Castillo, Pablo E

    2017-08-01

    Synaptic plasticity is critical for experience-dependent adjustments of brain function. While most research has focused on the mechanisms that underlie postsynaptic forms of plasticity, comparatively little is known about how neurotransmitter release is altered in a long-term manner. Emerging research suggests that many of the features of canonical 'postsynaptic' plasticity, such as associativity, structural changes and bidirectionality, also characterize long-term presynaptic plasticity. Recent studies demonstrate that presynaptic plasticity is a potent regulator of circuit output and function. Moreover, aberrant presynaptic plasticity is a convergent factor of synaptopathies like schizophrenia, addiction, and Autism Spectrum Disorders, and may be a potential target for treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation.

    Science.gov (United States)

    Hannan, Saad; Gerrow, Kim; Triller, Antoine; Smart, Trevor G

    2016-08-16

    Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca(2+)-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation

    Directory of Open Access Journals (Sweden)

    Saad Hannan

    2016-08-01

    Full Text Available Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca2+-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity.

  4. Making decisions with unknown sensory reliability.

    Science.gov (United States)

    Deneve, Sophie

    2012-01-01

    To make fast and accurate behavioral choices, we need to integrate noisy sensory input, take prior knowledge into account, and adjust our decision criteria. It was shown previously that in two-alternative-forced-choice tasks, optimal decision making can be formalized in the framework of a sequential probability ratio test and is then equivalent to a diffusion model. However, this analogy hides a "chicken and egg" problem: to know how quickly we should integrate the sensory input and set the optimal decision threshold, the reliability of the sensory observations must be known in advance. Most of the time, we cannot know this reliability without first observing the decision outcome. We consider here a Bayesian decision model that simultaneously infers the probability of two different choices and at the same time estimates the reliability of the sensory information on which this choice is based. We show that this can be achieved within a single trial, based on the noisy responses of sensory spiking neurons. The resulting model is a non-linear diffusion to bound where the weight of the sensory inputs and the decision threshold are both dynamically changing over time. In difficult decision trials, early sensory inputs have a stronger impact on the decision, and the threshold collapses such that choices are made faster but with low accuracy. The reverse is true in easy trials: the sensory weight and the threshold increase over time, leading to slower decisions but at much higher accuracy. In contrast to standard diffusion models, adaptive sensory weights construct an accurate representation for the probability of each choice. This information can then be combined appropriately with other unreliable cues, such as priors. We show that this model can account for recent findings in a motion discrimination task, and can be implemented in a neural architecture using fast Hebbian learning.

  5. Combining Optogenetics and Electrophysiology to Analyze Projection Neuron Circuits.

    Science.gov (United States)

    Yamawaki, Naoki; Suter, Benjamin A; Wickersham, Ian R; Shepherd, Gordon M G

    2016-10-03

    A set of methods is described for channelrhodopsin-2 (ChR2)-based synaptic circuit analysis that combines photostimulation of virally transfected presynaptic neurons' axons with whole-cell electrophysiological recordings from retrogradely labeled postsynaptic neurons. The approach exploits the preserved photoexcitability of ChR2-expressing axons in brain slices and can be used to assess either local or long-range functional connections. Stereotaxic injections are used both to express ChR2 selectively in presynaptic axons of interest (using rabies virus [RV] or adeno-associated virus [AAV]) and to label two types of postsynaptic projection neurons of interest with fluorescent retrograde tracers. In brain slices, tracer-labeled postsynaptic neurons are targeted for whole-cell electrophysiological recordings, and synaptic connections are assessed by sampling voltage or current responses to light-emitting diode (LED) photostimulation of ChR2-expressing axons. The data are analyzed to estimate the relative amplitude of synaptic input and other connectivity parameters. Pharmacological and electrophysiological manipulations extend the versatility of the basic approach, allowing the dissection of monosynaptic versus disynaptic responses, excitatory versus inhibitory responses, and more. The method enables rapid, quantitative characterization of synaptic connectivity between defined pre- and postsynaptic classes of neurons. © 2016 Cold Spring Harbor Laboratory Press.

  6. Protein synthesis in nerve terminals and the glia-neuron unit.

    Science.gov (United States)

    Crispino, Marianna; Cefaliello, Carolina; Kaplan, Barry; Giuditta, Antonio

    2009-01-01

    The progressive philogenetic lengthening of axonal processes and the increase in complexity of terminal axonal arborizations markedly augmented the demands of the neuronal cytoplasmic mass on somatic gene expression. It is proposed that in an adaptive response to this challenge, novel gene expression functions developed in the axon compartment, consisting of axonal and presynaptic translation systems that rely on the delivery of transcripts synthesized in adjacent glial cells. Such intercellular mode of gene expression would allow more rapid plastic changes to occur in spatially restricted neuronal domains, down to the size of individual synapses. The cell body contribution to local gene expression in well-differentiated neurons remains to be defined. The history of this concept and the experimental evidence supporting its validity are critically discussed in this article. The merit of this perspective lies with the recognition that plasticity events represent a major occurrence in the brain, and that they largely occur at synaptic sites, including presynaptic endings.

  7. MOLECULAR-BIOLOGY OF CLOSTRIDIAL TOXINS - EXPRESSION OF MESSENGER-RNAS ENCODING TETANUS AND BOTULINUM NEUROTOXINS IN APLYSIA NEURONS

    NARCIS (Netherlands)

    MOCHIDA, S; POULAIN, B; EISEL, U; BINZ, T; KURAZONO, H; NIEMANN, H; TAUC, L

    1990-01-01

    mRNAs encoding the light chain of tetanus and botulinum neurotoxins were transcribed, in vitro, from the cloned and specifically truncated genes of Clostridium tetani and Clostridium botulinum, respectively, and injected into presynaptic identified cholinergic neurons of the buccal ganglia of

  8. Microheterogeneity of the growth-associated neuronal protein B-50 (GAP 43). Contribution of phosphorylation by protein kinase C

    NARCIS (Netherlands)

    Gispen, W.H.; Schotman, P.; Nielander, H.B.; Rozen, A.J. van; Frankena, H.; Schrama, L.H.

    1989-01-01

    The neuron-specific, growth-associated protein B-50, also known as GAP-43, F1 and neuromodulin, shows a striking heterogeneous behaviour in many chromatographic and electrophoretic systems. A modulatory function has been proposed for the protein in receptor-mediated processes in the presynaptic

  9. Expression of presynaptic markers in a neurodevelopmental animal model with relevance to schizophrenia

    DEFF Research Database (Denmark)

    Karlsen, Anna S; Kaalund, Sanne Simone; Møller, Morten

    2013-01-01

    Administration of N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal......-associated protein of 25 kDa (Snap25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in...

  10. [What mirror neurons have revealed: revisited].

    Science.gov (United States)

    Murata, Akira; Maeda, Kazutaka

    2014-06-01

    The first paper on mirror neurons was published in 1992. In the span of over two decades since then, much knowledge about the relationship between social cognitive function and the motor control system has been accumulated. Direct matching of visual actions and their corresponding motor representations is the most important functional property of mirror neuron. Many studies have emphasized intrinsic simulation as a core concept for mirror neurons. Mirror neurons are thought to play a role in social cognitive function. However, the function of mirror neurons in the macaque remains unclear, because such cognitive functions are limited or lacking in macaque monkeys. It is therefore important to discuss these neurons in the context of motor function. Rizzolatti and colleagues have stressed that the most important function of mirror neurons in macaques is recognition of actions performed by other individuals. I suggest that mirror neurons in the Macaque inferior pariental lobule might be correlated with body schema. In the parieto-premotor network, matching of corollary discharge and actual sensory feedback is an essential neuronal operation. Recently, neurons showing mirror properties were found in some cortical areas outside the mirror neuron system. The current work would revisit the outcomes of mirror neuron studies to discuss the function of mirror neurons in the monkey.

  11. Influence of transcutaneous electrical nerve stimulation conditions on disynaptic reciprocal Ia inhibition and presynaptic inhibition in healthy adults.

    Science.gov (United States)

    Takeda, Kazuya; Tanabe, Shigeo; Koyama, Soichiro; Ushiroyama, Kosuke; Naoi, Yuki; Motoya, Ikuo; Sakurai, Hiroaki; Kanada, Yoshikiyo

    2017-03-01

    This study investigated the influence of stimulus conditions of transcutaneous electrical nerve stimulation (TENS) on disynaptic reciprocal Ia inhibition (RI) and presynaptic inhibition (D1 inhibition) in healthy adults. Eight healthy participants received TENS (stimulus frequencies of 50, 100, and 200 Hz) over the deep peroneal nerve and tibialis anterior (TA) muscle in the resting condition for 30 min. At pre- and post-intervention, the RI from the TA to the soleus (SOL) and D1 inhibition of the SOL alpha motor neuron were assessed by evoked electromyography. The results showed that RI was not changed by TENS at any stimulus frequency condition. Conversely, D1 inhibition was significantly changed by TENS regardless of the stimulus frequency. The present results and previous studies pertaining to RI suggest that the resting condition might strongly influence the lack of pre- vs. post-intervention change in the RI. Regarding the D1 inhibition, the present results suggest that the effect of TENS might be caused by post-tetanic potentiation. The knowledge gained from the present study might contribute to a better understanding of fundamental studies of TENS in healthy adults and its clinical application for stroke survivors.

  12. Axonal regeneration and neuronal function are preserved in motor neurons lacking ß-actin in vivo.

    Directory of Open Access Journals (Sweden)

    Thomas R Cheever

    2011-03-01

    Full Text Available The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA, suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo.

  13. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    Science.gov (United States)

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana Del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons

    Directory of Open Access Journals (Sweden)

    Vincent Adele J

    2011-03-01

    Full Text Available Abstract Background Familial amyloidotic polyneuropathy (FAP is a peripheral neuropathy caused by the extracellular accumulation and deposition of insoluble transthyretin (TTR aggregates. However the molecular mechanism that underlies TTR toxicity in peripheral nerves is unclear. Previous studies have suggested that amyloidogenic proteins can aggregate into oligomers which disrupt intracellular calcium homeostasis by increasing the permeability of the plasma membrane to extracellular calcium. The aim of the present study was to examine the effect of TTR on calcium influx in dorsal root ganglion neurons. Results Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC, as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8 channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones. Conclusions These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.

  15. Neural map formation and sensory coding in the vomeronasal system.

    Science.gov (United States)

    Brignall, Alexandra C; Cloutier, Jean-François

    2015-12-01

    Sensory systems enable us to encode a clear representation of our environment in the nervous system by spatially organizing sensory stimuli being received. The organization of neural circuitry to form a map of sensory activation is critical for the interpretation of these sensory stimuli. In rodents, social communication relies strongly on the detection of chemosignals by the vomeronasal system, which regulates a wide array of behaviours, including mate recognition, reproduction, and aggression. The binding of these chemosignals to receptors on vomeronasal sensory neurons leads to activation of second-order neurons within glomeruli of the accessory olfactory bulb. Here, vomeronasal receptor activation by a stimulus is organized into maps of glomerular activation that represent phenotypic qualities of the stimuli detected. Genetic, electrophysiological and imaging studies have shed light on the principles underlying cell connectivity and sensory map formation in the vomeronasal system, and have revealed important differences in sensory coding between the vomeronasal and main olfactory system. In this review, we summarize the key factors and mechanisms that dictate circuit formation and sensory coding logic in the vomeronasal system, emphasizing differences with the main olfactory system. Furthermore, we discuss how detection of chemosignals by the vomeronasal system regulates social behaviour in mice, specifically aggression.

  16. Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.

    Science.gov (United States)

    Liu, Jing-Jing; Bello, Nicholas T; Pang, Zhiping P

    2017-12-06

    Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states. SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food

  17. Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers

    Directory of Open Access Journals (Sweden)

    Sulejczak Dorota

    2009-12-01

    Full Text Available Abstract Background It has been postulated that exercise-induced activation of brain-derived neurotrophic factor (BDNF may account for improvement of stepping ability in animals after complete spinal cord transection. As we have shown previously, treadmill locomotor exercise leads to up-regulation of BDNF protein and mRNA in the entire neuronal network of intact spinal cord. The questions arise: (i how the treadmill locomotor training, supplemented with tail stimulation, affects the expression of molecular correlates of synaptic plasticity in spinal rats, and (ii if a response is related to BDNF protein level and distribution. We investigated the effect of training in rats spinalized at low thoracic segments on the level and distribution of BDNF immunoreactivity (IR in ventral quadrants of the lumbar segments, in conjunction with markers of presynaptic terminals, synaptophysin and synaptic zinc. Results Training improved hindlimb stepping in spinal animals evaluated with modified Basso-Beattie-Bresnahan scale. Grades of spinal trained animals ranged between 5 and 11, whereas those of spinal were between 2 and 4. Functional improvement was associated with changes in presynaptic markers and BDNF distribution. Six weeks after transection, synaptophysin IR was reduced by 18% around the large neurons of lamina IX and training elevated its expression by over 30%. The level of synaptic zinc staining in the ventral horn was unaltered, whereas in ventral funiculi it was decreased by 26% postlesion and tended to normalize after the training. Overall BDNF IR levels in the ventral horn, which were higher by 22% postlesion, were unchanged after the training. However, training modified distribution of BDNF in the processes with its predominance in the longer and thicker ones. It also caused selective up-regulation of BDNF in two classes of cells (soma ranging between 100-400 μm2 and over 1000 μm2 of the ventrolateral and laterodorsal motor nuclei

  18. Epilepsy and the Sensory Systems

    OpenAIRE

    Wolf, Peter

    2016-01-01

    The relations of epilepsy and the sensory systems are bidirectional. Epilepsy may act on sensory systems by producing sensory seizure symptoms, by altering sensory performance, and by epilepsy treatment causing sensory side effects. Sensory system activity may have an important role in both generation and inhibition of seizures.

  19. The Sensory Neocortex and Associative Memory.

    Science.gov (United States)

    Aschauer, Dominik; Rumpel, Simon

    2018-01-01

    Most behaviors in mammals are directly or indirectly guided by prior experience and therefore depend on the ability of our brains to form memories. The ability to form an association between an initially possibly neutral sensory stimulus and its behavioral relevance is essential for our ability to navigate in a changing environment. The formation of a memory is a complex process involving many areas of the brain. In this chapter we review classic and recent work that has shed light on the specific contribution of sensory cortical areas to the formation of associative memories. We discuss synaptic and circuit mechanisms that mediate plastic adaptations of functional properties in individual neurons as well as larger neuronal populations forming topographically organized representations. Furthermore, we describe commonly used behavioral paradigms that are used to study the mechanisms of memory formation. We focus on the auditory modality that is receiving increasing attention for the study of associative memory in rodent model systems. We argue that sensory cortical areas may play an important role for the memory-dependent categorical recognition of previously encountered sensory stimuli.

  20. Calcium Assists Dopamine Release by Preventing Aggregation on the Inner Leaflet of Presynaptic Vesicles

    DEFF Research Database (Denmark)

    Mokkila, Sini; Postila, Pekka A.; Rissanen, Sami

    2017-01-01

    . The inner leaflets of presynaptic vesicles, which are responsible for releasing neurotransmitters into the synaptic cleft, are mainly composed of neutral lipids such as phosphatidylcholine and phosphatidylethanolamine. The neutrality of the lipid head group region, enhanced by a low pH level, should limit...

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Integrative spike dynamics of rat CA1 neurons: a multineuronal imaging study.

    Science.gov (United States)

    Sasaki, Takuya; Kimura, Rie; Tsukamoto, Masako; Matsuki, Norio; Ikegaya, Yuji

    2006-07-01

    The brain operates through a coordinated interplay of numerous neurons, yet little is known about the collective behaviour of individual neurons embedded in a huge network. We used large-scale optical recordings to address synaptic integration in hundreds of neurons. In hippocampal slice cultures bolus-loaded with Ca2+ fluorophores, we stimulated the Schaffer collaterals and monitored the aggregate presynaptic activity from the stratum radiatum and individual postsynaptic spikes from the CA1 stratum pyramidale. Single neurons responded to varying synaptic inputs with unreliable spikes, but at the population level, the networks stably output a linear sum of synaptic inputs. Nonetheless, the network activity, even though given constant stimuli, varied from trial to trial. This variation emerged through time-varying recruitment of different neuron subsets, which were shaped by correlated background noise. We also mapped the input-frequency preference in spiking activity and found that the majority of CA1 neurons fired in response to a limited range of presynaptic firing rates (20-40 Hz), acting like a band-pass filter, although a few neurons had high pass-like or low pass-like characteristics. This frequency selectivity depended on phasic inhibitory transmission. Thus, our imaging approach enables the linking of single-cell behaviours to their communal dynamics, and we discovered that, even in a relatively simple CA1 circuit, neurons could be engaged in concordant information processing.

  3. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H

    2007-01-01

    Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron...... nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side...... of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal...

  4. Encoding of Naturalistic Optic Flow by a Population of Blowfly Motion-Sensitive Neurons

    NARCIS (Netherlands)

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

    In sensory systems information is encoded by the activity of populations of neurons. To analyze the coding properties of neuronal populations sensory stimuli have usually been used that were much simpler than those encountered in real life. It has been possible only recently to stimulate visual

  5. Intersession reliability of Hoffmann reflex gain and presynaptic inhibition in the human soleus muscle.

    Science.gov (United States)

    Hayes, Bradley T; Hicks-Little, Charlie A; Harter, Rod A; Widrick, Jeffrey J; Hoffman, Mark A

    2009-12-01

    Hayes BT, Hicks-Little CA, Harter RA, Widrick JJ, Hoffman MA. Intersession reliability of Hoffmann reflex gain and presynaptic inhibition in the human soleus muscle. To determine the day-to-day reliability of Hoffmann reflex (H-reflex) gain and presynaptic inhibition of spinal reflexes in the human soleus muscle. Controlled trial. Research laboratory. Volunteers (N=30; mean +/- SD age, 23.4+/-3.9y; height, 175.64+/-10.87cm; mass, 84.50+/-24.18kg) with no history of lower extremity pathology and/or injury participated. Subjects lay prone with the head, shoulders, arms, and hips supported in a static position by a massage body pillow and the ankle positioned at 90 degrees . Recording electrodes were placed over the soleus and tibialis anterior muscle bellies, and the stimulating electrodes were positioned over the tibial nerve in the popliteal space and the common peroneal nerve near the fibular head. The H-reflex and motor wave recruitment curves were then measured and recorded. Presynaptic inhibition was also assessed in the soleus muscle, and a conditioning stimulation of the common peroneal nerve (1 x motor threshold = motor threshold) was used prior to soleus H-reflex measurement. Two testing sessions took place between 2 and 7 days, and each session occurred at the same time of day. Assessments of H-reflex gain and presynaptic inhibition yielded test-retest reliability of R equal to . 95 and .91, respectively. Measures of presynaptic inhibition and H-reflex gain (H slope/M slope) in the human soleus muscle are consistent and reliable day to day.

  6. Prolonged cannabinoid exposure alters GABAA receptor mediated synaptic function in cultured hippocampal neurons

    Science.gov (United States)

    Deshpande, Laxmikant S.; Blair, Robert. E.; DeLorenzo, Robert. J.

    2011-01-01

    Developing cannabinoid based medication along with marijuana’s recreational use makes it important to investigate molecular adaptations the endocannabinoid system undergoes following prolonged use and withdrawal. Repeated cannabinoid administration results in development of tolerance and produces withdrawal symptoms that may include seizures. Here we employed electrophysiological and immunochemical techniques to investigate the effects of prolonged CB1 receptor agonist exposure on cultured hippocampal neurons. Approximately 60% of CB1 receptors colocalize to GABAergic terminals in hippocampal cultures. Prolonged treatment with the cannabinamimetic WIN 55,212-2 (+WIN, 1μM, 24-h) caused profound CB1 receptor downregulation accompanied by neuronal hyperexcitability. Furthermore, prolonged +WIN treatment resulted in increased GABA release as indicated by increased mIPSC frequency, a diminished GABAergic inhibition as indicated by reduction in mIPSC amplitude and a reduction in GABAA channel number. Additionally, surface staining for the GABAA β2/3 receptor subunits was decreased, while no changes in staining for the presynaptic vesicular GABA transporter were observed, indicating that GABAergic terminals remained intact. These findings demonstrate that agonist-induced downregulation of the CB1 receptor in hippocampal cultures results in neuronal hyperexcitability that may be attributed, in part, to alterations in both presynaptic GABA release mechanisms and postsynaptic GABAA receptor function demonstrating a novel role for cannabinoid-dependent presynaptic control of neuronal transmission. PMID:21324315

  7. Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease.

    Science.gov (United States)

    Purpura, D P; Suzuki, K

    1976-10-29

    Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

  8. Noisy Neurons

    Indian Academy of Sciences (India)

    IAS Admin

    Nerves are fibres that conduct electrical signals and hence pass on information from and to the brain. Nerves are made of nerve cells called neurons (Figure 1). Instructions in our body are sent via electrical signals that present themselves as variations in the potential across neuronal membranes. These potential differences ...

  9. Neurogenesis of cephalic sensory organs of Aplysia californica

    DEFF Research Database (Denmark)

    Wollesen, Tim; Wanninger, Andreas; Klussmann-Kolb, Annette

    2007-01-01

    The opisthobranch gastropod Aplysia californica serves as a model organism in experimental neurobiology because of its simple and well-known nervous system. However, its nervous periphery has been less intensely studied. We have reconstructed the ontogeny of the cephalic sensory organs (labial te...... of FMRFamide-like peptides in the modulation of peripheral sensory processes. This study is the first concerning the neurogenesis of cephalic sensory organs in A. californica and may serve as a basis for future studies of neuronal elements in gastropod molluscs....

  10. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.

    Science.gov (United States)

    García-Ramírez, David L; Calvo, Jorge R; Hochman, Shawn; Quevedo, Jorge N

    2014-01-01

    Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the

  11. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.

    Directory of Open Access Journals (Sweden)

    David L García-Ramírez

    Full Text Available Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD. PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT, dopamine (DA and noradrenaline (NA on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs or intracellular excitatory postsynaptic currents (EPSCs. The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75% but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic

  12. Conversion of sensory signals into perceptual decisions.

    Science.gov (United States)

    Romo, Ranulfo; de Lafuente, Victor

    2013-04-01

    A fundamental problem in neurobiology is to understand how brain circuits represent sensory information and how such representations give rise to perception, memory and decision-making. We demonstrate that a sensory stimulus engages multiple areas of the cerebral cortex, including primary sensory, prefrontal, premotor and motor cortices. As information transverses the cortical circuits it shows progressively more relation to perception, memory and decision reports. In particular, we show how somatosensory areas on the parietal lobe generate a parameterized representation of a tactile stimulus. This representation is maintained in working memory by prefrontal and premotor areas of the frontal lobe. The presentation of a second stimulus, that monkeys are trained to compare with the first, generates decision-related activity reflecting which stimulus had the higher frequency. Importantly, decision-related activity is observed across several cortical circuits including prefrontal, premotor and parietal cortices. Sensory information is encoded by neuronal populations with opposite tuning, and suggests that a simple subtraction operation could be the underlying mechanism by which past and present sensory information is compared to generate perceptual decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Conductive Hearing Loss Has Long-Lasting Structural and Molecular Effects on Presynaptic and Postsynaptic Structures of Auditory Nerve Synapses in the Cochlear Nucleus.

    Science.gov (United States)

    Clarkson, Cheryl; Antunes, Flora M; Rubio, Maria E

    2016-09-28

    the level of the lateral lemniscus, and to long-lasting presynaptic and postsynaptic structural and molecular effects at the endbulb of the Held synapse. Knowledge of the structural and molecular changes associated with decreased sensory experience, along with their potential reversibility, is important for the treatment of hearing deficits, such as hyperacusis and chronic otitis media with effusion, which is prevalent in young children with language acquisition or educational disabilities. Copyright © 2016 the authors 0270-6474/16/3610214-14$15.00/0.

  14. Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

    Science.gov (United States)

    Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

    2017-05-10

    Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

  15. Primary sensory cortices contain distinguishable spatial patterns of activity for each sense.

    Science.gov (United States)

    Liang, M; Mouraux, A; Hu, L; Iannetti, G D

    2013-01-01

    Whether primary sensory cortices are essentially multisensory or whether they respond to only one sense is an emerging debate in neuroscience. Here we use a multivariate pattern analysis of functional magnetic resonance imaging data in humans to demonstrate that simple and isolated stimuli of one sense elicit distinguishable spatial patterns of neuronal responses, not only in their corresponding primary sensory cortex, but in other primary sensory cortices. These results indicate that primary sensory cortices, traditionally regarded as unisensory, contain unique signatures of other senses and, thereby, prompt a reconsideration of how sensory information is coded in the human brain.

  16. The Wiring of Developing Sensory Circuits-From Patterned Spontaneous Activity to Synaptic Plasticity Mechanisms

    NARCIS (Netherlands)

    Leighton, Alexandra H; Lohmann, C.

    2016-01-01

    In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous

  17. Behavioral guides for sensory neurophysiology.

    Science.gov (United States)

    Konishi, M

    2006-06-01

    The study of natural behavior is important for understanding the coding schemes of sensory systems. The jamming avoidance response of the weakly electric fish Eigenmannia is an excellent example of a bottom-up approach, in which behavioral analyses guided neurophysiological studies. These studies started from the electroreceptive sense organs to the motor output consisting of pacemaker neurons. Going in the opposite direction, from the central nervous system to lower centers, is the characteristic of the top-down approach. Although this approach is perhaps more difficult than the bottom-up approach, it was successfully employed in the neuroethological analysis of sound localization in the barn owl. In the latter studies, high-order neurons selective for complex natural stimuli led to the discovery of neural pathways and networks responsible for the genesis of the stimulus selectivity. Comparison of Eigenmannia and barn owls, and their neural systems, has revealed similarities in network designs, such as parallel pathways and their convergence to produce stimulus selectivity necessary for detection of natural stimuli.

  18. Functional sensory symptoms

    NARCIS (Netherlands)

    Stone, J.; Vermeulen, M.

    2017-01-01

    Functional (psychogenic) sensory symptoms are those in which the patient genuinely experiences alteration or absence of normal sensation in the absence of neurologic disease. The hallmark of functional sensory symptoms is the presence of internal inconsistency revealing a pattern of symptoms

  19. DYSFUNCTIONAL PRESYNAPTIC ALPHA-2-ADRENOCEPTORS EXPOSE FACILITATORY BETA-2-ADRENOCEPTORS IN THE VASCULATURE OF SPONTANEOUSLY HYPERTENSIVE RATS

    NARCIS (Netherlands)

    REMIE, R; VANROSSUM, JXM; COPPES, RP; ZAAGSMA, J

    1992-01-01

    Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha(2)- and beta(2)-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of

  20. Immobilization induces changes in presynaptic control of group Ia afferents in healthy humans

    DEFF Research Database (Denmark)

    Jensen, Jesper Lundbye; Nielsen, Jens Bo

    2008-01-01

    Neural plasticity occurs throughout adult life in response to maturation, use and disuse. Recent studies have documented that H-reflex amplitudes increase following a period of immobilization. To elucidate the mechanisms contributing to the increase in H-reflex size following immobilization we...... immobilized the left foot and ankle joint for 2 weeks in 12 able-bodied subjects. Disynaptic reciprocal inhibition of soleus (SOL) motoneurones and presynaptic control of SOL group Ia afferents was measured before and after the immobilization as well as following 2 weeks of recovery. Following immobilization...... inhibition of SOL Ia afferents and taken together suggest that GABAergic presynaptic inhibition of the SOL Ia afferents is decreased following 2 weeks of immobilization. The depression of the SOL H-reflex when evoked at intervals shorter than 10 s (homosynaptic post-activation depression) also decreased...

  1. Sensory correlations in autism.

    Science.gov (United States)

    Kern, Janet K; Trivedi, Madhukar H; Grannemann, Bruce D; Garver, Carolyn R; Johnson, Danny G; Andrews, Alonzo A; Savla, Jayshree S; Mehta, Jyutika A; Schroeder, Jennifer L

    2007-03-01

    This study examined the relationship between auditory, visual, touch, and oral sensory dysfunction in autism and their relationship to multisensory dysfunction and severity of autism. The Sensory Profile was completed on 104 persons with a diagnosis of autism, 3 to 56 years of age. Analysis showed a significant correlation between the different processing modalities using total scores. Analysis also showed a significant correlation between processing modalities for both high and low thresholds, with the exception that auditory high threshold processing did not correlate with oral low threshold or touch low threshold processing. Examination of the different age groups suggests that sensory disturbance correlates with severity of autism in children, but not in adolescents and adults. Evidence from this study suggests that: all the main modalities and multisensory processing appear to be affected; sensory processing dysfunction in autism is global in nature; and sensory processing problems need to be considered part of the disorder.

  2. Probabilistic sensory recoding.

    Science.gov (United States)

    Jazayeri, Mehrdad

    2008-08-01

    A hallmark of higher brain functions is the ability to contemplate the world rather than to respond reflexively to it. To do so, the nervous system makes use of a modular architecture in which sensory representations are dissociated from areas that control actions. This flexibility however necessitates a recoding scheme that would put sensory information to use in the control of behavior. Sensory recoding faces two important challenges. First, recoding must take into account the inherent variability of sensory responses. Second, it must be flexible enough to satisfy the requirements of different perceptual goals. Recent progress in theory, psychophysics, and neurophysiology indicate that cortical circuitry might meet these challenges by evaluating sensory signals probabilistically.

  3. Identifying and tracking simulated synaptic inputs from neuronal firing: insights from in vitro experiments.

    Directory of Open Access Journals (Sweden)

    Maxim Volgushev

    2015-03-01

    Full Text Available Accurately describing synaptic interactions between neurons and how interactions change over time are key challenges for systems neuroscience. Although intracellular electrophysiology is a powerful tool for studying synaptic integration and plasticity, it is limited by the small number of neurons that can be recorded simultaneously in vitro and by the technical difficulty of intracellular recording in vivo. One way around these difficulties may be to use large-scale extracellular recording of spike trains and apply statistical methods to model and infer functional connections between neurons. These techniques have the potential to reveal large-scale connectivity structure based on the spike timing alone. However, the interpretation of functional connectivity is often approximate, since only a small fraction of presynaptic inputs are typically observed. Here we use in vitro current injection in layer 2/3 pyramidal neurons to validate methods for inferring functional connectivity in a setting where input to the neuron is controlled. In experiments with partially-defined input, we inject a single simulated input with known amplitude on a background of fluctuating noise. In a fully-defined input paradigm, we then control the synaptic weights and timing of many simulated presynaptic neurons. By analyzing the firing of neurons in response to these artificial inputs, we ask 1 How does functional connectivity inferred from spikes relate to simulated synaptic input? and 2 What are the limitations of connectivity inference? We find that individual current-based synaptic inputs are detectable over a broad range of amplitudes and conditions. Detectability depends on input amplitude and output firing rate, and excitatory inputs are detected more readily than inhibitory. Moreover, as we model increasing numbers of presynaptic inputs, we are able to estimate connection strengths more accurately and detect the presence of connections more quickly. These results

  4. Greater ethanol-induced locomotor activation in DBA/2J versus C57BL/6J mice is not predicted by presynaptic striatal dopamine dynamics.

    Directory of Open Access Journals (Sweden)

    Jamie H Rose

    Full Text Available A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.

  5. Presynaptic CaV2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held.

    Science.gov (United States)

    Inchauspe, Carlota González; Urbano, Francisco J; Di Guilmi, Mariano N; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Forsythe, Ian D; Uchitel, Osvaldo D

    2012-12-01

    Ca(V)2.1 Ca(2+) channels have a dominant and specific role in initiating fast synaptic transmission at central excitatory synapses, through a close association between release sites and calcium sensors. Familial hemiplegic migraine type 1 (FHM-1) is an autosomal-dominant subtype of migraine with aura, caused by missense mutations in the CACNA1A gene that encodes the α(1A) pore-forming subunit of Ca(V)2.1 channel. We used knock-in (KI) transgenic mice harboring the FHM-1 mutation R192Q to study the consequences of this mutation in neurotransmission at the giant synapse of the auditory system formed by the presynaptic calyx of Held terminal and the postsynaptic neurons of the medial nucleus of the trapezoid body (MNTB). Although synaptic transmission seems unaffected by low-frequency stimulation in physiological Ca(2+) concentration, we observed that with low Ca(2+) concentrations (transmitter release. In addition, when EPSCs were evoked by broadened presynaptic action potentials (achieved by inhibition of K(+) channels) via Ca(v)2.1-triggered exocytosis, R192Q KI mice exhibited further enhancement of EPSC amplitude and charge compared with WT mice. Repetitive stimulation of afferent axons to the MNTB at different frequencies caused short-term depression of EPSCs that recovered significantly faster in R192Q KI mice than in WT mice. Faster recovery in R192Q KI mice was prevented by the calcium chelator EGTA-AM, pointing to enlarged residual calcium as a key factor in accelerating the replenishment of synaptic vesicles.

  6. The power of projectomes: genetic mosaic labeling in the larval zebrafish brain reveals organizing principles of sensory circuits.

    Science.gov (United States)

    Robles, Estuardo

    2017-09-01

    In no vertebrate species do we possess an accurate, comprehensive tally of neuron types in the brain. This is in no small part due to the vast diversity of neuronal types that comprise complex vertebrate nervous systems. A fundamental goal of neuroscience is to construct comprehensive catalogs of cell types defined by structure, connectivity, and physiological response properties. This type of information will be invaluable for generating models of how assemblies of neurons encode and distribute sensory information and correspondingly alter behavior. This review summarizes recent efforts in the larval zebrafish to construct sensory projectomes, comprehensive analyses of axonal morphologies in sensory axon tracts. Focusing on the olfactory and optic tract, these studies revealed principles of sensory information processing in the olfactory and visual systems that could not have been directly quantified by other methods. In essence, these studies reconstructed the optic and olfactory tract in a virtual manner, providing insights into patterns of neuronal growth that underlie the formation of sensory axon tracts. Quantitative analysis of neuronal diversity revealed organizing principles that determine information flow through sensory systems in the zebrafish that are likely to be conserved across vertebrate species. The generation of comprehensive cell type classifications based on structural, physiological, and molecular features will lead to testable hypotheses on the functional role of individual sensory neuron subtypes in controlling specific sensory-evoked behaviors.

  7. 123-I ioflupane (Datscan) presynaptic nigrostriatal imaging in patients with movement disorders

    International Nuclear Information System (INIS)

    Soriano Castrejon, Angel; Garcia Vicente, Ana Maria; Cortes Romera, Montserrat; Rodado Marina, Sonia; Poblete Garcia, Victor Manuel; Ruiz Solis, Sebastian Ruiz; Talavera Rubio, Maria del Prado; Vaamonde Cano, Julia

    2005-01-01

    123-I Ioflupane (Datscan) presynaptic imaging has been shown to have a significant utility in the assessment of patients with movement disorders 123 I Ioflupane SPECT is able to distinguish between Parkinson's disease (PD) and other forms of parkinsonism without degeneration of the nigrostriatal pathway, including a common movement disorder such as essential tremor, and to assess disease progression in PD and other neuro degenerative disorders involving the substantia nigra. (author)

  8. New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

    Science.gov (United States)

    2015-07-01

    and 280nm using a BioMate 5 UV- visible spectrophotometer (Thermo Spectronic, Waltham, Massachusetts, USA). The integrity of the extracted RNA was...presynaptic P/Q-type voltage-dependent calcium channel to reduce glutamate release. In a different study, local perfusion with LEV (10, 30 and 100M) alone...the brain was used for protein expression analysis (western blotting) as described above while the other hemisphere was used for mRNA extraction . As

  9. Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans

    OpenAIRE

    Mukhopadhyay, Saikat; Lu, Yun; Shaham, Shai; Sengupta, Piali

    2008-01-01

    Non-motile primary cilia are sensory organelles comprised of a microtubular axoneme and a surrounding membrane sheath that houses signaling molecules. Optimal cellular function requires the precise regulation of axoneme assembly, membrane biogenesis and signaling protein targeting and localization via as yet poorly understood mechanisms. Here we show that sensory signaling is required to maintain the architecture of the specialized AWB olfactory neuron cilia in C. elegans. Decreased sensory s...

  10. NEUROPHYSIOLOGICAL EVALUATION OF SENSORY SYSTEMS'

    Science.gov (United States)

    Exposure to many neurotoxic compounds has been shown to produce a sensory system dysfunction. Neurophysiological assessment of sensory function in humans and animal models often uses techniques known as sensory evoked potentials. Because both humans and animals show analogous res...

  11. No consistent bioenergetic defects in presynaptic nerve terminals isolated from mouse models of Alzheimer’s disease

    OpenAIRE

    Choi, Sung W.; Gerencser, Akos A.; Ng, Ryan; Flynn, James M.; Melov, Simon; Danielson, Steven R.; Gibson, Bradford W.; Nicholls, David G.; Bredesen, Dale E.; Brand, Martin D.

    2012-01-01

    Depressed cortical energy supply and impaired synaptic function are predominant associations of Alzheimer’s disease (AD). To test the hypothesis that presynaptic bioenergetic deficits are associated with the progression of AD pathogenesis, we compared bioenergetic variables of cortical and hippocampal presynaptic nerve terminals (synaptosomes) from commonly used mouse models with AD-like phenotypes (J20 age 6 months, Tg2576 age 16 months and APP/PS age 9 and 14 months) to ag...

  12. Bilateral Pathways from the Basal Forebrain to Sensory Cortices May Contribute to Synchronous Sensory Processing

    Directory of Open Access Journals (Sweden)

    Irene Chaves-Coira

    2018-01-01

    Full Text Available Sensory processing in the cortex should integrate inputs arriving from receptive fields located on both sides of the body. This role could be played by the corpus callosum through precise projections between both hemispheres. However, different studies suggest that cholinergic projections from the basal forebrain (BF could also contribute to the synchronization and integration of cortical activities. Using tracer injections and optogenetic techniques in transgenic mice, we investigated whether the BF cells project bilaterally to sensory cortical areas, and have provided anatomical evidence to support a modulatory role for the cholinergic projections in sensory integration. Application of the retrograde tracer Fluor-Gold or Fast Blue in both hemispheres of the primary somatosensory (S1, auditory or visual cortical areas showed labeled neurons in the ipsi- and contralateral areas of the diagonal band of Broca and substantia innominata. The nucleus basalis magnocellularis only showed ipsilateral projections to the cortex. Optogenetic stimulation of the horizontal limb of the diagonal band of Broca facilitated whisker responses in the S1 cortex of both hemispheres through activation of muscarinic cholinergic receptors and this effect was diminished by atropine injection. In conclusion, our findings have revealed that specific areas of the BF project bilaterally to sensory cortices and may contribute to the coordination of neuronal activity on both hemispheres.

  13. Presynaptic active zones of mammalian neuromuscular junctions: Nanoarchitecture and selective impairments in aging.

    Science.gov (United States)

    Badawi, Yomna; Nishimune, Hiroshi

    2018-02-01

    Neurotransmitter release occurs at active zones, which are specialized regions of the presynaptic membrane. A dense collection of proteins at the active zone provides a platform for molecular interactions that promote recruitment, docking, and priming of synaptic vesicles. At mammalian neuromuscular junctions (NMJs), muscle-derived laminin β2 interacts with presynaptic voltage-gated calcium channels to organize active zones. The molecular architecture of presynaptic active zones has been revealed using super-resolution microscopy techniques that combine nanoscale resolution and multiple molecular identification. Interestingly, the active zones of adult NMJs are not stable structures and thus become impaired during aging due to the selective degeneration of specific active zone proteins. This review will discuss recent progress in the understanding of active zone nanoarchitecture and the mechanisms underlying active zone organization in mammalian NMJs. Furthermore, we will summarize the age-related degeneration of active zones at NMJs, and the role of exercise in maintaining active zones. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  14. Regarding the unitary theory of agonist and antagonist action at presynaptic adrenoceptors.

    Science.gov (United States)

    Kalsner, S; Abdali, S A

    2001-06-01

    1. The linkage between potentiation of field stimulation-induced noradrenaline release and blockade of the presynaptic inhibitory effect of exogenous noradrenaline by a presynaptic antagonist was examined in superfused rabbit aorta preparations. 2. Rauwolscine clearly potentiated the release of noradrenaline in response to 100 pulses at 2 Hz but reduced the capacity of noradrenaline to inhibit transmitter release to a questionable extent, and then only when comparisons were made with untreated, rather then to rauwolscine-treated, controls. 3. Aortic preparations exposed for 60 min to rauwolscine followed by superfusion with antagonist-free Krebs for 60 min retained the potentiation of stimulation-induced transmitter release but no antagonism of the noradrenaline-induced inhibition could be detected at either of two noradrenaline concentrations when comparisons were made with rauwolscine treated controls. 4. Comparisons of the inhibitory effect of exogenous noradrenaline (1.8 x 10-6 M) on transmitter efflux in the presence and absence of rauwolscine pretreatment revealed that the antagonist enhanced rather than antagonized the presynaptic inhibition by noradrenaline. 5 It is concluded that the unitary hypothesis that asserts that antagonist enhancement of transmitter release and its blockade of noradrenaline induced inhibition are manifestations of a unitary event are not supportable.

  15. Evidence against the unitary hypothesis of agonist and antagonist action at presynaptic adrenoceptors.

    Science.gov (United States)

    Kalsner, S.

    1982-01-01

    1 The concept that presynaptic receptors regulate noradrenergic transmitter release via a system of inhibitory receptors mediating negative feedback relies on a supposed association between increases in stimulation-induced efflux of [3H]-noradrenaline by antagonists and blockade by them of the inhibitory effects of exogenous noradrenaline. 2 It was shown in guinea-pig ureter, that yohimbine (3 X 10(-7)M), a presumed selective presynaptic antagonist, increased transmitter efflux substantially at 1 Hz and 5 Hz with 100 pulses, purportedly representing antagonism of the inhibitory effect of locally released noradrenaline but did not reduce the inhibitory effect of exogenous noradrenaline (1.8 X 10(-6)M or 1.8 X 10(-7)M) except in one case. 3 Additionally, the inhibitory effect of oxymetazoline (1.0 X 10(-7)M or 1.0 X 10(-8)M) on stimulation-induced efflux was in no way antagonized by yohimbine (3 X 10(-7)M). 4 It is concluded that the increased efflux of [3H]-noradrenaline produced by antagonists and the decreased efflux produced by exogenous agonists may represent actions at different loci and that the hypothesis of presynaptic feedback regulatory sites is still not substantiated. PMID:6128040

  16. No consistent bioenergetic defects in presynaptic nerve terminals isolated from mouse models of Alzheimer's disease.

    Science.gov (United States)

    Choi, Sung W; Gerencser, Akos A; Ng, Ryan; Flynn, James M; Melov, Simon; Danielson, Steven R; Gibson, Bradford W; Nicholls, David G; Bredesen, Dale E; Brand, Martin D

    2012-11-21

    Depressed cortical energy supply and impaired synaptic function are predominant associations of Alzheimer's disease (AD). To test the hypothesis that presynaptic bioenergetic deficits are associated with the progression of AD pathogenesis, we compared bioenergetic variables of cortical and hippocampal presynaptic nerve terminals (synaptosomes) from commonly used mouse models with AD-like phenotypes (J20 age 6 months, Tg2576 age 16 months, and APP/PS age 9 and 14 months) to age-matched controls. No consistent bioenergetic deficiencies were detected in synaptosomes from the three models; only APP/PS cortical synaptosomes from 14-month-old mice showed an increase in respiration associated with proton leak. J20 mice were chosen for a highly stringent investigation of mitochondrial function and content. There were no significant differences in the quality of the synaptosomal preparations or the mitochondrial volume fraction. Furthermore, respiratory variables, calcium handling, and membrane potentials of synaptosomes from symptomatic J20 mice under calcium-imposed stress were not consistently impaired. The recovery of marker proteins during synaptosome preparation was the same, ruling out the possibility that the lack of functional bioenergetic defects in synaptosomes from J20 mice was due to the selective loss of damaged synaptosomes during sample preparation. Our results support the conclusion that the intrinsic bioenergetic capacities of presynaptic nerve terminals are maintained in these symptomatic AD mouse models.

  17. Ototrauma induces sodium channel plasticity in auditory afferent neurons

    OpenAIRE

    Fryatt, Alistair G.; Mulheran, Mike; Egerton, Julie; Gunthorpe, Martin J.; Grubb, Blair D.

    2011-01-01

    Exposure to intense sound can cause damage to the delicate sensory and neuronal components of the cochlea leading to hearing loss. Such damage often causes the dendrites of the spiral ganglion neurons (SGN), the neurons that provide the afferent innervation of the hair cells, to swell and degenerate thus damaging the synapse. In models of neuropathic pain, axotomy, another form of afferen