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Sample records for cognition neuronal repolarization

  1. Kv2 Channel Regulation of Action Potential Repolarization and Firing Patterns in Superior Cervical Ganglion Neurons and Hippocampal CA1 Pyramidal Neurons

    Science.gov (United States)

    Liu, Pin W.

    2014-01-01

    Kv2 family “delayed-rectifier” potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60–80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from −70 mV, but not −80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at −70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation. PMID:24695716

  2. Mirror neurons, language, and embodied cognition.

    Science.gov (United States)

    Perlovsky, Leonid I; Ilin, Roman

    2013-05-01

    Basic mechanisms of the mind, cognition, language, its semantic and emotional mechanisms are modeled using dynamic logic (DL). This cognitively and mathematically motivated model leads to a dual-model hypothesis of language and cognition. The paper emphasizes that abstract cognition cannot evolve without language. The developed model is consistent with a joint emergence of language and cognition from a mirror neuron system. The dual language-cognition model leads to the dual mental hierarchy. The nature of cognition embodiment in the hierarchy is analyzed. Future theoretical and experimental research is discussed. Published by Elsevier Ltd.

  3. Cognitive and neuronal correlates of videogaming

    OpenAIRE

    Schlüter, Kim-John

    2016-01-01

    BACKGROUND: Within the past few decades video gaming has become a popular recreational activity all over the world and throughout all social classes. Nevertheless distinct scientific conclusions about potential harm or more importantly benefits of video gaming are lacking. However, recent studies point to possible improvements of some cognitive abilities through the high mental demands of modern games. The prefrontal cortex is the essential neuronal correlate of cognitive processing. Scientif...

  4. Mirror Neurons, Embodied Cognitive Agents and Imitation Learning

    OpenAIRE

    Wiedermann, Jiří

    2003-01-01

    Mirror neurons are a relatively recent discovery; it has been conjectured that these neurons play an important role in imitation learning and other cognitive phenomena. We will study a possible place and role of mirror neurons in the neural architecture of embodied cognitive agents. We will formulate and investigate the hypothesis that mirror neurons serve as a mechanism which coordinates the multimodal (i.e., motor, perceptional and proprioceptive) information and completes it so that the ag...

  5. Nicotinic modulaton of neuronal networks: from receptors to cognition

    NARCIS (Netherlands)

    Mansvelder, H.D.; van Aerde, K.I.; Couey, J.J.; Brussaard, A.B.

    2006-01-01

    Rationale: Nicotine affects many aspects of human cognition, including attention and memory. Activation of nicotinic acetylcholine receptors (nAChRs) in neuronal networks modulates activity and information processing during cognitive tasks, which can be observed in electroencephalograms (EEGs) and

  6. Postoperative cognitive dysfunction : Involvement of neuroinflammation and neuronal functioning

    NARCIS (Netherlands)

    Hovens, Iris B.; Schoemaker, Regien G.; van der Zee, Eddy A.; Absalom, Anthony R.; Heineman, Erik; van Leeuwen, Barbara L.

    Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced inflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as the brain derived neurotrophic factor (BDNF) mediated pathway.

  7. Diclofenac prolongs repolarization in ventricular muscle with impaired repolarization reserve.

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    Attila Kristóf

    Full Text Available BACKGROUND: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. METHODS: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. RESULTS: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM. The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2 application. Diclofenac (3 mg/kg did not prolong while dofetilide (25 µg/kg significantly lengthened the QT(c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%. In single ventricular cells diclofenac (30 µM decreased the amplitude of rapid (I(Kr and slow (I(Ks delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca was slightly diminished, but the transient outward (I(to and inward rectifier (I(K1 potassium currents were not influenced. CONCLUSIONS: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.

  8. Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

    Science.gov (United States)

    Kristóf, Attila; Husti, Zoltán; Koncz, István; Kohajda, Zsófia; Szél, Tamás; Juhász, Viktor; Biliczki, Péter; Jost, Norbert; Baczkó, István; Papp, Julius Gy; Varró, András; Virág, László

    2012-01-01

    Background The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QTc interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QTc. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (IKr) and slow (IKs) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (ICa) was slightly diminished, but the transient outward (Ito) and inward rectifier (IK1) potassium currents were not influenced. Conclusions Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve. PMID:23300901

  9. Does cerebellar neuronal integrity relate to cognitive ability?

    International Nuclear Information System (INIS)

    Rae, C.; Lee, M.; Dixon, R.M.; Blamire, A.; Thompson, C.; Styles, P.; Radda, G.K.; University of Sydney, NSW; Karmiloff-Smith, A.; Grant, J.

    1998-01-01

    Full text: Magnetic resonance spectroscopy (MRS) allows the non-invasive measurement of metabolite levels in the brain. One of these is N-acetylaspartate (NA), a molecule found solely in neurones, synthesised there by mitochondria. This compound can be considered as a marker of 1) neuronal density and 2) neuronal mitochondria function. We recently completed a joint MRS and neuropsychological investigation of Williams-Beuren syndrome (WBS), a rare (1/20,000) autosomal dominant disorder caused by a deletion which includes the elastin locus and LIM-kinase. The syndrome has an associated behavioural and cognitive profile which includes hyperactivity, hyperacusis and excessive sociability. Spatial skills are severely affected, while verbal skills are left relatively intact Our investigation showed loss of NA from the cerebellum in WBS compared with normal controls, with the subject population as a whole displaying a continuum of cerebellar NA concentration. Ability at cognitive tests, including the Weschler IQ scale and various verbal and spatial tests, was shown to correlate significantly and positively with the concentration of NA in the cerebellum. This finding can be interpreted in one of two ways: 1. Our sampling of cerebellar metabolite levels represents a 'global' sampling of total brain neuronal density and, as such, is independent of cerebellar integrity. 2. Cerebellar neuronal integrity is associated with performance at cognitive tests. If the latter interpretation is shown to be the case, it will have important implications for our current understanding of cerebellar function. Copyright (1998) Australian Neuroscience Society

  10. Cognitive and neuronal bases of expertise

    OpenAIRE

    Campitelli, Guillermo

    2003-01-01

    This thesis examines the cognitive and neural bases of expertise. In so doing, several psychological phenomena were investigated-imagery. memory and thinking-using different tasks, and a variety of techniques of data gathering, including standard behavioural experiments, questionnaires, eye-movement recording, and functional magnetic resonance imaging (fMRI). Chess players participated in all the studies, and chess tasks were used. The data confirmed the versatility and power of chess as ...

  11. Selective neuronal lapses precede human cognitive lapses following sleep deprivation.

    Science.gov (United States)

    Nir, Yuval; Andrillon, Thomas; Marmelshtein, Amit; Suthana, Nanthia; Cirelli, Chiara; Tononi, Giulio; Fried, Itzhak

    2017-12-01

    Sleep deprivation is a major source of morbidity with widespread health effects, including increased risk of hypertension, diabetes, obesity, heart attack, and stroke. Moreover, sleep deprivation brings about vehicle accidents and medical errors and is therefore an urgent topic of investigation. During sleep deprivation, homeostatic and circadian processes interact to build up sleep pressure, which results in slow behavioral performance (cognitive lapses) typically attributed to attentional thalamic and frontoparietal circuits, but the underlying mechanisms remain unclear. Recently, through study of electroencephalograms (EEGs) in humans and local field potentials (LFPs) in nonhuman primates and rodents it was found that, during sleep deprivation, regional 'sleep-like' slow and theta (slow/theta) waves co-occur with impaired behavioral performance during wakefulness. Here we used intracranial electrodes to record single-neuron activities and LFPs in human neurosurgical patients performing a face/nonface categorization psychomotor vigilance task (PVT) over multiple experimental sessions, including a session after full-night sleep deprivation. We find that, just before cognitive lapses, the selective spiking responses of individual neurons in the medial temporal lobe (MTL) are attenuated, delayed, and lengthened. These 'neuronal lapses' are evident on a trial-by-trial basis when comparing the slowest behavioral PVT reaction times to the fastest. Furthermore, during cognitive lapses, LFPs exhibit a relative local increase in slow/theta activity that is correlated with degraded single-neuron responses and with baseline theta activity. Our results show that cognitive lapses involve local state-dependent changes in neuronal activity already present in the MTL.

  12. Diet and cognition: interplay between cell metabolism and neuronal plasticity.

    Science.gov (United States)

    Gomez-Pinilla, Fernando; Tyagi, Ethika

    2013-11-01

    To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.

  13. Mirror Neurons, Embodied Cognitive Agents and Imitation Learning

    Czech Academy of Sciences Publication Activity Database

    Wiedermann, Jiří

    2003-01-01

    Roč. 22, č. 6 (2003), s. 545-559 ISSN 1335-9150 R&D Projects: GA ČR GA201/02/1456 Institutional research plan: CEZ:AV0Z1030915 Keywords : complete agents * mirror neurons * embodied cognition * imitation learning * sensorimotor control Subject RIV: BA - General Mathematics Impact factor: 0.254, year: 2003 http://www.cai.sk/ojs/index.php/cai/article/view/468

  14. Repolarization of hepatocytes in culture.

    Science.gov (United States)

    Talamini, M A; Kappus, B; Hubbard, A

    1997-01-01

    We have evaluated the biochemical, morphological, and functional redevelopment of polarity in freshly isolated hepatocytes cultured using a double layer collagen gel sandwich technique. Western blot analysis showed increased cellular levels of the cell adhesion protein uvomorulin as cultured hepatocytes repolarized. Immunofluorescence studies using antibodies against domain-specific membrane proteins showed polarity as early as 48 hours, although the pattern of the polymeric Immunoglobulin-A receptor (pIgA-R) differed from in vivo liver. Electron microscopy showed developing bile canaliculi at 1 day. However, the functional presence of tight junctions was absent at 1 day, but present at 5 days. We further showed functional polarity to be present at 4 days by documenting the ability of cultured hepatocytes to metabolize and excrete fluorescein diacetate into visible bile canaliculi. We conclude that hepatocytes cultured appropriately develop morphological and functional polarity. Hepatocyte culture is therefore a useful tool for the study of mechanisms responsible for the development of polarized function.

  15. Ventricular repolarization measures for arrhythmic risk stratification

    Institute of Scientific and Technical Information of China (English)

    Francesco Monitillo; Marta Leone; Caterina Rizzo; Andrea Passantino; Massimo Iacoviello

    2016-01-01

    Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave(QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice.

  16. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

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    Zhen Wei

    2016-01-01

    Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

  17. New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function.

    Science.gov (United States)

    Uehara, Takashi; Sumiyoshi, Tomiki; Kurachi, Masayoshi

    2015-01-01

    Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia.

  18. Cognitive Decline in Neuronal Aging and Alzheimer's Disease: Role of NMDA Receptors and Associated Proteins

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    Jesús Avila

    2017-11-01

    Full Text Available Molecular changes associated with neuronal aging lead to a decrease in cognitive capacity. Here we discuss these alterations at the level of brain regions, brain cells, and brain membrane and cytoskeletal proteins with an special focus in NMDA molecular changes through aging and its effect in cognitive decline and Alzheimer disease. Here, we propose that some neurodegenerative disorders, like Alzheimer's disease (AD, are characterized by an increase and acceleration of some of these changes.

  19. New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function

    OpenAIRE

    Jeon, Won Je; Sumiyoshi, Tomiki; Kurachi, Masayoshi

    2015-01-01

    Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive ?-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of exc...

  20. Cognitive Load Alters Neuronal Processing of Food Odors.

    Science.gov (United States)

    Hoffmann-Hensel, Sonja Maria; Sijben, Rik; Rodriguez-Raecke, Rea; Freiherr, Jessica

    2017-10-31

    Obesity is a major health concern in modern societies. Although decreased physical activity and enhanced intake of high-caloric foods are important risk factors for developing obesity, human behavior during eating also plays a role. Previous studies have shown that distraction while eating increases food intake and leads to impaired processing of food stimuli. As olfaction is the most important sense involved in flavor perception, we used functional magnetic resonance imaging techniques to investigate the influence of cognitive memory load on olfactory perception and processing. Low- and high-caloric food odors were presented in combination with either low or high cognitive loads utilizing a memory task. The efficacy of the memory task was verified by a decrease in participant recall accuracy and an increase in skin conductance response during high cognitive load. Our behavioral data reveal a diminished perceived intensity for low- but not high-caloric food odors during high cognitive load. For low-caloric food odors, bilateral orbitofrontal (OFC) and piriform cortices (pirC) showed significantly lower activity during high compared with low cognitive load. For high-caloric food odors, a similar effect was established in pirC, but not in OFC. Insula activity correlates with higher intensity ratings found during the low cognitive load condition. We conclude lower activity in pirC and OFC to be responsible for diminished intensity perception, comparable to results in olfactory impaired patients and elderly. Further studies should investigate the influence of olfactory/gustatory intensities on food choices under distraction with special regards to low-caloric food. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration

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    William Sealy Hambright

    2017-08-01

    Full Text Available Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD; however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4, a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD. Keywords: Ferroptosis, Neurodegeneration, Cognitive impairment, Alzheimer's disease, Glutathione peroxidase 4, Transgenic mice

  2. Identification of local myocardial repolarization time by bipolar electrode potential.

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    Namba, Tsunetoyo; Todo, Takahiro; Yao, Takenori; Ashihara, Takashi; Haraguchi, Ryo; Nakazawa, Kazuo; Ikeda, Takanori; Ohe, Tohru

    2007-01-01

    The aim of this study was to investigate whether bipolar electrode potentials (BEPs) reflect local myocardial repolarization dynamics, using computer simulation. Simulated action potential and BEP mapping of myocardial tissue during fibrillation was performed. The BEP was modified to make all the fluctuations have the same polarity. Then, the modified BEP (mBEP) was transformed to "dynamic relative amplitude" (DRA) designed to make all the fluctuations have the similar amplitude. The repolarization end point corresponded to the end of the repolarization-related small fluctuation that clearly appeared in the DRA of mBEP. Using the DRA of mBEP, we could reproduce the repolarization dynamics in the myocardial tissue during fibrillation. The BEP may facilitate identifying the repolarization time. Furthermore, BEP mapping has the possibility that it would be available for evaluating repolarization behavior in myocardial tissue even during fibrillation. The accuracy of activation-recovery interval was also reconfirmed.

  3. Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

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    Trenor, Beatriz; Cardona, Karen; Saiz, Javier; Noble, Denis; Giles, Wayne

    2017-11-01

    In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  4. Endoplasmic Reticulum Stress-Mediated Hippocampal Neuron Apoptosis Involved in Diabetic Cognitive Impairment

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    Xiaoming Zhang

    2013-01-01

    Full Text Available Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP, the prominent mediator of the endoplasmic reticulum (ER stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ- induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (P<0.05. The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (P<0.05. The present results suggested that the CHOP-dependent endoplasmic reticulum (ER stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment.

  5. GABA Neuron Alterations, Cortical Circuit Dysfunction and Cognitive Deficits in Schizophrenia

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    Guillermo Gonzalez-Burgos

    2011-01-01

    Full Text Available Schizophrenia is a brain disorder associated with cognitive deficits that severely affect the patients' capacity for daily functioning. Whereas our understanding of its pathophysiology is limited, postmortem studies suggest that schizophrenia is associated with deficits of GABA-mediated synaptic transmission. A major role of GABA-mediated transmission may be producing synchronized network oscillations which are currently hypothesized to be essential for normal cognitive function. Therefore, cognitive deficits in schizophrenia may result from a GABA synapse dysfunction that disturbs neural synchrony. Here, we highlight recent studies further suggesting alterations of GABA transmission and network oscillations in schizophrenia. We also review current models for the mechanisms of GABA-mediated synchronization of neural activity, focusing on parvalbumin-positive GABA neurons, which are altered in schizophrenia and whose function has been strongly linked to the production of neural synchrony. Alterations of GABA signaling that impair gamma oscillations and, as a result, cognitive function suggest paths for novel therapeutic interventions.

  6. GABA neuron alterations, cortical circuit dysfunction and cognitive deficits in schizophrenia.

    Science.gov (United States)

    Gonzalez-Burgos, Guillermo; Fish, Kenneth N; Lewis, David A

    2011-01-01

    Schizophrenia is a brain disorder associated with cognitive deficits that severely affect the patients' capacity for daily functioning. Whereas our understanding of its pathophysiology is limited, postmortem studies suggest that schizophrenia is associated with deficits of GABA-mediated synaptic transmission. A major role of GABA-mediated transmission may be producing synchronized network oscillations which are currently hypothesized to be essential for normal cognitive function. Therefore, cognitive deficits in schizophrenia may result from a GABA synapse dysfunction that disturbs neural synchrony. Here, we highlight recent studies further suggesting alterations of GABA transmission and network oscillations in schizophrenia. We also review current models for the mechanisms of GABA-mediated synchronization of neural activity, focusing on parvalbumin-positive GABA neurons, which are altered in schizophrenia and whose function has been strongly linked to the production of neural synchrony. Alterations of GABA signaling that impair gamma oscillations and, as a result, cognitive function suggest paths for novel therapeutic interventions.

  7. Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice.

    Science.gov (United States)

    Cabral-Costa, J V; Andreotti, D Z; Mello, N P; Scavone, C; Camandola, S; Kawamoto, E M

    2018-06-05

    Phosphatase and tensin homolog (PTEN) is an important protein with key modulatory functions in cell growth and survival. PTEN is crucial during embryogenesis and plays a key role in the central nervous system (CNS), where it directly modulates neuronal development and synaptic plasticity. Loss of PTEN signaling function is associated with cognitive deficits and synaptic plasticity impairment. Accordingly, Pten mutations have a strong link with autism spectrum disorder. In this study, neuronal Pten haploinsufficient male mice were subjected to a long-term environmental intervention - intermittent fasting (IF) - and then evaluated for alterations in exploratory, anxiety and learning and memory behaviors. Although no significant effects on spatial memory were observed, mutant mice showed impaired contextual fear memory in the passive avoidance test - an outcome that was effectively rescued by IF. In this study, we demonstrated that IF modulation, in addition to its rescue of the memory deficit, was also required to uncover behavioral phenotypes otherwise hidden in this neuronal Pten haploinsufficiency model.

  8. Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations.

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    Alex C Bender

    Full Text Available Brain oscillations play a critical role in information processing and may, therefore, be essential to uncovering the mechanisms of cognitive impairment in neurological disease. In Dravet syndrome (DS, a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures. While seizure frequency and severity do not correlate with the extent of impairment, the slowing of brain rhythms may be involved. Here we investigate the role of Nav1.1 on brain rhythms and cognition using RNA interference. We demonstrate that knockdown of Nav1.1 impairs fast- and burst-firing properties of neurons in the medial septum in vivo. The proportion of neurons that fired phase-locked to hippocampal theta oscillations was reduced, and medial septal regulation of theta rhythm was disrupted. During a working memory task, this deficit was characterized by a decrease in theta frequency and was negatively correlated with performance. These findings suggest a fundamental role for Nav1.1 in facilitating fast-firing properties in neurons, highlight the importance of precise temporal control of theta frequency for working memory, and imply that Nav1.1 deficits may disrupt information processing in DS via a dysregulation of brain rhythms.

  9. Components of action potential repolarization in cerebellar parallel fibres.

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    Pekala, Dobromila; Baginskas, Armantas; Szkudlarek, Hanna J; Raastad, Morten

    2014-11-15

    Repolarization of the presynaptic action potential is essential for transmitter release, excitability and energy expenditure. Little is known about repolarization in thin, unmyelinated axons forming en passant synapses, which represent the most common type of axons in the mammalian brain's grey matter.We used rat cerebellar parallel fibres, an example of typical grey matter axons, to investigate the effects of K(+) channel blockers on repolarization. We show that repolarization is composed of a fast tetraethylammonium (TEA)-sensitive component, determining the width and amplitude of the spike, and a slow margatoxin (MgTX)-sensitive depolarized after-potential (DAP). These two components could be recorded at the granule cell soma as antidromic action potentials and from the axons with a newly developed miniaturized grease-gap method. A considerable proportion of fast repolarization remained in the presence of TEA, MgTX, or both. This residual was abolished by the addition of quinine. The importance of proper control of fast repolarization was demonstrated by somatic recordings of antidromic action potentials. In these experiments, the relatively broad K(+) channel blocker 4-aminopyridine reduced the fast repolarization, resulting in bursts of action potentials forming on top of the DAP. We conclude that repolarization of the action potential in parallel fibres is supported by at least three groups of K(+) channels. Differences in their temporal profiles allow relatively independent control of the spike and the DAP, whereas overlap of their temporal profiles provides robust control of axonal bursting properties.

  10. Acupuncture at the Taixi (KI3) acupoint activates cerebral neurons in elderly patients with mild cognitive impairment

    OpenAIRE

    Chen, Shangjie; Xu, Maosheng; Li, Hong; Liang, Jiuping; Yin, Liang; Liu, Xia; Jia, Xinyan; Zhu, Fen; Wang, Dan; Shi, Xuemin; Zhao, Lihua

    2014-01-01

    Our previous findings have demonstrated that acupuncture at the Taixi (KI3) acupoint in healthy youths can activate neurons in cognitive-related cerebral cortex. Here, we investigated whether acupuncture at this acupoint in elderly patients with mild cognitive impairment can also activate neurons in these regions. Resting state and task-related functional magnetic resonance imaging showed that the pinprick senstation of acupuncture at the Taixi acupoint differed significantly between elderly ...

  11. Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery

    NARCIS (Netherlands)

    Kok, W F; Koerts, Janneke; Tucha, O; Scheeren, T W L; Absalom, A R

    Biomarkers of neurological injury can potentially predict postoperative cognitive dysfunction. We aimed to identify whether classical neuronal damage-specific biomarkers, including brain fatty acid-binding protein, neuron-specific enolase and S100 calcium-binding protein β, as well as plasma-free

  12. Mechanisms and neuronal networks involved in reactive and proactive cognitive control of interference in working memory.

    Science.gov (United States)

    Irlbacher, Kerstin; Kraft, Antje; Kehrer, Stefanie; Brandt, Stephan A

    2014-10-01

    Cognitive control can be reactive or proactive in nature. Reactive control mechanisms, which support the resolution of interference, start after its onset. Conversely, proactive control involves the anticipation and prevention of interference prior to its occurrence. The interrelation of both types of cognitive control is currently under debate: Are they mediated by different neuronal networks? Or are there neuronal structures that have the potential to act in a proactive as well as in a reactive manner? This review illustrates the way in which integrating knowledge gathered from behavioral studies, functional imaging, and human electroencephalography proves useful in answering these questions. We focus on studies that investigate interference resolution at the level of working memory representations. In summary, different mechanisms are instrumental in supporting reactive and proactive control. Distinct neuronal networks are involved, though some brain regions, especially pre-SMA, possess functions that are relevant to both control modes. Therefore, activation of these brain areas could be observed in reactive, as well as proactive control, but at different times during information processing. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment

    Directory of Open Access Journals (Sweden)

    Saswati ePaul

    2015-04-01

    Full Text Available A substantial number of studies on basal forebrain cholinergic neurons (BFCN have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD, and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine, glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, which could help decipher disease states and propose leads for pharmacological intervention.

  14. How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition

    DEFF Research Database (Denmark)

    Siebner, Hartwig R; Hartwigsen, Gesa; Kassuba, Tanja

    2009-01-01

    Transcranial magnetic stimulation (TMS) uses a magnetic field to "carry" a short lasting electrical current pulse into the brain where it stimulates neurones, particularly in superficial regions of cerebral cortex. TMS can interfere with cognitive functions in two ways. A high intensity TMS pulse...... in the human brain. This transient neurodisruption has been termed a "virtual lesion". Smaller intensities of stimulation produce less activity; in such cases, cognitive operations can probably continue but are disrupted because of the added noisy input from the TMS pulse. It is usually argued that if a TMS...... pulse affects performance, then the area stimulated must provide an essential contribution to behaviour being studied. However, there is one exception to this: the pulse could be applied to an area that is not involved in the task but which has projections to the critical site. Activation of outputs...

  15. Anatomical differences in the mirror neuron system and social cognition network in autism.

    Science.gov (United States)

    Hadjikhani, Nouchine; Joseph, Robert M; Snyder, Josh; Tager-Flusberg, Helen

    2006-09-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social and emotional skills, the anatomical substrate of which is still unknown. In this study, we compared a group of 14 high-functioning ASD adults with a group of controls matched for sex, age, intelligence quotient, and handedness. We used an automated technique of analysis that accurately measures the thickness of the cerebral cortex and generates cross-subject statistics in a coordinate system based on cortical anatomy. We found local decreases of gray matter in the ASD group in areas belonging to the mirror neuron system (MNS), argued to be the basis of empathic behavior. Cortical thinning of the MNS was correlated with ASD symptom severity. Cortical thinning was also observed in areas involved in emotion recognition and social cognition. These findings suggest that the social and emotional deficits characteristic of autism may reflect abnormal thinning of the MNS and the broader network of cortical areas subserving social cognition.

  16. Major rapid weight loss induces changes in cardiac repolarization

    DEFF Research Database (Denmark)

    Vedel-Larsen, Esben; Iepsen, Eva Winning; Lundgren, Julie

    2016-01-01

    INTRODUCTION: Obesity is associated with increased all-cause mortality, but weight loss may not decrease cardiovascular events. In fact, very low calorie diets have been linked to arrhythmias and sudden death. The QT interval is the standard marker for cardiac repolarization, but T-wave morphology...... analysis has been suggested as a more sensitive method to identify changes in cardiac repolarization. We examined the effect of a major and rapid weight loss on T-wave morphology. METHODS AND RESULTS: Twenty-six individuals had electrocardiograms (ECG) taken before and after eight weeks of weight loss......A1c (pweight loss induces changes in cardiac repolarization. Monitoring of MCS during calorie restriction makes it possible to detect repolarization changes with higher discriminative power than the QT-interval during major rapid weight...

  17. Heart rate profile during exercise in patients with early repolarization.

    Science.gov (United States)

    Cay, Serkan; Cagirci, Goksel; Atak, Ramazan; Balbay, Yucel; Demir, Ahmet Duran; Aydogdu, Sinan

    2010-09-01

    Both early repolarization and altered heart rate profile are associated with sudden death. In this study, we aimed to demonstrate an association between early repolarization and heart rate profile during exercise. A total of 84 subjects were included in the study. Comparable 44 subjects with early repolarization and 40 subjects with normal electrocardiogram underwent exercise stress testing. Resting heart rate, maximum heart rate, heart rate increment and decrement were analyzed. Both groups were comparable for baseline characteristics including resting heart rate. Maximum heart rate, heart rate increment and heart rate decrement of the subjects in early repolarization group had significantly decreased maximum heart rate, heart rate increment and heart rate decrement compared to control group (all P decrement (multiple-adjusted OR of the risk of presence of early repolarization was 2.98 (95%CI 1.21-7.34) (P = 0.018) and 7.73 (95%CI 2.84-21.03) (P decrement compared to higher levels, respectively. Subjects with early repolarization have altered heart rate profile during exercise compared to control subjects. This can be related to sudden death.

  18. Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

    Science.gov (United States)

    Xu, Xiaofeng; Zhang, Bin; Lu, Kaili; Deng, Jiangshan; Zhao, Fei; Zhao, Bing-Qiao; Zhao, Yuwu

    2016-07-01

    Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

  19. Neurocognitive Poetics: methods and models for investigating the neuronal and cognitive- affective bases of literature reception

    Directory of Open Access Journals (Sweden)

    Arthur M Jacobs

    2015-04-01

    Full Text Available A long tradition of research including classical rhetoric, aesthetics and poetics theory, formalism and structuralism, as well as current perspectives in (neurocognitive poetics has investigated structural and functional aspects of literature reception. Despite a wealth of literature published in specialised journals like Poetics, however, still little is known about how the brain processes and creates literary and poetic texts. Still, such stimulus material might be suited better than other genres for demonstrating the complexities with which our brain constructs the world in and around us, because it unifies thought and language, music and imagery in a clear, manageable way, most often with play, pleasure, and emotion (Schrott & Jacobs, 2011. In this paper, I discuss methods and models for investigating the neuronal and cognitive-affective bases of literary reading together with pertinent results from studies on poetics, text processing, emotion, or neuroaesthetics, and outline current challenges and future perspectives.

  20. Study on cognition disorder and morphologic change of neurons in hippocampus area following traumatic brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    洪军; 崔建忠; 周云涛; 高俊玲

    2002-01-01

    Objective: To explore the correlation between cognition disorder and morphologic change of hippocampal neurons after traumatic brain injury (TBI).   Methods: Wistar rat models with severe TBI were made by Marmarous method. The histopathological change of the neurons in the hippocampus area were studied with hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated X-dUPT nick end labeling (TUNEL), respectively. The cognitive function was evaluated with the Morris water maze test.   Results: The comprehensive neuronal degeneration and necrosis could be observed in CA2-3 regions of hippocampus at 3 days after injury. Apoptotic positive neurons in CA2-4 regions of hippocampus and dentate gyrus increased in the injured group at 24 hours following TBI. They peaked at 7 days and then declined. Significant impairment of spatial learning and memory was observed after injury in the rats.   Conclusions: The rats have obvious disorders in spatial learning and memory after severe TBI. Meanwhile, delayed neuronal necrosis and apoptosis can be observed in the neurons in the hippocampus area. It suggests that delayed hippocampal cell death may contribute to the functional deficit.

  1. Ablating ErbB4 in PV neurons attenuates synaptic and cognitive deficits in an animal model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Heng; Zhang, Ling; Zhou, Dongming; He, Xiao; Wang, Dongpi; Pan, Hongyu; Zhang, Xiaoqin; Mei, Yufei; Qian, Qi; Zheng, Tingting; Jones, Frank E; Sun, Binggui

    2017-10-01

    Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aβ-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aβ detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aβ-induced synaptic and cognitive dysfunctions without affecting Aβ levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Early effects of 16O radiation on neuronal morphology and cognition in a murine model

    Science.gov (United States)

    Carr, Hannah; Alexander, Tyler C.; Groves, Thomas; Kiffer, Frederico; Wang, Jing; Price, Elvin; Boerma, Marjan; Allen, Antiño R.

    2018-05-01

    Astronauts exposed to high linear energy transfer radiation may experience cognitive injury. The pathogenesis of this injury is unknown but may involve glutamate receptors or modifications to dendritic structure and/or dendritic spine density and morphology. Glutamate is the major excitatory neurotransmitter in the central nervous system, where it acts on ionotropic and metabotropic glutamate receptors located at the presynaptic terminal and in the postsynaptic membrane at synapses in the hippocampus. Dendritic spines are sites of excitatory synaptic transmission, and changes in spine structure and dendrite morphology are thought to be morphological correlates of altered brain function associated with hippocampal-dependent learning and memory. The aim of the current study is to assess whether behavior, glutamate receptor gene expression, and dendritic structure in the hippocampus are altered in mice after early exposure to 16O radiation in mice. Two weeks post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Y-maze. During Y-maze testing, mice exposed to 0.1 Gy and 0.25 Gy radiation failed to distinguish the novel arm, spending approximately the same amount of time in all 3 arms during the retention trial. Exposure to 16O significantly reduced the expression of Nr1 and GluR1 in the hippocampus and modulated spine morphology in the dentate gyrus and cornu Ammon 1 within the hippocampus. The present data provide evidence that 16O radiation has early deleterious effects on mature neurons that are associated with hippocampal learning and memory.

  3. Lychee Seed Saponins Improve Cognitive Function and Prevent Neuronal Injury via Inhibiting Neuronal Apoptosis in a Rat Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Xiuling Wang

    2017-02-01

    Full Text Available Lychee seed is a traditional Chinese medicine and possesses many activities, including hypoglycemia, liver protection, antioxidation, antivirus, and antitumor. However, its effect on neuroprotection is still unclear. The present study investigated the effects of lychee seed saponins (LSS on neuroprotection and associated mechanisms. We established a rat model of Alzheimer’s disease (AD by injecting Aβ25–35 into the lateral ventricle of rats and evaluated the effect of LSS on spatial learning and memory ability via the Morris water maze. Neuronal apoptosis was analyzed by hematoxylin and eosin stain and terminal deoxynucleotidyl transferase (Tdt-mediated dUTP nick-end labeling analysis, and mRNA expression of caspase-3 and protein expressions of Bax and Bcl-2 by reverse transcription-polymerase chain reaction (RT-PCR and Western blotting, respectively. The results showed that LSS remarkably improved cognitive function and alleviated neuronal injury by inhibiting apoptosis in the hippocampus of AD rats. Furthermore, the mRNA expression of caspase-3 and the protein expression of Bax were downregulated, while the protein expression of Bcl-2 and the ratio of Bcl-2/Bax were increased by LSS. We demonstrate that LSS significantly improves cognitive function and prevent neuronal injury in the AD rats via regulation of the apoptosis pathway. Therefore, LSS may be developed as a nutritional supplement and sold as a drug for AD prevention and/or treatment.

  4. 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.

  5. Probing cardiac repolarization reserve in drug safety assessment

    NARCIS (Netherlands)

    Nalos, L.

    2011-01-01

    Excessive prolongation of cardiac repolarization, manifested as QT prolongation on ECG, is common unwanted side effect of many drugs and drug candidates. Prolongation of QT interval may lead to life threatening cardiac arrhythmia – Torsade de Point (TdP). Number of drugs was withdrawn from the

  6. High-Rate Pacing Reduces Variability of Repolarization and Prevents Repolarization-Dependent Arrhythmias in Dogs With Chronic AV Block

    DEFF Research Database (Denmark)

    Oosterhoff, Peter; Thomsen, Morten Bækgaard; Maas, Joep N

    2010-01-01

    -term variability of repolarization (STV) as a feedback parameter of arrhythmic risk. Methods and Results: The minimal signal sampling frequency required for measuring STV was determined through computer simulation. Arrhythmogenic response to dofetilide (25 µg/kg/5minutes) was tested at two different paced heart...

  7. Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Choi, Soo Young; Lee, Yun Lyul; Kang, Il Jun; Hwang, In Koo; Lee, Tae-Kyeong; Shin, Bich-Na; Lee, Jae-Chul; Hong, Seongkweon; Jeon, Yong Hwan; Shin, Myoung Cheol; Cho, Jun Hwi; Won, Moo-Ho; Lee, Young Joo

    2018-03-01

    It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.

  8. Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.

    Science.gov (United States)

    Li, Fang; Yan, Chao-Qun; Lin, Li-Ting; Li, Hui; Zeng, Xiang-Hong; Liu, Yi; Du, Si-Qi; Zhu, Wen; Liu, Cun-Zhi

    2015-04-28

    Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P area in any of the groups (P > 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.

  9. A real-time hybrid neuron network for highly parallel cognitive systems.

    Science.gov (United States)

    Christiaanse, Gerrit Jan; Zjajo, Amir; Galuzzi, Carlo; van Leuken, Rene

    2016-08-01

    For comprehensive understanding of how neurons communicate with each other, new tools need to be developed that can accurately mimic the behaviour of such neurons and neuron networks under `real-time' constraints. In this paper, we propose an easily customisable, highly pipelined, neuron network design, which executes optimally scheduled floating-point operations for maximal amount of biophysically plausible neurons per FPGA family type. To reduce the required amount of resources without adverse effect on the calculation latency, a single exponent instance is used for multiple neuron calculation operations. Experimental results indicate that the proposed network design allows the simulation of up to 1188 neurons on Virtex7 (XC7VX550T) device in brain real-time yielding a speed-up of x12.4 compared to the state-of-the art.

  10. Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats.

    Science.gov (United States)

    Vidal, Blanca; Vázquez-Roque, Rubén A; Gnecco, Dino; Enríquez, Raúl G; Floran, Benjamin; Díaz, Alfonso; Flores, Gonzalo

    2017-03-01

    Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi-Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory. © 2016 Wiley Periodicals, Inc.

  11. Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer's Disease.

    Science.gov (United States)

    Li, Jinze; Ma, Xiaowei; Wang, Yu; Chen, Chengjuan; Hu, Min; Wang, Linlin; Fu, Junmin; Shi, Gaona; Zhang, Dongming; Zhang, Tiantai

    2018-01-01

    Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer's disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD.

  12. ECG-Based Measurements of Drug-induced Repolarization Changes

    DEFF Research Database (Denmark)

    Bhuiyan, Tanveer Ahmed

    The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore the proporti......The purpose of this thesis is to investigate the abnormal repolarization both in the cellular and the surface ECG along with their relationship. It has been identified that the certain morphological changes of the monophasic action potential are predictor of TdP arrhythmia. Therefore...... the proportional changes of the surface ECG which corresponds to the arrhythmia-triggering MAP morphology is warranted to increase the confidence of determining cardiotoxicity of drugs....

  13. [The influence of occupational lead exposure on transmural repolarization dispersion].

    Science.gov (United States)

    Zyśko, Dorota; Gajek, Jacek; Chlebda, Ewa; Mazurek, Walentyna

    2005-02-01

    The parts of QT interval: time from Q wave to the peak of T wave (QTp) representing the de- and repolarization of subepicardial layer and the time from the peak of T wave to its end (QTp-e) building the transmural dispersion of repolarization enable more exact assessment of repolarization period of the heart muscle. Occupational exposure to lead influences the electrophysiologic properties of the heart. The aim of our study was to assess the QTp and QTp-e interval in workers occupationally exposed to lead. The study was carried out in 22 copper smelters aged 41.8 +/- 8.7 years, occupationally exposed to lead. The control group consisted of 14 healthy men. In all studied subjects blood lead concentration (Pb) and the concentration of free protoporphyrins in erytrocytes were assessed. 24-hour ECG holter monitoring was done to study rhythm disturbances and the duration in lead CM5 of QT interval, QTp interval, RR interval preceding the assessed QT interval (pRR) during sleep, rest during the awake state and moderate daily activity. The QTp-e interval is the difference between the duration of QT and QTp interval. The duration of QTp and QTp-e in occupationally exposed workers and healthy persons did not differ significantly. These parameters were significantly lower in both groups during moderately physical activity comparing to the values during sleep. The QTp-e/ QTp ratio in occupationally exposed workers during night hours was significantly lower than during daily activity what was not the case in control persons. Occupational exposure to lead do not change significantly the transmural dispersion of repolarization. Occupational exposure to lead diminishes the QTp-e/QTp ratio during the night.

  14. Diurnal modulation and sources of variation affecting ventricular repolarization in Warmblood horses

    DEFF Research Database (Denmark)

    Pedersen, Philip Juul; Moeller, Sine B.; Madsen, Mette Flethøj

    2014-01-01

    Te) are used as repolarization markers. To support the use of these markers in horses, we sought to describe the possible influence of the environment, time of day, day-to-day effects, T wave conformation, age, body weight (BW), and horse-to-horse variation on repolarization measurements. ANIMALS: 12 Warmblood...... affecting these intervals. RESULTS: Differences between individual horses were the largest source of repolarization variability although the environment had a significant effect on repolarization as well. Diurnal variation affected both the RR interval and the repolarization markers. The QT, QTc and Tp......, diurnal variation, the environment, and T wave conformation. These factors must be considered if markers of equine repolarization are used diagnostically....

  15. Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease.

    Science.gov (United States)

    Becerril-Ortega, Javier; Bordji, Karim; Fréret, Thomas; Rush, Travis; Buisson, Alain

    2014-10-01

    Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    Science.gov (United States)

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  17. Reduced activation in the mirror neuron system during a virtual social cognition task in euthymic bipolar disorder.

    Science.gov (United States)

    Kim, Eosu; Jung, Young-Chul; Ku, Jeonghun; Kim, Jae-Jin; Lee, Hyeongrae; Kim, So Young; Kim, Sun I; Cho, Hyun-Sang

    2009-11-13

    Social cognition entails both cognitive and affective processing, and impairments in both have accounted for residual symptoms of bipolar disorder (BD). However, there has been a lack of studies identifying neural substrates responsible for social cognitive difficulties in BD patients. Fourteen euthymic BD patients and 14 healthy normal controls underwent functional MRI while performing a virtual reality social cognition task, which incorporated both cognitive and emotional dimensions, simulating real-world social situations. During the scanning, subjects tried to guess (attribute) possible reasons for expressed emotion of virtual humans (avatars) while viewing their facial expressions, just after observing their verbal and nonverbal (facial) expressions which were emotionally valenced (happy, angry and neutral). BD patients compared to normal controls showed delayed reaction times in emotional conditions, with comparable response accuracy. Healthy normal controls activated the right anterior cingulate cortex, inferior frontal, and insular cortex in emotional conditions contrasted with neutral control conditions, that is, the regions that have been related to empathic processes during viewing others' emotional expression. Relative to normal controls, BD patients showed reduced activations in the 'mirror neuron system', including the right inferior frontal cortex, premotor cortex, and insula, mainly in angry or happy condition. These results may suggest that, even during euthymic state, BD patients have difficulties in recruiting brain regions for the utilization of emotional cues as a means for understanding others. Clinical attention should be paid to emotion-related residual symptoms to help improve social outcomes in these patients.

  18. Ventricular Repolarization Evaluation From Surface ECG for Identification of the Patients With Increased Myocardial Electrical Instability

    National Research Council Canada - National Science Library

    Lass, Jaanus

    2001-01-01

    In order to reveal the possible correlation between the level of myocardial electrical instability assessed at Holter monitoring and certain ECG parameters characterizing ventricular repolarization...

  19. Getting from neuron to checkmark: Models and methods in cognitive survey research

    NARCIS (Netherlands)

    Holleman, B.C.; Murre, J.M.J.

    2008-01-01

    Since the 1980s much work has been done in the field of Cognitive Survey Research. In an interdisciplinary endeavour, survey methodologists and cognitive psychologists (as well as social psychologists and linguists) have worked to unravel the cognitive processes underlying survey responses: to

  20. Neurocognitive poetics: methods and models for investigating the neuronal and cognitive-affective bases of literature reception.

    Science.gov (United States)

    Jacobs, Arthur M

    2015-01-01

    A long tradition of research including classical rhetoric, esthetics and poetics theory, formalism and structuralism, as well as current perspectives in (neuro)cognitive poetics has investigated structural and functional aspects of literature reception. Despite a wealth of literature published in specialized journals like Poetics, however, still little is known about how the brain processes and creates literary and poetic texts. Still, such stimulus material might be suited better than other genres for demonstrating the complexities with which our brain constructs the world in and around us, because it unifies thought and language, music and imagery in a clear, manageable way, most often with play, pleasure, and emotion (Schrott and Jacobs, 2011). In this paper, I discuss methods and models for investigating the neuronal and cognitive-affective bases of literary reading together with pertinent results from studies on poetics, text processing, emotion, or neuroaesthetics, and outline current challenges and future perspectives.

  1. A neuronal model of a global workspace in effortful cognitive tasks.

    Science.gov (United States)

    Dehaene, S; Kerszberg, M; Changeux, J P

    1998-11-24

    A minimal hypothesis is proposed concerning the brain processes underlying effortful tasks. It distinguishes two main computational spaces: a unique global workspace composed of distributed and heavily interconnected neurons with long-range axons, and a set of specialized and modular perceptual, motor, memory, evaluative, and attentional processors. Workspace neurons are mobilized in effortful tasks for which the specialized processors do not suffice. They selectively mobilize or suppress, through descending connections, the contribution of specific processor neurons. In the course of task performance, workspace neurons become spontaneously coactivated, forming discrete though variable spatio-temporal patterns subject to modulation by vigilance signals and to selection by reward signals. A computer simulation of the Stroop task shows workspace activation to increase during acquisition of a novel task, effortful execution, and after errors. We outline predictions for spatio-temporal activation patterns during brain imaging, particularly about the contribution of dorsolateral prefrontal cortex and anterior cingulate to the workspace.

  2. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

    Directory of Open Access Journals (Sweden)

    Belarbi Karim

    2012-01-01

    Full Text Available Abstract Background Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT, an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. Methods Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. Results Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. Conclusion Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a

  3. Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons.

    Science.gov (United States)

    Noble, Emily E; Mavanji, Vijayakumar; Little, Morgan R; Billington, Charles J; Kotz, Catherine M; Wang, ChuanFeng

    2014-10-01

    Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (pdiet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. Published by Elsevier Inc.

  4. Comparison of a Mirror Neuron System among Elders with Mild Cognitive Impairment, Alzheimer's Disease, and No Disease

    International Nuclear Information System (INIS)

    Rattanachayoto, P.; Tritanon, O.; Laothamatas, J.; Sungkarat, W.

    2012-01-01

    Alzheimer's disease (AD) is the most common cause of dementia. There are lots of old people suffering from the disease. Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia. An individual with MCI has an increased risk of developing AD. The mirror neuron system (MNS), activated during the observation and execution of actions, has been linked with cognitive processes.The objective of this study is to examine the MNS abnormalities in elders with MCI and AD. Ninety-two subjects (5 MCI,7 mild AD, and 80 cognitively normal) were studied by using functional magnetic resonance imaging (fMRI). In the fMRI experiment, subjects were asked to observe a video showing hand movement (tearing a piece of paper) and a control condition (observing a fixation point).The image data were analyzed using SPM2 (Statistical Parametric Mapping).There were significant activations of bilateral inferior frontal lobule and inferior parietal lobule due to the observation of hand movement.The brain activations of the normal group were statistical significant greater than those in the MCI and mild AD groups.There was no significant difference between the MCI and mild AD groups. Elders with MCI and mild AD had fewer MNS activations than the normal controls, suggesting that the dysfunction of MNS may underlie cognitive impairments in MCI and AD patients.These findings imply that fMRI is sufficiently sensitive to detect MNS changes occurring in MCI and AD.

  5. Ginseng Rb fraction protects glia, neurons and cognitive function in a rat model of neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Kangning Xu

    Full Text Available The loss and injury of neurons play an important role in the onset of various neurodegenerative diseases, while both microgliosis and astrocyte loss or dysfunction are significant causes of neuronal degeneration. Previous studies have suggested that an extract enriched panaxadiol saponins from ginseng has more neuroprotective potential than the total saponins of ginseng. The present study investigated whether a fraction of highly purified panaxadiol saponins (termed as Rb fraction was protective for both glia and neurons, especially GABAergic interneurons, against kainic acid (KA-induced excitotoxicity in rats. Rats received Rb fraction at 30 mg/kg (i.p., 40 mg/kg (i.p. or saline followed 40 min later by an intracerebroventricular injection of KA. Acute hippocampal injury was determined at 48 h after KA, and impairment of hippocampus-dependent learning and memory as well as delayed neuronal injury was determined 16 to 21 days later. KA injection produced significant acute hippocampal injuries, including GAD67-positive GABAergic interneuron loss in CA1, paralbumin (PV-positive GABAergic interneuron loss, pyramidal neuron degeneration and astrocyte damage accompanied with reactive microglia in both CA1 and CA3 regions of the hippocampus. There was also a delayed loss of GAD67-positive interneurons in CA1, CA3, hilus and dentate gyrus. Microgliosis also became more severe 21 days later. Accordingly, KA injection resulted in hippocampus-dependent spatial memory impairment. Interestingly, the pretreatment with Rb fraction at 30 or 40 mg/kg significantly protected the pyramidal neurons and GABAergic interneurons against KA-induced acute excitotoxicity and delayed injury. Rb fraction also prevented memory impairments and protected astrocytes from KA-induced acute excitotoxicity. Additionally, microglial activation, especially the delayed microgliosis, was inhibited by Rb fraction. Overall, this study demonstrated that Rb fraction protected both

  6. Pharmacokinetics and repolarization effects of intravenous and transdermal granisetron.

    Science.gov (United States)

    Mason, Jay W; Selness, Daniel S; Moon, Thomas E; O'Mahony, Bridget; Donachie, Peter; Howell, Julian

    2012-05-15

    The need for greater clarity about the effects of 5-HT(3) receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT(3) receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.

  7. The Role of Serotonin in Ventricular Repolarization in Pregnant Mice.

    Science.gov (United States)

    Cui, Shanyu; Park, Hyewon; Park, Hyelim; Mun, Dasom; Lee, Seung Hyun; Kim, Hyoeun; Yun, Nuri; Kim, Hail; Kim, Michael; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung

    2018-03-01

    The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(-/-)-NP). During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(-/-)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents. © Copyright: Yonsei University College of Medicine 2018

  8. Essential role of neuron-enriched diacylglycerol kinase (DGK, DGKbeta in neurite spine formation, contributing to cognitive function.

    Directory of Open Access Journals (Sweden)

    Yasuhito Shirai

    Full Text Available BACKGROUND: Diacylglycerol (DG kinase (DGK phosphorylates DG to produce phosphatidic acid (PA. Of the 10 subtypes of mammalian DGKs, DGKbeta is a membrane-localized subtype and abundantly expressed in the cerebral cortex, hippocampus, and caudate-putamen. However, its physiological roles in neurons and higher brain function have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We, therefore, developed DGKbeta KO mice using the Sleeping Beauty transposon system, and found that its long-term potentiation in the hippocampal CA1 region was reduced, causing impairment of cognitive functions including spatial and long-term memories in Y-maze and Morris water-maze tests. The primary cultured hippocampal neurons from KO mice had less branches and spines compared to the wild type. This morphological impairment was rescued by overexpression of DGKbeta. In addition, overexpression of DGKbeta in SH-SY5Y cells or primary cultured mouse hippocampal neurons resulted in branch- and spine-formation, while a splice variant form of DGKbeta, which has kinase activity but loses membrane localization, did not induce branches and spines. In the cells overexpressing DGKbeta but not the splice variant form, DGK product, PA, was increased and the substrate, DG, was decreased on the plasma membrane. Importantly, lower spine density and abnormality of PA and DG contents in the CA1 region of the KO mice were confirmed. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that membrane-localized DGKbeta regulates spine formation by regulation of lipids, contributing to the maintenance of neural networks in synaptic transmission of cognitive processes including memory.

  9. Analysis of Ion Currents Contribution to Repolarization in Human Heart Failure Using Computer Models

    Energy Technology Data Exchange (ETDEWEB)

    Marotta, F.; Paci, M.A.; Severi, S.; Trenor, B.

    2016-07-01

    The mechanisms underlying repolarization of the ventricular action potential (AP) are subject of research for anti-arrhythmic drugs. In fact, the prolongation of the AP occurs in several conditions of heart disease, such as heart failure, a major problem precursor for serious arrhythmias. In this study, we investigated the phenomena of repolarization reserve, defined as the capacity of the cell to repolarize in case of a functional loss, and the all-or-none repolarization, which depends on the delicate balance of inward and outward currents in the different phases of the AP, under conditions of human heart failure (HF). To simulate HF conditions, the O'Hara et al. human AP model was modified and specific protocols for all-or-none repolarization were applied. Our results show that in the early repolarization the threshold for all-or-none repolarization is not altered in HF even if a decrease in potassium currents can be observed. To quantify the contribution of the individual ion currents to HF induced AP prolongation, we used a novel piecewise-linear approximation approach proposed by Paci et al. In particular, INaL and ICaL are the main responsible for APD prolongation due to HF (85 and 35 ms respectively). Our results highlight this novel algorithm as a powerful tool to have a more complete picture of the complex ionic mechanisms underlying this disease and confirm the important role of the late sodium current in HF repolarization. (Author)

  10. Monitoring and predicting cognitive state and performance via physiological correlates of neuronal signals.

    Science.gov (United States)

    Russo, Michael B; Stetz, Melba C; Thomas, Maria L

    2005-07-01

    Judgment, decision making, and situational awareness are higher-order mental abilities critically important to operational cognitive performance. Higher-order mental abilities rely on intact functioning of multiple brain regions, including the prefrontal, thalamus, and parietal areas. Real-time monitoring of individuals for cognitive performance capacity via an approach based on sampling multiple neurophysiologic signals and integrating those signals with performance prediction models potentially provides a method of supporting warfighters' and commanders' decision making and other operationally relevant mental processes and is consistent with the goals of augmented cognition. Cognitive neurophysiological assessments that directly measure brain function and subsequent cognition include positron emission tomography, functional magnetic resonance imaging, mass spectroscopy, near-infrared spectroscopy, magnetoencephalography, and electroencephalography (EEG); however, most direct measures are not practical to use in operational environments. More practical, albeit indirect measures that are generated by, but removed from the actual neural sources, are movement activity, oculometrics, heart rate, and voice stress signals. The goal of the papers in this section is to describe advances in selected direct and indirect cognitive neurophysiologic monitoring techniques as applied for the ultimate purpose of preventing operational performance failures. These papers present data acquired in a wide variety of environments, including laboratory, simulator, and clinical arenas. The papers discuss cognitive neurophysiologic measures such as digital signal processing wrist-mounted actigraphy; oculometrics including blinks, saccadic eye movements, pupillary movements, the pupil light reflex; and high-frequency EEG. These neurophysiological indices are related to cognitive performance as measured through standard test batteries and simulators with conditions including sleep loss

  11. ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage.

    Directory of Open Access Journals (Sweden)

    Carlos Ramírez

    Full Text Available Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD. Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR] of human familial hypercholesterolaemia (FH. From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100 levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing and impairment of the episodic-like memory (determined by the integrated memory test. This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.

  12. ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer’s Disease in Mouse Models

    Directory of Open Access Journals (Sweden)

    Wei Yue

    2015-11-01

    Full Text Available Degeneration of basal forebrain cholinergic neurons (BFCNs is associated with cognitive impairments of Alzheimer’s disease (AD, implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD.

  13. From Neurons to Brainpower: Cognitive Neuroscience and Brain-Based Learning

    Science.gov (United States)

    Phillips, Janet M.

    2005-01-01

    We have learned more about the brain in the past five years than the previous 100. Neuroimaging, lesion studies, and animal studies have revealed the intricate inner workings of the brain and learning. Synaptogenesis, pruning, sensitive periods, and plasticity have all become accepted concepts of cognitive neuroscience that are now being applied…

  14. Heterogeneity of ventricular repolarization in newborns with intrauterine growth restriction.

    Science.gov (United States)

    Fouzas, Sotirios; Karatza, Ageliki A; Davlouros, Periklis A; Chrysis, Dionisios; Alexopoulos, Dimitrios; Mantagos, Stefanos; Dimitriou, Gabriel

    2014-12-01

    Intrauterine growth restriction (IUGR) is associated with structural and functional cardiac alterations but the electrophysiological consequences of these disturbances remain unknown. To explore the distribution of ventricular repolarization and its relation to myocardial mechanics in newborns with IUGR. STUDY DESIGN, SUBJECTS AND OUTCOME MEASUREMENTS: Conventional and tissue Doppler echocardiographic data, and electrocardiographic parameters used to describe the distribution of ventricular repolarization (dispersion of QT [QTd] and JT [JTd]), were obtained on the second (D2) and fifth (D5) postnatal day and compared between 25 IUGR newborns and 25 matched-for-gestational age controls. IUGR was associated with relative interventricular septum hypertrophy, increased left ventricular (LV) E/E' ratio and higher LV myocardial performance index (MPI). On both study days, the IUGR infants presented higher QTd and JTd compared to controls (QTd-D2: 66±20 ms vs. 36±12 ms, P<0.001; JTd-D2: 54±13 ms vs. 34±9 ms, P<0.001; QTd-D5: 61±14 ms vs. 27±12 ms, P<0.001; JTd-D5: 54±13 ms vs. 27±9 ms, P<0.001). The association between QTd and LV E/E' (D2: regression coefficient beta 0.747, R(2) 0.585; D5: beta 0.843, R(2) 0.646) and QTd and MPI (D2: beta 0.680, R(2) 0.576; D5: beta 0.698, R(2) 0.650) was also significant (P<0.001 for all analyses). Our findings suggest that IUGR is associated with electrophysiological remodeling of the neonatal heart, a process which is closely related to the underlying alterations in ventricular mechanics and might predispose to adverse electrophysiological events. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Evidence supporting a role for astrocytes in the regulation of cognitive flexibility and neuronal oscillations through the Ca2+ binding protein S100β.

    Science.gov (United States)

    Brockett, Adam T; Kane, Gary A; Monari, Patrick K; Briones, Brandy A; Vigneron, Pierre-Antoine; Barber, Gabriela A; Bermudez, Andres; Dieffenbach, Uma; Kloth, Alexander D; Buschman, Timothy J; Gould, Elizabeth

    2018-01-01

    The medial prefrontal cortex (mPFC) is important for cognitive flexibility, the ability to switch between two task-relevant dimensions. Changes in neuronal oscillations and alterations in the coupling across frequency ranges have been correlated with attention and cognitive flexibility. Here we show that astrocytes in the mPFC of adult male Sprague Dawley rats, participate in cognitive flexibility through the astrocyte-specific Ca2+ binding protein S100β, which improves cognitive flexibility and increases phase amplitude coupling between theta and gamma oscillations. We further show that reduction of astrocyte number in the mPFC impairs cognitive flexibility and diminishes delta, alpha and gamma power. Conversely, chemogenetic activation of astrocytic intracellular Ca2+ signaling in the mPFC enhances cognitive flexibility, while inactivation of endogenous S100β among chemogenetically activated astrocytes in the mPFC prevents this improvement. Collectively, our work suggests that astrocytes make important contributions to cognitive flexibility and that they do so by releasing a Ca2+ binding protein which in turn enhances coordinated neuronal oscillations.

  16. Cognitive dysfunction in hereditary spastic paraplegias and other motor neuron disorders

    Directory of Open Access Journals (Sweden)

    Ingrid Faber

    Full Text Available ABSTRACT Hereditary spastic paraplegia (HSP is a diverse group of single-gene disorders that share the predominant clinical feature of progressive lower limb spasticity and weakness. More than 70 different genetic subtypes have been described and all modes of inheritance are possible. Intellectual dysfunction in HSP is frequent in recessive forms but rare in dominant families. It may manifest by either mental retardation and/or cognitive decline. The latter may be subtle, restricted to executive dysfunction or may evolve to severe dementia. The cognitive profile is thought to depend largely on the genetic subtype of HSP, although wide phenotypic variability within the same genetic subtype and also within the same family can be found.

  17. Repolarization Parameters Are Associated With Mortality In Chagas Disease Patients In The United States

    Directory of Open Access Journals (Sweden)

    Jason Bradfield, MD

    2014-07-01

    Conclusion: CD patients with CM and BBB or BBB alone have increased evidence of dispersion of repolarization compared to controls. QTd and (Tp-Ted were associated with increased mortality and/or need for transplant.

  18. Cognitive phase transitions in the cerebral cortex enhancing the neuron doctrine by modeling neural fields

    CERN Document Server

    Kozma, Robert

    2016-01-01

    This intriguing book was born out of the many discussions the authors had in the past 10 years about the role of scale-free structure and dynamics in producing intelligent behavior in brains. The microscopic dynamics of neural networks is well described by the prevailing paradigm based in a narrow interpretation of the neuron doctrine. This book broadens the doctrine by incorporating the dynamics of neural fields, as first revealed by modeling with differential equations (K-sets).  The book broadens that approach by application of random graph theory (neuropercolation). The book concludes with diverse commentaries that exemplify the wide range of mathematical/conceptual approaches to neural fields. This book is intended for researchers, postdocs, and graduate students, who see the limitations of network theory and seek a beachhead from which to embark on mesoscopic and macroscopic neurodynamics.

  19. Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease.

    Science.gov (United States)

    Ginsberg, Stephen D; Malek-Ahmadi, Michael H; Alldred, Melissa J; Che, Shaoli; Elarova, Irina; Chen, Yinghua; Jeanneteau, Freddy; Kranz, Thorsten M; Chao, Moses V; Counts, Scott E; Mufson, Elliott J

    2017-09-09

    Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction

  20. Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion

    Directory of Open Access Journals (Sweden)

    Jun-De Zhu

    2018-01-01

    Full Text Available Panax ginseng is a slow-growing perennial plant. Panax ginseng extract has numerous biological activities, including antitumor, anti-inflammatory and antistress activities. Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment. In this study, we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion, a well-known model of vascular dementia. The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract. Morris water maze and balance beam tests were used to evaluate memory deficits and motor function, respectively. Protein quantity was used to evaluate cholinergic neurons. Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells. Western blot assay was used to evaluate protein levels of vascular endothelial growth factor, basic fibroblast growth factor, Bcl-2 and Bax. Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and bFGF protein expression in the hippocampal CA3 area. Furthermore, Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells, and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression. The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine, a commonly used drug for the treatment of vascular dementia. These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion, and therefore might have therapeutic potential for preventing and treating the disease.

  1. The Association between Myocardial Iron Load and Ventricular Repolarization Parameters in Asymptomatic Beta-Thalassemia Patients

    Directory of Open Access Journals (Sweden)

    Mehmet Kayrak

    2012-01-01

    Full Text Available Previous studies have demonstrated impaired ventricular repolarization in patients with β-TM. However, the effect of iron overload with cardiac T2* magnetic resonance imaging (MRI on cardiac repolarization remains unclear yet. We aimed to examine relationship between repolarization parameters and iron loading using cardiac T2* MRI in asymptomatic β-TM patients. Twenty-two β-TM patients and 22 age- and gender-matched healthy controls were enrolled to the study. From the 12-lead surface electrocardiography, regional and transmyocardial repolarization parameters were evaluated manually by two experienced cardiologists. All patients were also undergone MRI for cardiac T2* evaluation. Cardiac T2* score <20 msec was considered as iron overload status. Of the QT parameters, QT duration, corrected QT interval, and QT peak duration were significantly longer in the β-TM group compared to the healthy controls. Tp−Te and Tp−Te dispersions were also significantly prolonged in β-TM group compared to healthy controls. (Tp-Te/QT was similar between groups. There was no correlation between repolarization parameters and cardiac T2* MRI values. In conclusion, although repolarization parameters were prolonged in asymptomatic β-TM patients compared with control, we could not find any relation between ECG findings and cardiac iron load.

  2. Mapping human temporal and parietal neuronal population activity and functional coupling during mathematical cognition

    Science.gov (United States)

    Daitch, Amy L.; Foster, Brett L.; Schrouff, Jessica; Rangarajan, Vinitha; Kaşikçi, Itır; Gattas, Sandra; Parvizi, Josef

    2016-01-01

    Brain areas within the lateral parietal cortex (LPC) and ventral temporal cortex (VTC) have been shown to code for abstract quantity representations and for symbolic numerical representations, respectively. To explore the fast dynamics of activity within each region and the interaction between them, we used electrocorticography recordings from 16 neurosurgical subjects implanted with grids of electrodes over these two regions and tracked the activity within and between the regions as subjects performed three different numerical tasks. Although our results reconfirm the presence of math-selective hubs within the VTC and LPC, we report here a remarkable heterogeneity of neural responses within each region at both millimeter and millisecond scales. Moreover, we show that the heterogeneity of response profiles within each hub mirrors the distinct patterns of functional coupling between them. Our results support the existence of multiple bidirectional functional loops operating between discrete populations of neurons within the VTC and LPC during the visual processing of numerals and the performance of arithmetic functions. These findings reveal information about the dynamics of numerical processing in the brain and also provide insight into the fine-grained functional architecture and connectivity within the human brain. PMID:27821758

  3. Zinc Improves Cognitive and Neuronal Dysfunction During Aluminium-Induced Neurodegeneration.

    Science.gov (United States)

    Singla, Neha; Dhawan, D K

    2017-01-01

    Metals are considered as important components of a physiologically active cell, and imbalance in their levels can lead to various diseased conditions. Aluminium (Al) is an environmental neurotoxicant, which is etiologically related to several neurodegenerative disorders like Alzheimer's, whereas zinc (Zn) is an essential trace element that regulates a large number of metabolic processes in the brain. The objective of the present study was to understand whether Zn provides any physiological protection during Al-induced neurodegeneration. Male Sprague Dawley rats weighing 140-160 g received either aluminium chloride (AlCl 3 ) orally (100 mg/kg b.wt./day), zinc sulphate (ZnSO 4 ) in drinking water (227 mg/L) or combined treatment of aluminium and zinc for 8 weeks. Al treatment resulted in a significant decline in the cognitive behaviour of rats, whereas zinc supplementation caused an improvement in various neurobehavior parameters. Further, Al exposure decreased (p ≤ 0.001) the levels of neurotransmitters, acetylcholinesterase activity, but increased (p ≤ 0.001) the levels of L-citrulline as well as activities of nitric oxide and monoamine oxidase in the brain. However, zinc administration to Al-treated animals increased the levels of neurotransmitters and regulated the altered activities of brain markers. Western blot of tau, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ubiquitin, α-synuclein and Hsp 70 were also found to be elevated after Al exposure, which however were reversed following Zn treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of loss of pyramidal and Purkinje cells, which were improved upon zinc co-administration. Therefore, the present study demonstrates that zinc improves cognitive functions by regulating α-synuclein and APP-mediated molecular pathways during aluminium-induced neurodegeneration.

  4. Analysis of neuron-astrocyte metabolic cooperation in the brain of db/db mice with cognitive decline using 13C NMR spectroscopy.

    Science.gov (United States)

    Zheng, Hong; Zheng, Yongquan; Wang, Dan; Cai, Aimin; Lin, Qiuting; Zhao, Liangcai; Chen, Minjiang; Deng, Mingjie; Ye, Xinjian; Gao, Hongchang

    2017-01-01

    Type 2 diabetes has been linked to cognitive impairment, but its potential metabolic mechanism is still unclear. The present study aimed to explore neuron-astrocyte metabolic cooperation in the brain of diabetic (db/db, BKS.Cg-m +/+ Leprdb/J) mice with cognitive decline using 13 C NMR technique in combination with intravenous [2- 13 C]-acetate and [3- 13 C]-lactate infusions. We found that the 13 C-enrichment from [2- 13 C]-acetate into tricarboxylic acid cycle intermediate, succinate, was significantly decreased in db/db mice with cognitive decline compared with wild-type (WT, C57BLKS/J) mice, while an opposite result was obtained after [3- 13 C]-lactate infusion. Relative to WT mice, db/db mice with cognitive decline had significantly lower 13 C labeling percentages in neurotransmitters including glutamine, glutamate, and γ-aminobutyric acid after [2- 13 C]-acetate infusion. However, [3- 13 C]-lactate resulted in increased 13 C-enrichments in neurotransmitters in db/db mice with cognitive decline. This may indicate that the disturbance of neurotransmitter metabolism occurred during the development of cognitive decline. In addition, a reduction in 13 C-labeling of lactate and an increase in gluconeogenesis were found from both labeled infusions in db/db mice with cognitive decline. Therefore, our results suggest that the development of cognitive decline in type 2 diabetes may be implicated to an unbalanced metabolism in neuron-astrocyte cooperation and an enhancement of gluconeogenesis. © The Author(s) 2016.

  5. Heart rate variability alters cardiac repolarization and electromechanical dynamics.

    Science.gov (United States)

    Phadumdeo, Vrishti M; Weinberg, Seth H

    2018-04-07

    Heart rate continuously varies due to autonomic regulation, stochasticity in pacemaking, and circadian rhythm, collectively termed heart rate variability (HRV), during normal physiological conditions. Low HRV is clinically associated with an elevated risk of cardiac arrhythmias. Alternans, a beat-to-beat alternation in action potential duration (APD) and/or intracellular calcium (Ca) transient, is a well-known risk factor associated with cardiac arrhythmias that is typically studied under conditions of a constant pacing rate, i.e., the absence of HRV. In this study, we investigate the effects of HRV on the interplay between APD, Ca, and electromechanical properties, employing a nonlinear discrete-time map model that governs APD and intracellular Ca cycling with a stochastic pacing period. We find that HRV can decrease variation in APD and peak Ca at fast pacing rates for which alternans is present. Further, increased HRV typically disrupts the alternating pattern for both APD and peak Ca and weakens the correlation between APD and peak Ca, thus decoupling Ca-mediated instabilities from repolarization alternation. We find that the efficacy of these effects is regulated by the sarcoplasmic reticulum Ca uptake rate. Overall, these results demonstrate that HRV disrupts arrhythmogenic alternans and suggests that HRV may be a significant factor in preventing life-threatening arrhythmias. Copyright © 2018 Elsevier Ltd. All rights reserved.

  6. Naringin Improves Neuronal Insulin Signaling, Brain Mitochondrial Function, and Cognitive Function in High-Fat Diet-Induced Obese Mice.

    Science.gov (United States)

    Wang, Dongmei; Yan, Junqiang; Chen, Jing; Wu, Wenlan; Zhu, Xiaoying; Wang, Yong

    2015-10-01

    The epidemic and experimental studies have confirmed that the obesity induced by high-fat diet not only caused neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment in mice. Naringin has been reported to posses biological functions which are beneficial to human cognitions, but its protective effects on HFD-induced cognitive deficits and underlying mechanisms have not been well characterized. In the present study Male C57BL/6 J mice were fed either a control or high-fat diet for 20 weeks and then randomized into four groups treated with their respective diets including control diet, control diet + naringin, high-fat diet (HFD), and high-fat diet + naringin (HFDN). The behavioral performance was assessed by using novel object recognition test and Morris water maze test. Hippocampal mitochondrial parameters were analyzed. Then the protein levels of insulin signaling pathway and the AMP-activated protein kinase (AMPK) in the hippocampus were detected by Western blot method. Our results showed that oral administration of naringin significantly improved the learning and memory abilities as evidenced by increasing recognition index by 52.5% in the novel object recognition test and inducing a 1.05-fold increase in the crossing-target number in the probe test, and ameliorated mitochondrial dysfunction in mice caused by HFD consumption. Moreover, naringin significantly enhanced insulin signaling pathway as indicated by a 34.5% increase in the expression levels of IRS-1, a 47.8% decrease in the p-IRS-1, a 1.43-fold increase in the p-Akt, and a 1.89-fold increase in the p-GSK-3β in the hippocampus of the HFDN mice versus HFD mice. Furthermore, the AMPK activity significantly increased in the naringin-treated (100 mg kg(-1) d(-1)) group. These findings suggest that an enhancement in insulin signaling and a decrease in mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms that naringin

  7. Short-term variability of repolarization is superior to other repolarization parameters in the evaluation of diverse antiarrhythmic interventions in the chronic atrioventricular block dog

    NARCIS (Netherlands)

    Bossu, Alexandre; Varkevisser, Rosanne; Beekman, Henriette D.M.; Houtman, Marien J C; Van Der Heyden, Marcel A.G.; Vos, Marc A.

    2017-01-01

    Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also

  8. Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

    Science.gov (United States)

    Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

    2013-05-01

    Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

  9. Brains are not just neurons. Comment on “Toward a computational framework for cognitive biology: Unifying approaches from cognitive neuroscience and comparative cognition” by Fitch

    Science.gov (United States)

    Huber, Ludwig

    2014-09-01

    This comment addresses the first component of Fitch's framework: the computational power of single neurons [3]. Although I agree that traditional models of neural computation have vastly underestimated the computational power of single neurons, I am hesitant to follow him completely. The exclusive focus on neurons is likely to underestimate the importance of other cells in the brain. In the last years, two such cell types have received appropriate attention by neuroscientists: interneurons and glia. Interneurons are small, tightly packed cells involved in the control of information processing in learning and memory. Rather than transmitting externally (like motor or sensory neurons), these neurons process information within internal circuits of the brain (therefore also called 'relay neurons'). Some specialized interneuron subtypes temporally regulate the flow of information in a given cortical circuit during relevant behavioral events [4]. In the human brain approx. 100 billion interneurons control information processing and are implicated in disorders such as epilepsy and Parkinson's.

  10. Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer’s Disease

    Science.gov (United States)

    Li, Jinze; Ma, Xiaowei; Wang, Yu; Chen, Chengjuan; Hu, Min; Wang, Linlin; Fu, Junmin; Shi, Gaona; Zhang, Dongming; Zhang, Tiantai

    2018-01-01

    Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer’s disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD. PMID:29636677

  11. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    Science.gov (United States)

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W.H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; zu Schwabedissen, Henriette Meyer; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; consortium, HRGEN; den Hoed, Marcel; Loos, Ruth J.F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A.M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; Fabiola Del, Greco M.; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C.M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Leach, Irene Mateo; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C.M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R.P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I.W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD. PMID:24952745

  12. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard; Verduyn, S Cora; Stengl, Milan

    2004-01-01

    Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat...

  13. Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model.

    Science.gov (United States)

    Toib, Amir; Zhang, Chen; Borghetti, Giulia; Zhang, Xiaoxiao; Wallner, Markus; Yang, Yijun; Troupes, Constantine D; Kubo, Hajime; Sharp, Thomas E; Feldsott, Eric; Berretta, Remus M; Zalavadia, Neil; Trappanese, Danielle M; Harper, Shavonn; Gross, Polina; Chen, Xiongwen; Mohsin, Sadia; Houser, Steven R

    2017-09-01

    Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na + and Ca 2+ in the development of HCM, but the role of repolarizing K + currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K + currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K + currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K + channel subunits. In conclusion, decrease in repolarizing K + currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility. NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K + currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. Copyright © 2017

  14. Sudden cardiac death in dogs with remodeled hearts is associated with larger beat-to-beat variability of repolarization

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard; Truin, Michiel; van Opstal, Jurren M

    2005-01-01

    Increased proarrhythmia in dogs with chronic AV block (AVB) has been explained by ventricular remodeling causing a decrease in repolarization reserve. Beat-to-beat variability of repolarization (BVR) has been suggested to reflect repolarization reserve, in which high variability represents...... diminished reserve and larger propensity for repolarization-dependent ventricular arrhythmia. A subset of chronic AVB dogs (10%) suffers sudden cardiac death (SCD). With the assumption that repolarization defects constitute a potentially lethal proarrhythmic substrate, we hypothesized that BVR in SCD dogs...... are larger than in matched control chronic AVB dogs. From a population of 200 chronic AVB dogs, initially two groups were chosen retrospectively: 8 dogs that died suddenly (SCD) and 8 control dogs. Control dogs had a longer lifespan after AVB (10 to 18 weeks) than SCD dogs (5 to 10 weeks). All dogs had...

  15. Wolff-Parkinson-White syndrome concomitant with idiopathic ventricular fibrillation associated with inferior early repolarization.

    Science.gov (United States)

    Takahashi, Naohiko; Shinohara, Tetsuji; Hara, Masahide; Saikawa, Tetsunori

    2012-01-01

    We encountered a 39-year-old man with documented ventricular fibrillation (VF). His ECGs showed intermittent Wolff-Parkinson-White (WPW) syndrome pattern. During electrophysiological study, no ventricular preexcitation was observed. An accessory pathway located at the posterior mitral annulus was identified, and successfully eliminated by radiofrequency catheter ablation. VF was not induced. His ECGs in the absence of delta waves demonstrated early repolarization in the inferior leads. This case raises the possibility that patients with manifest WPW syndrome may have an arrhythmogenic substrate associated with early repolarization, and the characteristic J waves can be masked by the presence of ventricular preexcitation.

  16. Dynamic fatigue on repolarization of lead zirconate-titanate base ceramics with various ferroelectric hardness

    International Nuclear Information System (INIS)

    Gavrilyachenko, V.G.; Semenchev, A.F.; Sklyarova, E.N.; Kuznetsova, E.M.

    2006-01-01

    One studied experimentally changes of the residual polarization in lead zirconate-titanate base ceramics with various ferroelectric hardness under the effect of a strong varying field. The twinning and untwinning of crystallites accompanying repolarization is assumed to be the basic mechanism of propagation of the crystalline structure defects governing the fatigue rates of the ferroelectric-soft ceramics. In ferroelectric-hard ceramics crystallites the stable configurations of mechanical twins, the result of the secondary twinning, are formed when the hysteresis loop is formed. At repolarization in the mentioned structures one observes no motion of the twin boundaries, and the fatigue rates are low ones [ru

  17. The T-peak–T-end Interval as a Marker of Repolarization Abnormality

    DEFF Research Database (Denmark)

    Bhuiyan, Tanveer A.; Graff, Claus; Kanters, Jørgen K.

    2015-01-01

    BACKGROUND AND OBJECTIVE: The T-peak to T-end (TpTe) interval has been suggested as an index of transmural dispersion and as a marker of drug-induced abnormal repolarization. In this study, we investigate the relation between TpTe and the QT interval. METHODS: Electrocardiograms (ECGs) from five...

  18. Glucose ingestion causes cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects

    DEFF Research Database (Denmark)

    Hyltén-Cavallius, Louise; Iepsen, Eva W; Christiansen, Michael

    2017-01-01

    BACKGROUND: Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk...

  19. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    DEFF Research Database (Denmark)

    Arking, Dan E; Pulit, Sara L; Crotti, Lia

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Usi...

  20. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    NARCIS (Netherlands)

    D.E. Arking (Dan); S.L. Pulit (Sara); L. Crotti (Lia); P. van der Harst (Pim); P. Munroe (Patricia); T.T. Koopmann (Tamara); N. Sotoodehnia (Nona); E. Rossin (Elizabeth); M. Morley (Michael); X. Wang (Xinchen); A.D. Johnson (Andrew); A. Lundby (Alicia); D.F. Gudbjartsson (Daniel); P.A. Noseworthy (Peter); M. Eijgelsheim (Mark); Y. Bradford (Yuki); K.V. Tarasov (Kirill); M. Dörr (Marcus); M. Müller-Nurasyid (Martina); A.M. Lahtinen (Annukka); I.M. Nolte (Ilja); G.D. Smith; J.C. Bis (Joshua); A.J. Isaacs (Aaron); S.J. Newhouse (Stephen); D.S. Evans (Daniel); W.S. Post (Wendy S.); D. Waggott (Daryl); L.-P. Lyytikäinen (Leo-Pekka); A.A. Hicks (Andrew); L. Eisele (Lewin); D. Ellinghaus (David); C. Hayward (Caroline); P. Navarro (Pau); S. Ulivi (Shelia); T. Tanaka (Toshiko); D.J. Tester (David); S. Chatel (Stéphanie); S. Gustafsson (Stefan); M. Kumari (Meena); R. Morris (Richard); A.T. Naluai (Asa); S. Padmanabhan (Sandosh); A. Kluttig (Alexander); B. Strohmer (Bernhard); A.G. Panayiotou (Andrie); M. Torres (Maria); M. Knoflach (Michael); J.A. Hubacek (Jaroslav A.); K. Slowikowski (Kamil); S. Raychaudhuri (Soumya); R.D. Kumar (Runjun); T.B. Harris (Tamara); L.J. Launer (Lenore); A.R. Shuldiner (Alan); A. Alonso (Alvaro); J.S. Bader (Joel); G.B. Ehret (Georg); H. Huang (Hailiang); W.H.L. Kao (Wen); J.B. Strait (James); P.W. Macfarlane (Peter); M.J. Brown (Morris); M. Caulfield (Mark); N.J. Samani (Nilesh); F. Kronenberg (Florian); J. Willeit (Johann); J.G. Smith (J. Gustav); K.H. Greiser (Karin Halina); H.M. Zu Schwabedissen (Henriette Meyer); K. Werdan (Karl); C. Carella (Cintia); L. Zelante (Leopoldo); S.R. Heckbert (Susan); B.M. Psaty (Bruce); J.I. Rotter (Jerome); I. Kolcic (Ivana); O. Polasek (Ozren); A.F. Wright (Alan); M. Griffin (Maura); M.J. Daly (Mark); D.O. Arnar (David); H. Hólm (Hilma); U. Thorsteinsdottir (Unnur); J.C. Denny (Joshua); D.M. Roden (Dan); R.L. Zuvich (Rebecca); V. Emilsson (Valur); A.S. Plump (Andrew); M.G. Larson (Martin); C.J. O'Donnell (Christopher); X. Yin (Xiaoyan); M. Bobbo (Marco); P. d' Adamo (Pio); A. Iorio (Annamaria); G. Sinagra (Gianfranco); A. Carracedo (Angel); S.R. Cummings (Steven); M.A. Nalls (Michael); A. Jula (Antti); K.K. Kontula (Kimmo); A. Marjamaa (Annukka); L. Oikarinen (Lasse); M. Perola (Markus); K. Porthan (Kimmo); R. Erbel (Raimund); P. Hoffmann (Per); K.-H. Jöckel (Karl-Heinz); H. Kälsch (Hagen); M.M. Nöthen (Markus); M. den Hoed (Marcel); R.J.F. Loos (Ruth); D.S. Thelle (Dag); C. Gieger (Christian); T. Meitinger (Thomas); S. Perz (Siegfried); A. Peters (Annette); H. Prucha (Hanna); M.F. Sinner (Moritz); M. Waldenberger (Melanie); R.A. de Boer (Rudolf); L. Franke (Lude); P.A. van der Vleuten (Pieter); B.M. Beckmann (Britt); E. Martens (Eimo); A. Bardai (Abdennasser); N. Hofman (Nynke); A.A.M. Wilde (Arthur); E.R. Behr (Elijah ); C. Dalageorgou (Chrysoula); J.R. Giudicessi (John); A. Medeiros-Domingo (Argelia); J. Barc (Julien); F. Kyndt (Florence); V. Probst (Vincent); A. Ghidoni (Alice); R. Insolia (Roberto); R.M. Hamilton (Robert); S.W. Scherer (Stephen); J. Brandimarto (Jeffrey); K. Margulies (Kenneth); C.E. Moravec (Christine); F. Del Greco M (Fabiola); C. Fuchsberger (Christian); J.R. O'Connell (Jeffery); W.K. Lee (Wai); G.C.M. Watt (Graham); H. Campbell (Harry); S.H. Wild (Sarah); N.E. El Mokhtari (Nour); N. Frey (Norbert); F.W. Asselbergs (Folkert); I.M. Leach (Irene Mateo); G. Navis (Gerjan); M.P. van den Berg (Maarten); D.J. van Veldhuisen (Dirk); M. Kellis (Manolis); B.P. Krijthe (Bouwe); O.H. Franco (Oscar); A. Hofman (Albert); J.A. Kors (Jan); A.G. Uitterlinden (André); J.C.M. Witteman (Jacqueline); L. Kedenko (Lyudmyla); C. Lamina (Claudia); B.A. Oostra (Ben); G.R. Abecasis (Gonçalo); E. Lakatta (Edward); A. Mulas (Antonella); M. Orrù (Marco); D. Schlessinger (David); M. Uda (Manuela); M.R.P. Markus (Marcello R. P.); U. Völker (Uwe); H. Snieder (Harold); T.D. Spector (Timothy); J. Ärnlöv (Johan); L. Lind (Lars); J. Sundstrom (Johan); A.C. Syvanen; M. Kivimaki (Mika); M. Kähönen (Mika); K. Mononen (Kari); O. Raitakari (Olli); J. Viikari (Jorma); V. Adamkova (Vera); S. Kiechl (Stefan); M.-J. Brion (Maria); A.N. Nicolaides (Andrew); B. Paulweber (Bernhard); J. Haerting (Johannes); A. Dominiczak (Anna); F. Nyberg (Fredrik); P.H. Whincup (Peter); A. Hingorani (Aroon); J.-J. Schott (Jean-Jacques); C.R. Bezzina (Connie); E. Ingelsson (Erik); L. Ferrucci (Luigi); P. Gasparini (Paolo); J.F. Wilson (James); I. Rudan (Igor); A. Franke (Andre); T.W. Mühleisen (Thomas); P.P. Pramstaller (Peter Paul); T. Lehtimäki (Terho); A.D. Paterson (Andrew); A. Parsa (Afshin); Y. Liu (YongMei); C.M. van Duijn (Cornelia); D.S. Siscovick (David); V. Gudnason (Vilmundur); Y. Jamshidi (Yalda); V. Salomaa (Veikko); S.B. Felix (Stephan); S. Sanna (Serena); M.D. Ritchie (Marylyn); B.H.Ch. Stricker (Bruno); J-A. Zwart (John-Anker); L.A. Boyer (Laurie); T.P. Cappola (Thomas); J.V. Olsen (Jesper); P. Lage (Pedro); P.J. Schwartz (Peter); S. Kääb (Stefan); A. Chakravarti (Aravinda); M. Ackerman (Margaret); A. Pfeufer (Arne); P.I.W. de Bakker (Paul); C. Newton-Cheh (Christopher)

    2014-01-01

    textabstractThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome

  1. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

    NARCIS (Netherlands)

    Arking, Dan E.; Pulit, Sara L.; Crotti, Lia; van der Harst, Pim; Munroe, Patricia B.; Koopmann, Tamara T.; Sotoodehnia, Nona; Rossin, Elizabeth J.; Morley, Michael; Wang, Xinchen; Johnson, Andrew D.; Lundby, Alicia; Gudbjartsson, Daníel F.; Noseworthy, Peter A.; Eijgelsheim, Mark; Bradford, Yuki; Tarasov, Kirill V.; Dörr, Marcus; Müller-Nurasyid, Martina; Lahtinen, Annukka M.; Nolte, Ilja M.; Smith, Albert Vernon; Bis, Joshua C.; Isaacs, Aaron; Newhouse, Stephen J.; Evans, Daniel S.; Post, Wendy S.; Waggott, Daryl; Lyytikäinen, Leo-Pekka; Hicks, Andrew A.; Eisele, Lewin; Ellinghaus, David; Hayward, Caroline; Navarro, Pau; Ulivi, Sheila; Tanaka, Toshiko; Tester, David J.; Chatel, Stéphanie; Gustafsson, Stefan; Kumari, Meena; Morris, Richard W.; Naluai, Åsa T.; Padmanabhan, Sandosh; Kluttig, Alexander; Strohmer, Bernhard; Panayiotou, Andrie G.; Torres, Maria; Knoflach, Michael; Hubacek, Jaroslav A.; Slowikowski, Kamil; Raychaudhuri, Soumya; Kumar, Runjun D.; Harris, Tamara B.; Launer, Lenore J.; Shuldiner, Alan R.; Alonso, Alvaro; Bader, Joel S.; Ehret, Georg; Huang, Hailiang; Kao, W. H. Linda; Strait, James B.; Macfarlane, Peter W.; Brown, Morris; Caulfield, Mark J.; Samani, Nilesh J.; Kronenberg, Florian; Willeit, Johann; Smith, J. Gustav; Greiser, Karin H.; Meyer zu Schwabedissen, Henriette; Werdan, Karl; Carella, Massimo; Zelante, Leopoldo; Heckbert, Susan R.; Psaty, Bruce M.; Rotter, Jerome I.; Kolcic, Ivana; Polašek, Ozren; Wright, Alan F.; Griffin, Maura; Daly, Mark J.; Arnar, David O.; Hólm, Hilma; Thorsteinsdottir, Unnur; Denny, Joshua C.; Roden, Dan M.; Zuvich, Rebecca L.; Emilsson, Valur; Plump, Andrew S.; Larson, Martin G.; O'Donnell, Christopher J.; Yin, Xiaoyan; Bobbo, Marco; D'Adamo, Adamo P.; Iorio, Annamaria; Sinagra, Gianfranco; Carracedo, Angel; Cummings, Steven R.; Nalls, Michael A.; Jula, Antti; Kontula, Kimmo K.; Marjamaa, Annukka; Oikarinen, Lasse; Perola, Markus; Porthan, Kimmo; Erbel, Raimund; Hoffmann, Per; Jöckel, Karl-Heinz; Kälsch, Hagen; Nöthen, Markus M.; den Hoed, Marcel; Loos, Ruth J. F.; Thelle, Dag S.; Gieger, Christian; Meitinger, Thomas; Perz, Siegfried; Peters, Annette; Prucha, Hanna; Sinner, Moritz F.; Waldenberger, Melanie; de Boer, Rudolf A.; Franke, Lude; van der Vleuten, Pieter A.; Beckmann, Britt Maria; Martens, Eimo; Bardai, Abdennasser; Hofman, Nynke; Wilde, Arthur A. M.; Behr, Elijah R.; Dalageorgou, Chrysoula; Giudicessi, John R.; Medeiros-Domingo, Argelia; Barc, Julien; Kyndt, Florence; Probst, Vincent; Ghidoni, Alice; Insolia, Roberto; Hamilton, Robert M.; Scherer, Stephen W.; Brandimarto, Jeffrey; Margulies, Kenneth; Moravec, Christine E.; del Greco M, Fabiola; Fuchsberger, Christian; O'Connell, Jeffrey R.; Lee, Wai K.; Watt, Graham C. M.; Campbell, Harry; Wild, Sarah H.; El Mokhtari, Nour E.; Frey, Norbert; Asselbergs, Folkert W.; Mateo Leach, Irene; Navis, Gerjan; van den Berg, Maarten P.; van Veldhuisen, Dirk J.; Kellis, Manolis; Krijthe, Bouwe P.; Franco, Oscar H.; Hofman, Albert; Kors, Jan A.; Uitterlinden, André G.; Witteman, Jacqueline C. M.; Kedenko, Lyudmyla; Lamina, Claudia; Oostra, Ben A.; Abecasis, Gonçalo R.; Lakatta, Edward G.; Mulas, Antonella; Orrú, Marco; Schlessinger, David; Uda, Manuela; Markus, Marcello R. P.; Völker, Uwe; Snieder, Harold; Spector, Timothy D.; Ärnlöv, Johan; Lind, Lars; Sundström, Johan; Syvänen, Ann-Christine; Kivimaki, Mika; Kähönen, Mika; Mononen, Nina; Raitakari, Olli T.; Viikari, Jorma S.; Adamkova, Vera; Kiechl, Stefan; Brion, Maria; Nicolaides, Andrew N.; Paulweber, Bernhard; Haerting, Johannes; Dominiczak, Anna F.; Nyberg, Fredrik; Whincup, Peter H.; Hingorani, Aroon D.; Schott, Jean-Jacques; Bezzina, Connie R.; Ingelsson, Erik; Ferrucci, Luigi; Gasparini, Paolo; Wilson, James F.; Rudan, Igor; Franke, Andre; Mühleisen, Thomas W.; Pramstaller, Peter P.; Lehtimäki, Terho J.; Paterson, Andrew D.; Parsa, Afshin; Liu, Yongmei; van Duijn, Cornelia M.; Siscovick, David S.; Gudnason, Vilmundur; Jamshidi, Yalda; Salomaa, Veikko; Felix, Stephan B.; Sanna, Serena; Ritchie, Marylyn D.; Stricker, Bruno H.; Stefansson, Kari; Boyer, Laurie A.; Cappola, Thomas P.; Olsen, Jesper V.; Lage, Kasper; Schwartz, Peter J.; Kääb, Stefan; Chakravarti, Aravinda; Ackerman, Michael J.; Pfeufer, Arne; de Bakker, Paul I. W.; Newton-Cheh, Christopher

    2014-01-01

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using

  2. Mesmerising mirror neurons.

    Science.gov (United States)

    Heyes, Cecilia

    2010-06-01

    Mirror neurons have been hailed as the key to understanding social cognition. I argue that three currents of thought-relating to evolution, atomism and telepathy-have magnified the perceived importance of mirror neurons. When they are understood to be a product of associative learning, rather than an adaptation for social cognition, mirror neurons are no longer mesmerising, but they continue to raise important questions about both the psychology of science and the neural bases of social cognition. Copyright 2010 Elsevier Inc. All rights reserved.

  3. Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

    KAUST Repository

    Bueno-Orovio, Alfonso

    2013-05-15

    The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies. © 2013 Springer-Verlag Berlin Heidelberg.

  4. Na/K pump regulation of cardiac repolarization: insights from a systems biology approach.

    Science.gov (United States)

    Bueno-Orovio, Alfonso; Sánchez, Carlos; Pueyo, Esther; Rodriguez, Blanca

    2014-02-01

    The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.

  5. Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Annamaria Morelli

    2017-10-01

    Full Text Available The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM in the basal forebrain (BF is associated to the cognitive decline of Alzheimer’s disease (AD patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase and acetylcholine (Ach release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa and potassium (IK currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF, through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs (labeled with PKH26 fluorescent dye prior to administration reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for AD.

  6. What neuromodulation and lesion studies tell us about the function of the mirror neuron system and embodied cognition

    NARCIS (Netherlands)

    Keysers, Christian; Paracampo, Riccardo; Gazzola, V.

    2018-01-01

    We review neuromodulation and lesion studies that address how activations in the mirror neuron system contribute to our perception of observed actions. Past reviews showed disruptions of this parieto-premotor network impair imitation and goal and kinematic processing. Recent studies bring five new

  7. Role of suppression of the inward rectifier current in terminal action potential repolarization in the failing heart.

    Science.gov (United States)

    Klein, Michael G; Shou, Matie; Stohlman, Jayna; Solhjoo, Soroosh; Haigney, Myles; Tidwell, Richard R; Goldstein, Robert E; Flagg, Thomas P; Haigney, Mark C

    2017-08-01

    The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K + current (I K1 ) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear. The purpose of this study was to define the effect of I K1 suppression on the cardiac AP and excitability in the normal and failing hearts. We used electrophysiological and pharmacological approaches to investigate I K1 function in a swine tachy-pacing model of heart failure (HF). Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific I K1 inhibitor, PA-6 (pentamidine analog 6), indicating that I K1 is the primary determinant of the final phase of repolarization. Moreover, we find that I K1 suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction. Using an objective measure of terminal repolarization, we conclude that I K1 is the major determinant of the terminal repolarization time course. Moreover, suppression of I K1 prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how I K1 suppression may contribute to arrhythmogenesis in the failing heart. Published by Elsevier Inc.

  8. Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa.

    Science.gov (United States)

    Padfield, Gareth J; Escudero, Carolina A; DeSouza, Astrid M; Steinberg, Christian; Gibbs, Karen; Puyat, Joseph H; Lam, Pei Yoong; Sanatani, Shubhayan; Sherwin, Elizabeth; Potts, James E; Sandor, George; Krahn, Andrew D

    2016-02-09

    Patients with anorexia nervosa exhibit abnormal myocardial repolarization and are susceptible to sudden cardiac death. Exercise testing is useful in unmasking QT prolongation in disorders associated with abnormal repolarization. We characterized QT adaptation during exercise in anorexia. Sixty-one adolescent female patients with anorexia nervosa and 45 age- and sex-matched healthy volunteers performed symptom-limited cycle ergometry during 12-lead ECG monitoring. Changes in the QT interval during exercise were measured, and QT/RR-interval slopes were determined by using mixed-effects regression modeling. Patients had significantly lower body mass index than controls; however, resting heart rates and QT/QTc intervals were similar at baseline. Patients had shorter exercise times (13.7±4.5 versus 20.6±4.5 minutes; Panorexia nervosa. © 2016 American Heart Association, Inc.

  9. A dual potassium channel activator improves repolarization reserve and normalizes ventricular action potentials

    DEFF Research Database (Denmark)

    Calloe, Kirstine; Di Diego, José M; Hansen, Rie Schultz

    2016-01-01

    in cultured canine cardiac myocytes and determined whether a dual K(+) current activator can normalize K(+) currents and restore action potential (AP) configuration. METHODS AND RESULTS: Ventricular myocytes were isolated and cultured for up to 48h. Current and voltage clamp recordings were made using patch...... of EADs. Our results suggest a potential benefit of K(+) current activators under conditions of reduced repolarization reserve including heart failure....

  10. Transplantation of NSC-derived cholinergic neuron-like cells improves cognitive function in APP/PS1 transgenic mice.

    Science.gov (United States)

    Gu, G; Zhang, W; Li, M; Ni, J; Wang, P

    2015-04-16

    The ability to selectively control the differentiation of neural stem cells (NSCs) into cholinergic neurons in vivo would be an important step toward cell replacement therapy. First, green fluorescent protein (GFP)-NSCs were induced to differentiate into cholinergic neuron-like cells (CNLs) with retinoic acid (RA) pre-induction followed by nerve growth factor (NGF) induction. Then, these CNLs were transplanted into bilateral hippocampus of APP/PS1 transgenic mice. Behavioral parameters showed by Morris water maze (MWM) tests and the percentages of GFP-labeled cholinergic neurons of CNL transplanted mice were compared with those of controls. Brain levels of choline acetyltransferase (ChAT) mRNA and proteins were analyzed by quantitative real-time PCR and Western blotting, ChAT activity and acetylcholine (ACh) concentration were also evaluated by ChAT activity and ACh concentration assay kits. Immunofluorescence analysis showed that 80.3±1.5% NSCs differentiated into CNLs after RA pre-induction followed by NGF induction in vitro. Three months after transplantation, 82.4±6.3% CNLs differentiated into cholinergic neurons in vivo. APP/PS1 mice transplanted with CNLs showed a significant improvement in learning and memory ability compared with control groups at different time points. Furthermore, CNLs transplantation dramatically increased in the expressions of ChAT mRNA and protein, as well ChAT activity and ACh concentration in APP/PS1 mice. Our findings support the prospect of using NSC-derived CNLs in developing therapies for Alzheimer's disease (AD). Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. Changes of Functional and Directed Resting-State Connectivity Are Associated with Neuronal Oscillations, ApoE Genotype and Amyloid Deposition in Mild Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Lars Michels

    2017-09-01

    Full Text Available The assessment of effects associated with cognitive impairment using electroencephalography (EEG power mapping allows the visualization of frequency-band specific local changes in oscillatory activity. In contrast, measures of coherence and dynamic source synchronization allow for the study of functional and effective connectivity, respectively. Yet, these measures have rarely been assessed in parallel in the context of mild cognitive impairment (MCI and furthermore it has not been examined if they are related to risk factors of Alzheimer’s disease (AD such as amyloid deposition and apolipoprotein ε4 (ApoE allele occurrence. Here, we investigated functional and directed connectivities with Renormalized Partial Directed Coherence (RPDC in 17 healthy controls (HC and 17 participants with MCI. Participants underwent ApoE-genotyping and Pittsburgh compound B positron emission tomography (PiB-PET to assess amyloid deposition. We observed lower spectral source power in MCI in the alpha and beta bands. Coherence was stronger in HC than MCI across different neuronal sources in the delta, theta, alpha, beta and gamma bands. The directed coherence analysis indicated lower information flow between fronto-temporal (including the hippocampus sources and unidirectional connectivity in MCI. In MCI, alpha and beta RPDC showed an inverse correlation to age and gender; global amyloid deposition was inversely correlated to alpha coherence, RPDC and beta and gamma coherence. Furthermore, the ApoE status was negatively correlated to alpha coherence and RPDC, beta RPDC and gamma coherence. A classification analysis of cognitive state revealed the highest accuracy using EEG power, coherence and RPDC as input. For this small but statistically robust (Bayesian power analyses sample, our results suggest that resting EEG related functional and directed connectivities are sensitive to the cognitive state and are linked to ApoE and amyloid burden.

  12. Characterization of ventricular depolarization and repolarization changes in a porcine model of myocardial infarction.

    Science.gov (United States)

    Romero, Daniel; Ringborn, Michael; Demidova, Marina; Koul, Sasha; Laguna, Pablo; Platonov, Pyotr G; Pueyo, Esther

    2012-12-01

    In this study, several electrocardiogram (ECG)-derived indices corresponding to both ventricular depolarization and repolarization were evaluated during acute myocardial ischemia in an experimental model of myocardial infarction produced by 40 min coronary balloon inflation in 13 pigs. Significant changes were rapidly observed from minute 4 after the start of coronary occlusion, achieving their maximum values between 11 and 22 min for depolarization and between 9 and 12 min for repolarization indices, respectively. Subsequently, these maximum changes started to decrease during the latter part of the occlusion. Depolarization changes associated with the second half of the QRS complex showed a significant but inverse correlation with the myocardium at risk (MaR) estimated by scintigraphic images. The correlation between MaR and changes of the downward slope of the QRS complex, [Formula: see text], evaluated at the two more relevant peaks observed during the occlusion, was r = -0.75, p evolution, respectively. Repolarization changes, analyzed by evaluation of ST segment elevation at the main observed positive peak, also showed negative, however non-significant correlation with MaR: r = -0.34, p = 0.28. Our results suggest that changes evaluated in the latter part of the depolarization, such as those described by [Formula: see text], which are influenced by R-wave amplitude, QRS width and ST level variations simultaneously, correlate better with the amount of ischemia than other indices evaluated in the earlier part of depolarization or during the ST segment.

  13. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    Directory of Open Access Journals (Sweden)

    Xu Zhao

    Full Text Available Lignan compounds extracted from Schisandra chinensis (Turcz. Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC, as well as the level of malondialdehyde (MDA both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP, change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway. Moreover, TLS also decreased the activity of β-secretase 1 (BACE1, crucial protease contributes to the hydrolysis of amyloid precursor protein (APP, and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways.

  14. Assay of Calcium Transients and Synapses in Rat Hippocampal Neurons by Kinetic Image Cytometry and High-Content Analysis: An In Vitro Model System for Postchemotherapy Cognitive Impairment.

    Science.gov (United States)

    McDonough, Patrick M; Prigozhina, Natalie L; Basa, Ranor C B; Price, Jeffrey H

    2017-07-01

    Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17β-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6-14 days. Kinetic Image Cytometry™ (KIC™) methods were developed to quantify spontaneously occurring intracellular calcium transients representing the activity of the neurons, and high-content analysis (HCA) methods were developed to quantify the expression, colocalization, and puncta formed by synaptic proteins (postsynaptic density protein-95 [PSD-95] and presynaptic protein Synapsin-1 [Syn-1]). As quantified by KIC, FSK increased the occurrence and synchronization of the calcium transients indicating stimulatory effects on RHN activity, whereas TAM had inhibitory effects. As quantified by HCA, FSK also increased PSD-95 puncta and PSD-95:Syn-1 colocalization, whereas ES increased the puncta of both PSD-95 and Syn-1 with little effect on colocalization. The estrogen receptor antagonist FUL also increased PSD-95 puncta. In contrast, TAM reduced Syn-1 and PSD-95:Syn-1 colocalization, consistent with its inhibitory effects on the calcium transients. Thus TAM reduced activity and synapse formation by the RHNs, which may relate to the ability of this agent to cause PCCI. The results illustrate that KIC and HCA can be used to quantify neurotoxic and neuroprotective effects of chemicals in RHNs to investigate mechanisms and potential therapeutics for PCCI.

  15. [Role of hippocampal neuronal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia].

    Science.gov (United States)

    Ming, Hong; Chen, Rui; Wang, Jing; Ju, Jingmei; Sun, Li; Zhang, Guoxing

    2014-12-01

    To investigate the role of hippocampal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia. 45 ICR male mice were randomly divided into 3 groups: the unhandled control group (UC group, n = 15), the chronic intermittent hypoxia (CIH group, n = 15) and the pretreatment memantine group (MEM group, n = 15). CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks. Mice in the MEM group were pretreated with memantine (5 mg/kg) by intraperitoneal injection before the cycle started, and those in the UC group and the CIH group were treated with same volume of physiological saline. Neurobehavioral assessments were performed by Open filed and Morris water maze, [Ca²⁺]i in hippocampal neurons was evaluate by flow cytometry, and the expression of cleaved caspase-3, phospho-ERK1/2 in hippocampus were detected by Western blotting. Compared with the UC group, CIH mice displayed markedly more locomotor activity (P overload, neuron apoptosis, dephosphorylation of ERK1/2, which can be attenuated by memantine. Memantine may have a therapeutic effect in the neurocognitive impairment associated with OSAHS.

  16. The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction

    OpenAIRE

    Jani, Ylber; Kamberi, Ahmet; Xhunga, Sotir; Pocesta, Bekim; Ferati, Fatmir; Lala, Dali; Zeqiri, Agim; Rexhepi, Atila

    2015-01-01

    Objective: To assess the influence of type 2 DM and gender, on the QT dispersion, Tpeak-Tend dispersion of ventricular repolarization, in patients with sub-clinic left ventricular diastolic dysfunction of the heart. Background: QT dispersion, that reflects spatial inhomogeneity in ventricular repolarization, Tpeak-Tend dispersion, this on the other hand reflects transmural inhomogeneity in ventricular repolarization, that is increased in an early stage of cardiomyopathy, and in patients with ...

  17. Layer 5 Callosal Parvalbumin-Expressing Neurons: A Distinct Functional Group of GABAergic Neurons.

    Science.gov (United States)

    Zurita, Hector; Feyen, Paul L C; Apicella, Alfonso Junior

    2018-01-01

    Previous studies have shown that parvalbumin-expressing neurons (CC-Parv neurons) connect the two hemispheres of motor and sensory areas via the corpus callosum, and are a functional part of the cortical circuit. Here we test the hypothesis that layer 5 CC-Parv neurons possess anatomical and molecular mechanisms which dampen excitability and modulate the gating of interhemispheric inhibition. In order to investigate this hypothesis we use viral tracing to determine the anatomical and electrophysiological properties of layer 5 CC-Parv and parvalbumin-expressing (Parv) neurons of the mouse auditory cortex (AC). Here we show that layer 5 CC-Parv neurons had larger dendritic fields characterized by longer dendrites that branched farther from the soma, whereas layer 5 Parv neurons had smaller dendritic fields characterized by shorter dendrites that branched nearer to the soma. The layer 5 CC-Parv neurons are characterized by delayed action potential (AP) responses to threshold currents, lower firing rates, and lower instantaneous frequencies compared to the layer 5 Parv neurons. Kv1.1 containing K + channels are the main source of the AP repolarization of the layer 5 CC-Parv and have a major role in determining both the spike delayed response, firing rate and instantaneous frequency of these neurons.

  18. The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study.

    Science.gov (United States)

    Britton, Oliver J; Bueno-Orovio, Alfonso; Virág, László; Varró, András; Rodriguez, Blanca

    2017-01-01

    Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions. Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. I Kr block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na + /K + pump conductance below 50% of baseline, and I CaL conductance above 70% of baseline. Furthermore, I NaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% I Kr block. Reversing intracellular Na + overload caused by reduced I NaK was not sufficient to prevent abnormalities in models with low Na + /K + pump conductance, while returning Na + /K + pump conductance to normal substantially reduced abnormality occurrence, indicating I NaK is an important repolarization current. Conclusions: I NaK is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found I Kr block to be necessary for repolarization abnormalities to occur, I NaK decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced I Kr block in humans.

  19. The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study

    Directory of Open Access Journals (Sweden)

    Oliver J. Britton

    2017-05-01

    Full Text Available Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions.Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. IKr block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na+/K+ pump conductance below 50% of baseline, and ICaL conductance above 70% of baseline. Furthermore, INaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% IKr block. Reversing intracellular Na+ overload caused by reduced INaK was not sufficient to prevent abnormalities in models with low Na+/K+ pump conductance, while returning Na+/K+ pump conductance to normal substantially reduced abnormality occurrence, indicating INaK is an important repolarization current.Conclusions: INaK is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found IKr block to be necessary for repolarization abnormalities to occur, INaK decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced IKr block in humans.

  20. LV function monitoring to discard functional abnormalities in athletes with altered ventricular re-polarization

    International Nuclear Information System (INIS)

    Flotats, A.; Camacho, V.; Mena, E.; Tembl, A.; Estorch, M.; Carrio, I.; Serra-Grima, R.; Borras, X.; Cinca, J.

    2002-01-01

    Aim: Marked ventricular re-polarization abnormalities (MRA) in athletes may suggest the presence of associated heart disease. Assessment of LV function during exercise may contribute to rule out heart disease and help to decide continuation of physical training. The aim of the study was to assess whether athletes with MRA show a particular response of LV function to exhausting exercise. Material and Methods: Thirty-nine male athletes underwent monitoring of LV function with a miniaturised radionuclide detector (VEST, Capintec, Inc.) during bicycle exhausting exercise. There were 22 athletes with MRA in the ECG at rest (negative T waves equal or more than 2mm in up to 3 ECG leads) and 17 with normal ECG. All were symptom free. Age and physical fitness were comparable in both groups. Clinical examination, ECG, exercise test and echocardiography were performed in all athletes. Results: In all cases LV wall thickness was that expected for highly conditioned sportsmen. Both groups of athletes attained a similar energy expenditure. During exercise, athletes with MRA showed a tendency to normalise re-polarization. There were no differences in heart rate, LV end-systolic volume, LVEF, cardiac output , and peak ejection and filling rates at rest, 50%, 75%, 85% and 100% of peak HR, nor at 2, 5 and 10 min of recovery between both groups of athletes. At rest stroke volume was lower in athletes with MRA (60% vs. 64%, p=0.044). There were also no differences in LV end-diastolic volume (EDV), except at peak HR, when EDV increased in athletes with normal ECG while it decreased in athletes with MRA (p=0.047). Conclusions: The presence of marked ventricular re-polarization abnormalities in athletes does not substantially affect exercise performance nor LV function and should not preclude physical training. The VEST is a useful means to assess LV function during exhausting upright bicycle exercise

  1. Early repolarization in Wolff-Parkinson-White syndrome: prevalence and clinical significance.

    Science.gov (United States)

    Mizumaki, Koichi; Nishida, Kunihiro; Iwamoto, Jotaro; Nakatani, Yosuke; Yamaguchi, Yoshiaki; Sakamoto, Tamotsu; Tsuneda, Takayuki; Inoue, Hiroshi; Sakabe, Masao; Fujiki, Akira

    2011-08-01

    Idiopathic ventricular fibrillation (IVF) with early repolarization (ER) has recently been reported; however, ER is a common finding in healthy subjects and is also found sporadically in patients with Wolff-Parkinson-White (WPW) syndrome. The present study was designed to evaluate the prevalence and clinical significance of ER in patients with WPW syndrome. One hundred and eleven patients with WPW syndrome were studied retrospectively. Early repolarization was defined as QRS slurring or notching with J-point elevation ≥ 1 mm. The prevalence of ER was determined before and after successful catheter ablation. Before ablation, ER was found in 35 of 75 patients with a left free wall, 6 of 23 with a right free wall, and 7 of 13 with a septal accessory pathway (48 of 111, 43% as a whole). Early repolarization was always observed in leads with positive deflection of the initial part of the delta wave. After successful ablation of accessory pathways, ER was preserved in 28 (25%), disappeared in 20 (18%), and newly developed in 8 (7%) patients. In the remaining 55 (50%) patients, ER was not observed either before or after ablation. In patients with persistent ER, the amplitude and width of ER were significantly decreased 3-7 days after the ablation (1.7 ± 0.7 vs. 1.4 ± 0.6 mm, P syndrome, ER could be partly related to early depolarization through the accessory pathway. However, persistent ER and new ER appearing after the ablation were frequently found. Therefore, in these patients, mechanisms other than early depolarization may be involved in the genesis of ER.

  2. Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

    Science.gov (United States)

    Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

    2015-05-01

    Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  3. Double pharmacological challenge on repolarization opens new avenues for drug safety research

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard

    2007-01-01

    pointes (TdP) arrhythmia. Both the pharmaceutical industry and the regulatory bodies are neglecting the available proarrhythmia models. In vitro studies have suggested that combined pharmacological hits on repolarization will produce a superior substrate for in vivo proarrhythmia, compared to the single......-drug assessment. By using consecutive pharmacological challenges, a simple model is proposed, in which combinatorial pharmacology is employed to provoke TdP in the conscious dog. The pharmaceutical industry interested in evaluating the proarrhythmic potential of their present and future drugs now has a simple...

  4. Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice

    DEFF Research Database (Denmark)

    Speerschneider, T; Grubb, Søren Jahn; Olesen, S P

    2017-01-01

    ) were measured in isolated hearts using floating microelectrodes. RESULTS: Proarrhythmia in WT and KChIP2(-/-) was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2(-/-) hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion...... of repolarization time, whereas hearts from KChIP2(-/-) mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2(-/-) mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. CONCLUSION: Large...

  5. Coronary Artery Disease Alters Ventricular Repolarization Dynamics in Type 2 Diabetes

    Science.gov (United States)

    Vrtovec, Bojan; Sinkovec, Matjaz; Starc, Vito; Radovancevic, Branislav; Schlegel, Todd T.

    2005-01-01

    Ventricular repolarization dynamics (VRD) is an important predictor of outcome in diabetes. We examined the potential impact of coronary artery disease (CAD) on VRD in type 2 diabetic patients. We recorded 5-min high-resolution resting electrocardiograms (ECG) in 38 diabetic patients undergoing elective coronary angiography, and in 38 age- and gender- matched apparently healthy subjects (Controls). Using leads I and II, time-domain indices of VRD were calculated. Coronary angiography was regarded as positive if a 350% stenosis was found. Angiography was positive in 21 diabetic patients (55%). Patients with CAD had a significantly higher degree of VRD than Controls (SDNN(QT): 15.81+/-7.22 ms vs. 8.94+/-6.04 ms; P <0.001, rMSSD(QT): 21.02k7.07 ms vs. 11.18k7.45 ms; P <0.001). VRD in diabetic patients with negative angiograms did not differ from VRD in Controls (SDNN(QT): 8.94+/-6.04 ms vs. 7.44+/-5.72 ms; P=0.67, rMSSD(QT): 11.18+/-7.45 ms vs. 10.22+/-5.35 ms; P=O. 82). CAD increases VRD in patients with type 2 diabetes. Therefore, changes in ventricular repolarization in diabetic patients may be due to silent CAD rather than to diabetes per se.

  6. Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome

    NARCIS (Netherlands)

    Meijborg, Veronique M F; Chauveau, Samuel; Janse, Michiel J; Anyukhovsky, Evgeny P; Danilo, Peter R; Rosen, Michael R; Opthof, Tobias; Coronel, Ruben

    BACKGROUND: Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. OBJECTIVE: The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. METHODS: We simultaneously recorded surface

  7. Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome

    NARCIS (Netherlands)

    Meijborg, Veronique M. F.; Chauveau, Samuel; Janse, Michiel J.; Anyukhovsky, Evgeny P.; Danilo, Peter R.; Rosen, Michael R.; Opthof, Tobias; Coronel, Ruben

    2015-01-01

    Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. We simultaneously recorded surface ECG and unipolar electrograms at

  8. Repolarization gradients in the canine left ventricle before and after induction of short-term cardiac memory

    NARCIS (Netherlands)

    Janse, Michiel J.; Sosunov, Eugene A.; Coronel, Ruben; Opthof, Tobias; Anyukhovsky, Evgeny P.; de Bakker, Jacques M. T.; Plotnikov, Alexei N.; Shlapakova, Iryna N.; Danilo, Peter; Tijssen, Jan G. P.; Rosen, Michael R.

    2005-01-01

    Background - Questions remain about the contributions of transmural versus apicobasal repolarization gradients to the configuration of the T wave in control settings and after the induction of short-term cardiac memory. Methods and Results - Short-term cardiac memory is seen as T-wave changes

  9. Long-term cardiac memory in canine heart is associated with the evolution of a transmural repolarization gradient

    NARCIS (Netherlands)

    Coronel, Ruben; Opthof, Tobias; Plotnikov, Alexei N.; Wilms-Schopman, Francien J. G.; Shlapakova, Iryna N.; Danilo, Peter; Sosunov, Eugene A.; Anyukhovsky, Evgeny P.; Janse, Michiel J.; Rosen, Michael R.

    2007-01-01

    OBJECTIVE: The contribution of regional electrophysiologic heterogeneity to the T-wave changes of long-term cardiac memory (CM) is not known. We mapped activation and repolarization in dogs after induction of CM and in sham animals. METHODS AND RESULTS: CM was induced by three weeks of AV-sequential

  10. Dispersion of repolarization in canine ventricle and the electrocardiographic T wave: Tp-e interval does not reflect transmural dispersion

    NARCIS (Netherlands)

    Opthof, Tobias; Coronel, Ruben; Wilms-Schopman, Francien J. G.; Plotnikov, Alexei N.; Shlapakova, Iryna N.; Danilo, Peter; Rosen, Michael R.; Janse, Michiel J.

    2007-01-01

    BACKGROUND: The concept that the interval between the peak (T(peak)) and the end (T(end)) of the T wave (T(p-e)) is a measure of transmural dispersion of repolarization time is widely accepted but has not been tested rigorously by transmural mapping of the intact heart. OBJECTIVES: The purpose of

  11. Assessing common classification methods for the identification of abnormal repolarization using indicators of T-wave morphology and QT interval

    DEFF Research Database (Denmark)

    Shakibfar, Saeed; Graff, Claus; Ehlers, Lars Holger

    2012-01-01

    Various parameters based on QTc and T-wave morphology have been shown to be useful discriminators for drug induced I(Kr)-blocking. Using different classification methods this study compares the potential of these two features for identifying abnormal repolarization on the ECG. A group of healthy ...... the approach has not been tested in this setting....

  12. Covariate analysis of QTc and T-wave morphology: new possibilities in the evaluation of drugs that affect cardiac repolarization

    DEFF Research Database (Denmark)

    Graff, Claus; Struijk, Johannes J.; Matz, J

    2010-01-01

    This study adds the dimension of a T-wave morphology composite score (MCS) to the QTc interval-based evaluation of drugs that affect cardiac repolarization. Electrocardiographic recordings from 62 subjects on placebo and 400 mg moxifloxacin were compared with those from 21 subjects on 160 and 320...

  13. Diffuse interstitial fibrosis assessed by cardiac magnetic resonance is associated with dispersion of ventricular repolarization in patients with hypertrophic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    David Hurtado-de-Mendoza, MD

    2017-06-01

    Conclusion: Diffuse interstitial fibrosis is associated with increased dispersion of ventricular repolarization in leads, reflecting electrical activity in the hypertrophied septum. Interstitial fibrosis combined with ion channel/gap junction remodeling in the septum could lead to inhomogeneity of ventricular refractoriness, resulting in increased QTc dispersion in leads V1–V4.

  14. Intrinsic and integrative properties of substantia nigra pars reticulata neurons

    Science.gov (United States)

    Zhou, Fu-Ming; Lee, Christian R.

    2011-01-01

    The GABA projection neurons of the substantia nigra pars reticulata (SNr) are output neurons for the basal ganglia and thus critical for movement control. Their most striking neurophysiological feature is sustained, spontaneous high frequency spike firing. A fundamental question is: what are the key ion channels supporting the remarkable firing capability in these neurons? Recent studies indicate that these neurons express tonically active TRPC3 channels that conduct a Na-dependent inward current even at hyperpolarized membrane potentials. When the membrane potential reaches −60 mV, a voltage-gated persistent sodium current (INaP) starts to activate, further depolarizing the membrane potential. At or slightly below −50 mV, the large transient voltage-activated sodium current (INaT) starts to activate and eventually triggers the rapid rising phase of action potentials. SNr GABA neurons have a higher density of (INaT), contributing to the faster rise and larger amplitude of action potentials, compared with the slow-spiking dopamine neurons. INaT also recovers from inactivation more quickly in SNr GABA neurons than in nigral dopamine neurons. In SNr GABA neurons, the rising phase of the action potential triggers the activation of high-threshold, inactivation-resistant Kv3-like channels that can rapidly repolarize the membrane. These intrinsic ion channels provide SNr GABA neurons with the ability to fire spontaneous and sustained high frequency spikes. Additionally, robust GABA inputs from direct pathway medium spiny neurons in the striatum and GABA neurons in the globus pallidus may inhibit and silence SNr GABA neurons, whereas glutamate synaptic input from the subthalamic nucleus may induce burst firing in SNr GABA neurons. Thus, afferent GABA and glutamate synaptic inputs sculpt the tonic high frequency firing of SNr GABA neurons and the consequent inhibition of their targets into an integrated motor control signal that is further fine-tuned by neuromodulators

  15. Imitation, mirror neurons and autism

    OpenAIRE

    Williams, Justin H.G.; Whiten, Andrew; Suddendorf, Thomas; Perrett, David I.

    2001-01-01

    Various deficits in the cognitive functioning of people with autism have been documented in recent years but these provide only partial explanations for the condition. We focus instead on an imitative disturbance involving difficulties both in copying actions and in inhibiting more stereotyped mimicking, such as echolalia. A candidate for the neural basis of this disturbance may be found in a recently discovered class of neurons in frontal cortex, 'mirror neurons' (MNs). These neurons show ac...

  16. The Neuronal Ceroid-Lipofuscinoses

    Science.gov (United States)

    Bennett, Michael J.; Rakheja, Dinesh

    2013-01-01

    The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in…

  17. Role of the Purkinje-Muscle Junction on the Ventricular Repolarization Heterogeneity in the Healthy and Ischemic Ovine Ventricular Myocardium

    Directory of Open Access Journals (Sweden)

    Marine E. Martinez

    2018-06-01

    Full Text Available Alteration of action potential duration (APD heterogeneity contributes to arrhythmogenesis. Purkinje-muscle junctions (PMJs present differential electrophysiological properties including longer APD. The goal of this study was to determine if Purkinje-related or myocardial focal activation modulates ventricular repolarization differentially in healthy and ischemic myocardium. Simultaneous epicardial (EPI and endocardial (ENDO optical mapping was performed on sheep left ventricular (LV wedges with intact free-running Purkinje network (N = 7. Preparations were paced on either ENDO or EPI surfaces, or the free-running Purkinje fibers (PFs, mimicking normal activation. EPI and ENDO APDs were assessed for each pacing configuration, before and after (7 min of the onset of no-flow ischemia. Experiments were supported by simulations. In control conditions, maximal APD was found at endocardial PMJ sites. We observed a significant transmural APD gradient for PF pacing with PMJ APD = 347 ± 41 ms and EPI APD = 273 ± 36 ms (p < 0.001. A similar transmural gradient was observed when pacing ENDO (49 ± 31 ms; p = 0.005. However, the gradient was reduced when pacing EPI (37 ± 20 ms; p = 0.005. Global dispersion of repolarization was the most pronounced for EPI pacing. In ischemia, both ENDO and EPI APD were reduced (p = 0.005 and the transmural APD gradient (109 ± 55 ms was increased when pacing ENDO compared to control condition or when pacing EPI (p < 0.05. APD maxima remained localized at functional PMJs during ischemia. Local repolarization dispersion was significantly higher at the PMJ than at other sites. The results were consistent with simulations. We found that the activation sequence modulates repolarization heterogeneity in the ischemic sheep LV. PMJs remain active following ischemia and exert significant influence on local repolarization patterns.

  18. Injection of Aβ1-40 into hippocampus induced cognitive lesion associated with neuronal apoptosis and multiple gene expressions in the tree shrew.

    Science.gov (United States)

    Lin, Na; Xiong, Liu-Lin; Zhang, Rong-Ping; Zheng, Hong; Wang, Lei; Qian, Zhong-Yi; Zhang, Piao; Chen, Zhi-Wei; Gao, Fa-Bao; Wang, Ting-Hua

    2016-05-01

    Alzheimer's disease (AD) can incur significant health care costs to the patient, their families, and society; furthermore, effective treatments are limited, as the mechanisms of AD are not fully understood. This study utilized twelve adult male tree shrews (TS), which were randomly divided into PBS and amyloidbetapeptide1-40 (Aβ1-40) groups. AD model was established via an intracerebroventricular (icv) injection of Aβ1-40 after being incubated for 4 days at 37 °C. Behavioral, pathophysiological and molecular changes were evaluated by hippocampal-dependent tasks, magnetic resonance imaging (MRI), silver staining, hematoxylin-eosin (HE) staining, TUNEL assay and gene sequencing, respectively. At 4 weeks post-injection, as compared with the PBS group, in Aβ1-40 injected animals: cognitive impairments happened, and the hippocampus had atrophied indicated by MRI findings; meanwhile, HE staining showed the cells of the CA3 and DG were significantly thinner and smaller. The average number of cells in the DG, but not the CA3, was also significantly reduced; furthermore, silver staining revealed neurotic plaques and neurofibrillary tangles (NFTs) in the hippocampi; TUNEL assay showed many cells exhibited apoptosis, which was associated with downregulated BCL-2/BCL-XL-associated death promoter (Bad), inhibitor of apoptosis protein (IAP), Cytochrome c (CytC) and upregulated tumor necrosis factor receptor 1 (TNF-R1); lastly, gene sequencing reported a total of 924 mobilized genes, among which 13 of the downregulated and 19 of the upregulated genes were common to the AD pathway. The present study not only established AD models in TS, but also reported on the underlying mechanism involved in neuronal apoptosis associated with multiple gene expression.

  19. Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation.

    Science.gov (United States)

    Takeda, A; Suzuki, M; Tempaku, M; Ohashi, K; Tamano, H

    2015-09-24

    Physiological significance of synaptic Zn(2+) signaling was examined in the CA1 of young rats. In vivo CA1 long-term potentiation (LTP) was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. In vivo CA1 LTP was inhibited under perfusion with CaEDTA and ZnAF-2DA, extracellular and intracellular Zn(2+) chelators, respectively, suggesting that the influx of extracellular Zn(2+) is required for in vivo CA1 LTP induction. The increase in intracellular Zn(2+) was chelated with intracellular ZnAF-2 in the CA1 1h after local injection of ZnAF-2DA into the CA1, suggesting that intracellular Zn(2+) signaling induced during learning is blocked with intracellular ZnAF-2 when the learning was performed 1h after ZnAF-2DA injection. Object recognition was affected when training of object recognition test was performed 1h after ZnAF-2DA injection. These data suggest that intracellular Zn(2+) signaling in the CA1 is required for object recognition memory via LTP. Surprisingly, in vivo CA1 LTP was affected under perfusion with 0.1-1μM ZnCl2, unlike the previous data that in vitro CA1 LTP was enhanced in the presence of 1-5μM ZnCl2. The influx of extracellular Zn(2+) into CA1 pyramidal cells has bidirectional action in CA1 LTP. The present study indicates that the degree of extracellular Zn(2+) influx into CA1 neurons is critical for LTP and cognitive performance. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Brain signal variability differentially affects cognitive flexibility and cognitive stability

    NARCIS (Netherlands)

    Armbruster-Genç, D.J.N.; Ültzhöffer, K.; Fiebach, C.J.

    2016-01-01

    Recent research yielded the intriguing conclusion that, in healthy adults, higher levels of variability in neuronal processes are beneficial for cognitive functioning. Beneficial effects of variability in neuronal processing can also be inferred from neurocomputational theories of working memory,

  1. Ventricular repolarization alterations in women with angina pectoris and suspected coronary microvascular dysfunction

    DEFF Research Database (Denmark)

    Dose, Nynne; Michelsen, Marie Mide; Mygind, Naja Dam

    2018-01-01

    OBJECTIVES: CMD could be the explanation of angina pectoris with no obstructive CAD and may cause ventricular repolarization changes. We compared T-wave morphology and QTc interval in women with angina pectoris with a control group as well as the associations with CMD. METHODS: Women with angina...... echocardiography. RESULTS: Women with angina pectoris had significantly longer QTc intervals (429±20ms) and increased MCS (IQR) (0.73 [0.64-0.80]) compared with the controls (419±20ms) and (0.63 [(0.53-0.73]), respectively (both p... was attenuated after multivariable adjustment (p=0.08). CONCLUSION: This study suggests that women with angina pectoris have alterations in T-wave morphology as well as longer QTc interval compared with a reference population. CMD might be an explanation....

  2. Prevention of Pazopanib-Induced Prolonged Cardiac Repolarization and Proarrhythmic Effects

    Directory of Open Access Journals (Sweden)

    Tulay Akman

    2014-11-01

    Full Text Available Background: Pazopanib (PZP may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors. Objectives: To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT in an experimental rat model. Methods: Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6. The first group (normal group received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP, to the normal group and to the second group (control-PZP+SP group; 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca, to the third group (PZP+metoprolol group; and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat, to the fourth group (PZP+diltiazem group. One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I. Results: The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001. Conclusion: Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.

  3. Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization.

    Science.gov (United States)

    Langenickel, Thomas H; Jordaan, Pierre; Petruck, Jesika; Kode, Kiran; Pal, Parasar; Vaidya, Soniya; Chandra, Priya; Rajman, Iris

    2016-08-01

    Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.

  4. Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT.

    Science.gov (United States)

    London, Barry; Baker, Linda C; Petkova-Kirova, Polina; Nerbonne, Jeanne M; Choi, Bum-Rak; Salama, Guy

    2007-01-01

    Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, I(to,f), have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4-/-) that lack the slow component of I(to) (I(to,s)), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN x Kv1.4-/-) mice that lack both I(to,f) and I(to,s), have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 +/- 2.5 ms, P mice than controls (20.3 +/- 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 +/- 0.5 ms, n = 6, P mice compared with controls (10 +/- 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4-/- (n = 4/5) and Kv4.2DN x Kv1.4-/- hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that I(to,f) was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.

  5. The analysis of QT interval and repolarization morphology of the heart in chronic exposure to lead.

    Science.gov (United States)

    Kiełtucki, J; Dobrakowski, M; Pawlas, N; Średniawa, B; Boroń, M; Kasperczyk, S

    2017-10-01

    There are no common recommendations regarding electrocardiographic monitoring in occupationally exposed workers. Therefore, the present study was designed to investigate whether exposure to lead results in an increase of selected electrocardiography (ECG) pathologies, such as QT interval prolongation and repolarization disorders, in occupationally exposed workers. The study group included 180 workers occupationally exposed to lead compounds. The exposed group was divided according to the median of the mean blood lead level (PbB mean ) calculated based on a series of measurements performed during 5-year observation period (35 µg/dl) into two subgroups: low exposure (LE, PbB mean = 20.0-35.0 µg/dl) and high exposure (HE, PbB mean = 35.1-46.4 µg/dl). The control group consisted of 69 healthy workers without occupational exposure to lead. ECG evaluation included the analysis of heart rate (HR), QT interval and repolarization abnormalities. Mean QT interval was significantly greater in the exposed population than in the control group by 2%. In the HE group, mean QT interval was significantly greater than in the control group by 4% and significantly different from those noted in the LE group. Positive correlations between QT interval and lead exposure indices were also reported. Besides, there was a negative correlation between HR and blood lead level. Increased concentration of lead in the blood above 35 μg/dl is associated with the QT interval prolongation, which may trigger arrhythmias when combined with other abnormalities, such as long QT syndrome. Therefore, electrocardiographic evaluation should be a part of a routine monitoring of occupationally exposed populations.

  6. Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

    Science.gov (United States)

    Cho, Jae Hyung; Zhang, Rui; Kilfoil, Peter J; Gallet, Romain; de Couto, Geoffrey; Bresee, Catherine; Goldhaber, Joshua I; Marbán, Eduardo; Cingolani, Eugenio

    2017-11-21

    Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats ( P hearts demonstrated prolonged action potentials ( P hearts. Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death. © 2017 American Heart Association, Inc.

  7. Interactions between Activation and Repolarization Restitution Properties in the Intact Human Heart: In-Vivo Whole-Heart Data and Mathematical Description.

    Directory of Open Access Journals (Sweden)

    Michele Orini

    Full Text Available The restitution of the action potential duration (APDR and conduction velocity (CVR are mechanisms whereby cardiac excitation and repolarization adapt to changes in heart rate. They modulate the vulnerability to dangerous arrhythmia, but the mechanistic link between restitution and arrhythmogenesis remains only partially understood.This paper provides an experimental and theoretical study of repolarization and excitation restitution properties and their interactions in the intact human epicardium. The interdependence between excitation and repolarization dynamic is studied in 8 patients (14 restitution protocols, 1722 restitution curves undergoing global epicardial mapping with multi-electrode socks before open heart surgery. A mathematical description of the contribution of both repolarization and conduction dynamics to the steepness of the APDR slope is proposed.This study demonstrates that the APDR slope is a function of both activation and repolarization dynamics. At short cycle length, conduction delay significantly increases the APDR slope by interacting with the diastolic interval. As predicted by the proposed mathematical formulation, the APDR slope was more sensitive to activation time prolongation than to the simultaneous shortening of repolarization time. A steep APDR slope was frequently identified, with 61% of all cardiac sites exhibiting an APDR slope > 1, suggesting that a slope > 1 may not necessarily promote electrical instability in the human epicardium. APDR slope did not change for different activation or repolarization times, and it was not a function of local baseline APD. However, it was affected by the spatial organization of electrical excitation, suggesting that in tissue APDR is not a unique function of local electrophysiological properties. Spatial heterogeneity in both activation and repolarization restitution contributed to the increase in the modulated dispersion of repolarization, which for short cycle length was

  8. Augmenting cognition by neuronal oscillations

    NARCIS (Netherlands)

    Horschig, J.M.; Zumer, J.; Bahramisharif, A.

    2014-01-01

    Cortical oscillations have been shown to represent fundamental functions of a working brain, e.g., communication, stimulus binding, error monitoring, and inhibition, and are directly linked to behavior. Recent studies intervening with these oscillations have demonstrated effective modulation of both

  9. How the knowledge of genetic "makeup" and cellular data can affect the analysis of repolarization in surface electrocardiogram.

    Science.gov (United States)

    Shimizu, Wataru

    2010-01-01

    This review article sought to describe patterns of repolarization on the surface electrocardiogram in inherited cardiac arrhythmias and to discuss how the knowledge of genetic makeup and cellular data can affect the analysis based on the data derived from the experimental studies using arterially perfused canine ventricular wedge preparations. Molecular genetic studies have established a link between a number of inherited cardiac arrhythmia syndromes and mutations in genes encoding cardiac ion channels or membrane components during the past 2 decades. Twelve forms of congenital long QT syndrome have been so far identified, and genotype-phenotype correlations have been investigated especially in the 3 major genotypes-LQT1, LQT2, and LQT3. Abnormal T waves are reported in the LQT1, LQT2, and LQT3, and the differences in the time course of repolarization of the epicardial, midmyocardial, and endocardial cells give rise to voltage gradients responsible for the manifestation of phenotypic appearance of abnormal T waves. Brugada syndrome is characterized by ST-segment elevation in leads V1 to V3 and an episode of ventricular fibrillation, in which 7 genotypes have been reported. An intrinsically prominent transient outward current (I(to))-mediated action potential notch and a subsequent loss of action potential dome in the epicardium, but not in the endocardium of the right ventricular outflow tract, give rise to a transmural voltage gradient, resulting in ST-segment elevation, and a subsequent phase 2 reentry-induced ventricular fibrillation. In conclusion, transmural electrical heterogeneity of repolarization across the ventricular wall profoundly affects the phenotypic manifestation of repolarization patterns on the surface electrocardiogram in inherited cardiac arrhythmias. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Acute effects of Red Bull energy drink on ventricular repolarization in healthy young volunteers: a prospective study

    Science.gov (United States)

    Elitok, Ali; Öz, Fahrettin; Panc, Cafer; Sarıkaya, Remzi; Sezikli, Selim; Pala, Yasin; Bugan, Övgü Sinem; Ateş, Müge; Parıldar, Hilal; Ayaz, Mustafa Buğra; Atıcı, Adem; Oflaz, Hüseyin

    2016-01-01

    Objective: Energy drinks (EDs) are widely consumed products of the beverage industry and are often chosen by teenagers and young adults. Several adverse cardiovascular events and malignant cardiac arrhythmias following consumption of EDs have been reported in the literature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the dispersion of repolarization and that an increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. This study investigated the acute effects of Red Bull ED on ventricular repolarization as assessed by the Tp-e interval and Tp-e/QT ratio. Methods: A prospective, open-label study design was used. After an 8-h fast, 50 young, healthy subjects consumed 355 mL of Red Bull ED. The Tp-e interval, Tp-e/QTc ratio, and several other electrocardiographic parameters were measured at baseline and 2 h after ingestion of Red Bull ED. Results: No significant changes in the Tp-e interval or Tp-e/QTc ratio were observed with Red Bull ED consumption. Red Bull ED consumption led to increases in both systolic and diastolic blood pressures, which were associated with an increased heart rate. Conclusion: Although ingestion of Red Bull ED increases the heart rate and diastolic and systolic blood pressures, it does not cause alterations in ventricular repolarization as assessed by the Tp-e interval and Tp-e/QTc ratio. PMID:25868042

  11. Acute effects of Red Bull energy drink on ventricular repolarization in healthy young volunteers: a prospective study.

    Science.gov (United States)

    Elitok, Ali; Öz, Fahrettin; Panc, Cafer; Sarıkaya, Remzi; Sezikli, Selim; Pala, Yasin; Bugan, Övgü Sinem; Ateş, Müge; Parıldar, Hilal; Ayaz, Mustafa Buğra; Atıcı, Adem; Oflaz, Hüseyin

    2015-11-01

    Energy drinks (EDs) are widely consumed products of the beverage industry and are often chosen by teenagers and young adults. Several adverse cardiovascular events and malignant cardiac arrhythmias following consumption of EDs have been reported in the literature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the dispersion of repolarization and that an increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. This study investigated the acute effects of Red Bull ED on ventricular repolarization as assessed by the Tp-e interval and Tp-e/QT ratio. A prospective, open-label study design was used. After an 8-h fast, 50 young, healthy subjects consumed 355 mL of Red Bull ED. The Tp-e interval, Tp-e/QTc ratio, and several other electrocardiographic parameters were measured at baseline and 2 h after ingestion of Red Bull ED. No significant changes in the Tp-e interval or Tp-e/QTc ratio were observed with Red Bull ED consumption. Red Bull ED consumption led to increases in both systolic and diastolic blood pressures, which were associated with an increased heart rate. Although ingestion of Red Bull ED increases the heart rate and diastolic and systolic blood pressures, it does not cause alterations in ventricular repolarization as assessed by the Tp-e interval and Tp-e/QTc ratio.

  12. Early repolarization with horizontal ST segment may be associated with aborted sudden cardiac arrest: a retrospective case control study

    Directory of Open Access Journals (Sweden)

    Kim Sung

    2012-12-01

    Full Text Available Abstract Background Risk stratification of the early repolarization pattern (ERP is needed to identify malignant early repolarization. J-point elevation with a horizontal ST segment was recently suggested as a malignant feature of the ERP. In this study, the prevalence of the ERP with a horizontal ST segment was examined among survivors of sudden cardiac arrest (SCA without structural heart disease to evaluate the value of ST-segment morphology in risk stratification of the ERP. Methods We reviewed the data of 83 survivors of SCA who were admitted from August 2005 to August 2010. Among them, 25 subjects without structural heart disease were included. The control group comprised 60 healthy subjects who visited our health promotion center; all control subjects were matched for age, sex, and underlying disease (diabetes mellitus, hypertension. Early repolarization was defined as an elevation of the J point of at least 0.1 mV above the baseline in at least two continuous inferior or lateral leads that manifested as QRS slurring or notching. An ST-segment pattern of Results The SCA group included 17 men (64% with a mean age of 49.7 ± 14.5 years. The corrected QTc was not significantly different between the SCA and control groups (432.7 ± 37.96 vs. 420.4 ± 26.3, respectively; p = 0.089. The prevalence of ERP was not statistically different between the SCA and control groups (5/25, 20% vs. 4/60, 6.7%, respectively; p = 0.116. The prevalence of early repolarization with a horizontal ST segment was more frequent in the SCA than in the control group (20% vs. 3.3%, respectively; p = 0.021. Four SCA subjects (16% and one control subject (1.7% had a J-point elevation of >2 mm (p = 0.025. Four SCA subjects (16% and one (1.7% control subject had an ERP in the inferior lead (p = 0.025. Conclusion The prevalence of ERP with a horizontal ST segment was higher in patients with aborted SCA than in matched controls. This result suggests that ST morphology has

  13. Reconstruction of action potential of repolarization in patients with congenital long-QT syndrome

    International Nuclear Information System (INIS)

    Kandori, Akihiko; Shimizu, Wataru; Yokokawa, Miki; Kamakura, Shiro; Miyatake, Kunio; Murakami, Masahiro; Miyashita, Tsuyoshi; Ogata, Kuniomi; Tsukada, Keiji

    2004-01-01

    A method for reconstructing an action potential during the repolarization period was developed. This method uses a current distribution-plotted as a current-arrow map (CAM)-calculated using magnetocardiogram (MCG) signals. The current arrows are summarized during the QRS complex period and subtracted during the ST-T wave period in order to reconstruct the action-potential waveform. To ensure the similarity between a real action potential and the reconstructed action potential using CAM, a monophasic action potential (MAP) and an MCG of the same patient with type-I long-QT syndrome were measured. Although the MAP had one notch that was associated with early afterdepolarization (EAD), the reconstructed action potential had two large and small notches. The small notch timing agreed with the occurrence of the EAD in the MAP. On the other hand, the initiation time of an abnormal current distribution coincides with the appearance timing of the first large notch, and its end time coincides with that of the second small notch. These results suggest that a simple reconstruction method using a CAM based on MCG data can provide a similar action-potential waveform to a MAP waveform without having to introduce a catheter

  14. Imitation, mirror neurons and autism.

    Science.gov (United States)

    Williams, J H; Whiten, A; Suddendorf, T; Perrett, D I

    2001-06-01

    Various deficits in the cognitive functioning of people with autism have been documented in recent years but these provide only partial explanations for the condition. We focus instead on an imitative disturbance involving difficulties both in copying actions and in inhibiting more stereotyped mimicking, such as echolalia. A candidate for the neural basis of this disturbance may be found in a recently discovered class of neurons in frontal cortex, 'mirror neurons' (MNs). These neurons show activity in relation both to specific actions performed by self and matching actions performed by others, providing a potential bridge between minds. MN systems exist in primates without imitative and 'theory of mind' abilities and we suggest that in order for them to have become utilized to perform social cognitive functions, sophisticated cortical neuronal systems have evolved in which MNs function as key elements. Early developmental failures of MN systems are likely to result in a consequent cascade of developmental impairments characterised by the clinical syndrome of autism.

  15. Effects of Atorvastatin on Ventricular Late Potentials and Repolarization Dispersion in Patients with Hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    Chih-Sheng Chu

    2007-05-01

    Full Text Available Emerging evidence suggests that statins have a favorable impact on the reduction of arrhythmia events and sudden cardiac death in patients with structural heart disease. We aimed to investigate the possibly and directly favorable effects of statins on ventricular late potentials, QT dispersion, and transmural dispersion of repolarization attained by analyzing clinical electrocardiography (ECG risk stratification parameters in patients with hypercholesterolemia without structural heart disease. In total, 82 patients (45 females; mean age, 62 ± 10 years with hypercholesterolemia were enrolled in this prospective study to examine the effects of statin therapy (atorvastatin 10mg/day for 3 months on ECG risk stratification parameters. Surface 12-lead ECG and signal-average ECG (SAECG were recorded before and after statin treatment. The SAECG parameters, QT dispersion, Bazett-corrected QT (QTc dispersion, T wave peak-to-end interval (Tpe, and percentage of Tpe/QT interval were calculated and compared before and after statin therapy. Twelve-lead ambulatory 24-hour ECGs were recorded in 12 patients. The results demonstrated that after statin therapy for 3 months, serum levels of total cholesterol and low-density lipoprotein cholesterol were significantly reduced (both p values < 0.001. However, neither significant changes of each SAECG parameter nor the frequency of late potentials were demonstrated after atorvastatin therapy. In addition, no significant changes in QT dispersion, QTc dispersion, Tpe, or Tpe/QT were found. However, 24-hour ambulatory ECG revealed a flattening effect of circadian variation of QTc dispersion after atorvastatin therapy. In conclusion, the favorable antiarrhythmia effect of atorvastatin (10 mg/day therapy cannot be directly reflected by analyzing these noninvasive ECG risk stratification parameters in low-risk patients with hypercholesterolemia.

  16. Electrical storm in patients with brugada syndrome is associated with early repolarization.

    Science.gov (United States)

    Kaneko, Yoshiaki; Horie, Minoru; Niwano, Shinichi; Kusano, Kengo F; Takatsuki, Seiji; Kurita, Takashi; Mitsuhashi, Takeshi; Nakajima, Tadashi; Irie, Tadanobu; Hasegawa, Kanae; Noda, Takashi; Kamakura, Shiro; Aizawa, Yoshiyasu; Yasuoka, Ryobun; Torigoe, Katsumi; Suzuki, Hiroshi; Ohe, Toru; Shimizu, Akihiko; Fukuda, Keiichi; Kurabayashi, Masahiko; Aizawa, Yoshifusa

    2014-12-01

    Electrical storms (ESs) in patients with Brugada syndrome (BrS) are rare though potentially lethal. We studied 22 men with BrS and ES, defined as ≥3 episodes/d of ventricular fibrillation (VF) and compared their characteristics with those of 110 age-matched, control men with BrS without ES. BrS was diagnosed by a spontaneous or drug-induced type 1 pattern on the ECG in the absence of structural heart disease. Early repolarization (ER) was diagnosed by J waves, ie, >0.1 mV notches or slurs of the terminal portion of the QRS complex. The BrS ECG pattern was provoked with pilsicainide. A spontaneous type I ECG pattern, J waves, and horizontal/descending ST elevation were found, respectively, in 77%, 36%, and 88% of patients with ES, versus 28% (P<0.0001), 9% (P=0.003), and 60% (P=0.06) of controls. The J-wave amplitude was significantly higher in patients with than without ES (P=0.03). VF occurred during undisturbed sinus rhythm in 14 of 19 patients (74%), and ES were controlled by isoproterenol administration. All patients with ES received an implantable cardioverter defibrillator and over a 6.0±5.4 years follow-up, the prognosis of patients with ES was significantly worse than that of patients without ES. Bepridil was effective in preventing VF in 6 patients. A high prevalence of ER was found in a subgroup of patients with BrS associated with ES. ES appeared to be suppressed by isoproterenol or quinidine, whereas bepridil and quinidine were effective in the long-term prevention of VF in the highest-risk patients. © 2014 American Heart Association, Inc.

  17. Differential diagnosis between early repolarization of athlete's heart and coved-type Brugada electrocardiogram.

    Science.gov (United States)

    Zorzi, Alessandro; Leoni, Loira; Di Paolo, Fernando M; Rigato, Ilaria; Migliore, Federico; Bauce, Barbara; Pelliccia, Antonio; Corrado, Domenico

    2015-02-15

    Early repolarization (ER) is typically observed in highly trained athletes as a physiologic consequence of increased vagal tone. The variant of anterior (V1 to V3) ER characterized by "domed" ST-segment elevation and negative T wave raises problems of differential diagnosis with the "coved-type" electrocardiographic pattern seen in Brugada syndrome (BS). This study was designed to identify electrocardiographic criteria for distinguishing athlete's ER from BS. The study compared the electrocardiographic tracings of 61 healthy athletes (80% men, median age 23 ± 8 years), showing "domed" ST-segment elevation and negative T wave in leads V1 to V3, with those of 92 consecutive age- and sex-matched BS patients with a "coved-type" electrocardiographic pattern. The electrocardiographic analysis focused on the ST-segment elevation at J point (STJ) and at 80 milliseconds after J point (ST₈₀). Athletes had a lower maximum amplitude of STJ (1.46 ± 0.7 vs 3.25 ± 0.6 mm, p 1) versus only 2 (3%) athletes (p <0.001). An upsloping ST-segment configuration (STJ/ST₈₀ <1) showed a sensitivity of 97%, a specificity of 100%, and a diagnostic accuracy of 98.7% for the diagnosis of ER. At multivariate analysis, STJ/ST₈₀ ratio remained the only independent predictor for ER (odds ratio 87, 95% confidence interval 19 to 357, p <0.001). In conclusion, the STJ/ST₈₀ ratio is a highly accurate electrocardiographic parameter for differential diagnosis between anterior ER of the athlete and BS. Our results may help in reducing the number of athletes who undergo expensive diagnostic workup or are unnecessarily disqualified from competition for changes that fall within the normal range of athlete's heart. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.

    Science.gov (United States)

    Lee, Hsiang-Chun; Rudy, Yoram; Po-Yuan, Phd; Sheu, Sheng-Hsiung; Chang, Jan-Gowth; Cui, Jianmin

    2013-08-01

    Slow delayed-rectifier potassium current (IKs) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (APs) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with and without isoproterenol. With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. Amiloride regulates IKs and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  19. Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Poulet, Claire; Diness, Jonas Goldin

    2014-01-01

    (+) currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential......, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue. CONCLUSIONS: SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down...

  20. Influence of type of sport on cardiac repolarization assessed by electrocardiographic T-wave morphology combination score

    DEFF Research Database (Denmark)

    Glasius, Susanne; Graff, Claus; Ellervik, Christina

    2018-01-01

    was influenced by the sport performed. MATERIALS AND METHODS: Digital electrocardiograms of 469 young elite athletes were analyzed for T-wave asymmetry, flatness and notching, and combined in the MCS. Athletes >22years were compared to a sex-and age matched control group from the general population (N=198......). RESULTS: MCS increased with increasing endurance component of the sport performed ranging from 0.79±0.15 (low) to 0.92±0.21 (high) (p... suggests that sport induces repolarization changes detected by T-wave morphology, and a greater level of changes is seen in athletes from high endurance sports....

  1. A case of short-coupled premature ventricular beat-induced ventricular fibrillation with early repolarization in the inferolateral leads

    Directory of Open Access Journals (Sweden)

    Hidekazu Kondo, MD

    2015-02-01

    Full Text Available This case report describes a 19-year-old man with early repolarization (ER in the inferolateral leads and a normal QT interval who survived a cardiac arrest that was likely related to polymorphic ventricular tachycardia (VT. Electrocardiograms (ECGs also showed unifocal premature ventricular beats (PVBs with a relatively narrow QRS duration. A Holter ECG documented occasional short-coupled PVBs following non-sustained VTs. Pharmacological stress testing was also performed to assess the effects of anti-arrhythmic drugs on ER (the J wave and PVBs. We performed successful radiofrequency catheter ablation to prevent the recurrence of ventricular fibrillation after cardioverter-defibrillator implantation.

  2. Spatially divergent cardiac responses to nicotinic stimulation of ganglionated plexus neurons in the canine heart.

    Science.gov (United States)

    Cardinal, René; Pagé, Pierre; Vermeulen, Michel; Ardell, Jeffrey L; Armour, J Andrew

    2009-01-28

    Ganglionated plexuses (GPs) are major constituents of the intrinsic cardiac nervous system, the final common integrator of regional cardiac control. We hypothesized that nicotinic stimulation of individual GPs exerts divergent regional influences, affecting atrial as well as ventricular functions. In 22 anesthetized canines, unipolar electrograms were recorded from 127 atrial and 127 ventricular epicardial loci during nicotine injection (100 mcg in 0.1 ml) into either the 1) right atrial (RA), 2) dorsal atrial, 3) left atrial, 4) inferior vena cava-inferior left atrial, 5) right ventricular, 6) ventral septal ventricular or 7) cranial medial ventricular (CMV) GP. In addition to sinus and AV nodal function, neural effects on atrial and ventricular repolarization were identified as changes in the area subtended by unipolar recordings under basal conditions and at maximum neurally-induced effects. Animals were studied with intact AV node or following ablation to achieve ventricular rate control. Atrial rate was affected in response to stimulation of all 7 GPs with an incidence of 50-95% of the animals among the different GPs. AV conduction was affected following stimulation of 6/7 GP with an incidence of 22-75% among GPs. Atrial and ventricular repolarization properties were affected by atrial as well as ventricular GP stimulation. Distinct regional patterns of repolarization changes were identified in response to stimulation of individual GPs. RAGP predominantly affected the RA and posterior right ventricular walls whereas CMVGP elicited biatrial and biventricular repolarization changes. Spatially divergent and overlapping cardiac regions are affected in response to nicotinic stimulation of neurons in individual GPs.

  3. SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice

    Directory of Open Access Journals (Sweden)

    Zhen-Yi Hong

    2015-08-01

    Full Text Available SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson’s disease and Alzheimer’s disease (AD. In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1 double-transgenic mice without affecting amyloid-β (Aβ burden. In addition, decreases in cAMP-response element-binding protein (CREB phosphorylation, brain-derived neurotrophic factor (BDNF and tropomyosin-related kinase B (TrkB phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

  4. SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice.

    Science.gov (United States)

    Hong, Zhen-Yi; Yu, Shuang-Shuang; Wang, Zhi-Jun; Zhu, Yi-Zhun

    2015-08-07

    SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

  5. A Longitudinal Study of Cognition, Proton MR Spectroscopy and Synaptic and Neuronal Pathology in Aging Wild-type and AβPPswe-PS1dE9 Mice

    Science.gov (United States)

    Jansen, Diane; Zerbi, Valerio; Janssen, Carola I. F.; Dederen, Pieter J. W. C.; Mutsaers, Martina P. C.; Hafkemeijer, Anne; Janssen, Anna-Lena; Nobelen, Cindy L. M.; Veltien, Andor; Asten, Jack J.; Heerschap, Arend; Kiliaan, Amanda J.

    2013-01-01

    Proton magnetic resonance spectroscopy (1H MRS) is a valuable tool in Alzheimer’s disease research, investigating the functional integrity of the brain. The present longitudinal study set out to characterize the neurochemical profile of the hippocampus, measured by single voxel 1H MRS at 7 Tesla, in the brains of AβPPSswe-PS1dE9 and wild-type mice at 8 and 12 months of age. Furthermore, we wanted to determine whether alterations in hippocampal metabolite levels coincided with behavioral changes, cognitive decline and neuropathological features, to gain a better understanding of the underlying neurodegenerative processes. Moreover, correlation analyses were performed in the 12-month-old AβPP-PS1 animals with the hippocampal amyloid-β deposition, TBS-T soluble Aβ levels and high-molecular weight Aβ aggregate levels to gain a better understanding of the possible involvement of Aβ in neurochemical and behavioral changes, cognitive decline and neuropathological features in AβPP-PS1 transgenic mice. Our results show that at 8 months of age AβPPswe-PS1dE9 mice display behavioral and cognitive changes compared to age-matched wild-type mice, as determined in the open field and the (reverse) Morris water maze. However, there were no variations in hippocampal metabolite levels at this age. AβPP-PS1 mice at 12 months of age display more severe behavioral and cognitive impairment, which coincided with alterations in hippocampal metabolite levels that suggest reduced neuronal integrity. Furthermore, correlation analyses suggest a possible role of Aβ in inflammatory processes, synaptic dysfunction and impaired neurogenesis. PMID:23717459

  6. Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring.

    Science.gov (United States)

    Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R

    2016-01-15

    Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. C. elegans model of neuronal aging

    OpenAIRE

    Peng, Chiu-Ying; Chen, Chun-Hao; Hsu, Jiun-Min; Pan, Chun-Liang

    2011-01-01

    Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and...

  8. Brainstem neurons survive the identical ischemic stress that kills higher neurons: insight to the persistent vegetative state.

    Directory of Open Access Journals (Sweden)

    C Devin Brisson

    Full Text Available Global ischemia caused by heart attack, pulmonary failure, near-drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a 'persistent vegetative state' where the patient is awake but not aware. Approximately 30,000 U.S. patients are held captive in this condition but not a single research study has addressed how the lower brain is preferentially protected in these people. In the higher brain, ischemia elicits a profound anoxic depolarization (AD causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging AD and so be more resilient? Here we compared resistance to acute injury induced from simulated ischemia by 'higher' hippocampal and striatal neurons versus brainstem neurons in live slices from rat and mouse. Light transmittance (LT imaging in response to 10 minutes of oxygen/glucose deprivation (OGD revealed immediate and acutely damaging AD propagating through gray matter of neocortex, hippocampus, striatum, thalamus and cerebellar cortex. In adjacent brainstem nuclei, OGD-evoked AD caused little tissue injury. Whole-cell patch recordings from hippocampal and striatal neurons under OGD revealed sudden membrane potential loss that did not recover. In contrast brainstem neurons from locus ceruleus and mesencephalic nucleus as well as from sensory and motor nuclei only slowly depolarized and then repolarized post-OGD. Two-photon microscopy confirmed non-recoverable swelling and dendritic beading of hippocampal neurons during OGD, while mesencephalic neurons in midbrain appeared uninjured. All of the above responses were mimicked by bath exposure to 100 µM ouabain which inhibits the Na+/K+ pump or to 1-10 nM palytoxin which converts the pump into an open cationic channel. Therefore during ischemia the Na+/K+ pump of higher neurons fails quickly and extensively compared to naturally resilient hypothalamic and brainstem neurons. The selective survival

  9. Neuronal coherence and its functional role in communication between neurons

    NARCIS (Netherlands)

    Zeitler-Geurds, M.

    2010-01-01

    Neuronal oscillations are observed in many brain areas in various frequency bands. Each of the frequency bands is associated with a particular functional role. Gamma oscillations (30-80 Hz) are thought to be related to cognitive tasks like memory and attention and possibly also involved in the

  10. Left ventricular epicardial activation increases transmural dispersion of repolarization in healthy, long QT, and dilated cardiomyopathy dogs.

    Science.gov (United States)

    Bai, Rong; Lü, Jiagao; Pu, Jun; Liu, Nian; Zhou, Qiang; Ruan, Yanfei; Niu, Huiyan; Zhang, Cuntai; Wang, Lin; Kam, Ruth

    2005-10-01

    Benefits of cardiac resynchronization therapy (CRT) are well established. However, less is understood concerning its effects on myocardial repolarization and the potential proarrhythmic risk. Healthy dogs (n = 8) were compared to a long QT interval (LQT) model (n = 8, induced by cesium chloride, CsCl) and a dilated cardiomyopathy with congestive heart failure (DCM-CHF, induced by rapid ventricular pacing, n = 5). Monophasic action potential (MAP) recordings were obtained from the subendocardium, midmyocardium, subepicardium, and the transmural dispersion of repolarization (TDR) was calculated. The QT interval and the interval from the peak to the end of the T wave (T(p-e)) were measured. All these characteristics were compared during left ventricular epicardial (LV-Epi), right ventricular endocardial (RV-Endo), and biventricular (Bi-V) pacing. In healthy dogs, TDR prolonged to 37.54 ms for Bi-V pacing and to 47.16 ms for LV-Epi pacing as compared to 26.75 ms for RV-Endo pacing (P canine models in addition to their intrinsic transmural heterogeneity in the intact heart. This mechanism may contribute to the development of malignant ventricular arrhythmias, such as torsades de pointes (TdP) in congestive heart failure (CHF) patients treated with CRT.

  11. Automatic Identification of the Repolarization Endpoint by Computing the Dominant T-wave on a Reduced Number of Leads.

    Science.gov (United States)

    Giuliani, C; Agostinelli, A; Di Nardo, F; Fioretti, S; Burattini, L

    2016-01-01

    Electrocardiographic (ECG) T-wave endpoint (Tend) identification suffers lack of reliability due to the presence of noise and variability among leads. Tend identification can be improved by using global repolarization waveforms obtained by combining several leads. The dominant T-wave (DTW) is a global repolarization waveform that proved to improve Tend identification when computed using the 15 (I to III, aVr, aVl, aVf, V1 to V6, X, Y, Z) leads usually available in clinics, of which only 8 (I, II, V1 to V6) are independent. The aim of the present study was to evaluate if the 8 independent leads are sufficient to obtain a DTW which allows a reliable Tend identification. To this aim Tend measures automatically identified from 15-dependent-lead DTWs of 46 control healthy subjects (CHS) and 103 acute myocardial infarction patients (AMIP) were compared with those obtained from 8-independent-lead DTWs. Results indicate that Tend distributions have not statistically different median values (CHS: 340 ms vs. 340 ms, respectively; AMIP: 325 ms vs. 320 ms, respectively), besides being strongly correlated (CHS: ρ=0.97, AMIP: 0.88; Pautomatic Tend identification from DTW, the 8 independent leads can be used without a statistically significant loss of accuracy but with a significant decrement of computational effort. The lead dependence of 7 out of 15 leads does not introduce a significant bias in the Tend determination from 15 dependent lead DTWs.

  12. Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons.

    Science.gov (United States)

    Vila-Luna, S; Cabrera-Isidoro, S; Vila-Luna, L; Juárez-Díaz, I; Bata-García, J L; Alvarez-Cervera, F J; Zapata-Vázquez, R E; Arankowsky-Sandoval, G; Heredia-López, F; Flores, G; Góngora-Alfaro, J L

    2012-01-27

    Chronic caffeine consumption has been inversely associated with the risk of developing dementia and Alzheimer's disease. Here we assessed whether chronic caffeine treatment prevents the behavioral and cognitive decline that male Wistar rats experience from young (≈3 months) to middle age (≈10 months). When animals were young they were evaluated at weekly intervals in three tests: motor activity habituation in the open field (30-min sessions at the same time on consecutive days), continuous spontaneous alternation in the Y-maze (8 min), and elevated plus-maze (5 min). Afterward, rats from the same litter were randomly assigned either to a caffeine-treated group (n=13) or a control group (n=11), which received only tap water. Caffeine treatment (5 mg/kg/day) began when animals were ≈4 months old, and lasted for 6 months. Behavioral tests were repeated from day 14 to day 28 after caffeine withdrawal, a time period that is far in excess for the full excretion of a caffeine dose in this species. Thirty days after caffeine discontinuation brains were processed for Golgi-Cox staining. Compared with controls, we found that middle-aged rats that had chronically consumed low doses of caffeine (1) maintained their locomotor habituation during the second consecutive day exposure to the open field (an index of non-associative learning), (2) maintained their exploratory drive to complete the conventional minimum of nine arm visits required to calculate the alternation performance in the Y-maze in a greater proportion, (3) maintained their alternation percentage above chance level (an index of working memory), and (4) did not increase the anxiety indexes assessed by measuring the time spent in the open arms of the elevated plus maze. In addition, morphometric analysis of hippocampal neurons revealed that dendritic branching (90-140 μm from the soma), length of 4th and 5th order branches, total dendritic length, and spine density in distal dendritic branches were greater in

  13. Motor Neurons

    DEFF Research Database (Denmark)

    Hounsgaard, Jorn

    2017-01-01

    Motor neurons translate synaptic input from widely distributed premotor networks into patterns of action potentials that orchestrate motor unit force and motor behavior. Intercalated between the CNS and muscles, motor neurons add to and adjust the final motor command. The identity and functional...... in in vitro preparations is far from complete. Nevertheless, a foundation has been provided for pursuing functional significance of intrinsic response properties in motoneurons in vivo during motor behavior at levels from molecules to systems....

  14. High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.

    Science.gov (United States)

    Brückner, Melanie; Lasarzik, Irina; Jahn-Eimermacher, Antje; Peetz, Dirk; Werner, Christian; Engelhard, Kristin; Thal, Serge C

    2013-09-13

    Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10. rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity. Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Electromagnetic radiation-2450 MHz exposure causes cognition ...

    Indian Academy of Sciences (India)

    83

    Electromagnetic radiation-2450 MHz exposure causes cognition deficit with mitochondrial. 1 ... decrease in levels of acetylcholine, and increase in activity of acetyl ...... neuronal apoptosis and cognitive disturbances in sevoflurane or propofol ...

  16. EXPERIENCE OF USING A NON-SELECTIVE BETA-BLOCKER IN COMPLEX THERAPY OF REPOLARIZATION DISORDERS IN YOUNG ATHLETES

    Directory of Open Access Journals (Sweden)

    A. Yu. Tikhomirov

    2017-01-01

    Full Text Available Purpose. To study the effectiveness of various schemes of correction of repolarization disorder syndrome, including with the use of beta-blockers, in young athletes of the initial training group.Materials and methods. At the first stage, 410 children involved in sports sections were examined. The average age of the examined was 12.22 ± 3.11 years. At the second stage, the athletes (boys of the initial training group were selected from the surveyed contingent, engaged in martial arts. The groups were formed: A – people with violation of myocardial repolarization processes (72 patients, the average age 10,50 ± 0,35 years, the control group – people without changes in an electrocardiogram (33 people, the average age 10.36 ± 0, 62 years old. All underwent an electrocardiographic study at rest and after physical activity on the Innomed HS80GL apparatus with analysis of the main indicators. The vegetative status and the state of adaptation were estimated by Kerdo index and adaptive potential by Baevsky. After the examination, the subgroup A1 (40 people was prescribed metabolic and antioxidant drugs. Additionally, in the subgroup A2 (32 people, a non-selective beta-blocker was included in the treatment regimen. The course of treatment is 10 days. The analysis of indicators was carried out in 10 days and in a month after the initiation treatment. Statistical processing was carried out in the program Statistica.Results. An earlier disappearance of cardialgia was determined in the subgroup A2 (p < 0.05, whereas in the subgroup A1, 5% of patients had complaints not only at the end of the course, but also a month later after the initiation treatment. The more rapid positive dynamics of the electrocardiographic pattern with a more stable result was observed with the prescription of a beta-blocker.Conclusion. It was proved the advisability of prescribing of beta-blockers in the treatment of beginning athletes with violation of myocardial repolarization

  17. Mirror neurons and language in schizophrenia

    OpenAIRE

    Bendová, Marie

    2016-01-01

    Mirror neurons are a specific kind of visuomotor neurons that are involved in action execution and also in action perception. The mirror mechanism is linked to a variety of complex psychological functions such as social-cognitive functions and language. People with schizophrenia have often difficulties both in mirror neuron system and in language skills. In the first part of our research we studied the connectivity of mirror neuron areas (such as IFG, STG, PMC, SMC and so on) by fMRI in resti...

  18. Transient extracellular application of gold nanostars increases hippocampal neuronal activity.

    Science.gov (United States)

    Salinas, Kirstie; Kereselidze, Zurab; DeLuna, Frank; Peralta, Xomalin G; Santamaria, Fidel

    2014-08-20

    With the increased use of nanoparticles in biomedical applications there is a growing need to understand the effects that nanoparticles may have on cell function. Identifying these effects and understanding the mechanism through which nanoparticles interfere with the normal functioning of a cell is necessary for any therapeutic or diagnostic application. The aim of this study is to evaluate if gold nanoparticles can affect the normal function of neurons, namely their activity and coding properties. We synthesized star shaped gold nanoparticles of 180 nm average size. We applied the nanoparticles to acute mouse hippocampal slices while recording the action potentials from single neurons in the CA3 region. Our results show that CA3 hippocampal neurons increase their firing rate by 17% after the application of gold nanostars. The increase in excitability lasted for as much as 50 minutes after a transient 5 min application of the nanoparticles. Further analyses of the action potential shape and computational modeling suggest that nanoparticles block potassium channels responsible for the repolarization of the action potentials, thus allowing the cell to increase its firing rate. Our results show that gold nanoparticles can affect the coding properties of neurons by modifying their excitability.

  19. Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome.

    Science.gov (United States)

    Patocskai, Bence; Barajas-Martinez, Hector; Hu, Dan; Gurabi, Zsolt; Koncz, István; Antzelevitch, Charles

    2016-06-01

    Early repolarization syndrome (ERS) is associated with polymorphic ventricular tachycardia (PVT) and ventricular fibrillation, leading to sudden cardiac death. The present study tests the hypothesis that the transient outward potassium current (Ito)-blocking effect of phosphodiesterase-3 (PDE-3) inhibitors plays a role in reversing repolarization heterogeneities responsible for arrhythmogenesis in experimental models of ERS. Transmembrane action potentials (APs) were simultaneously recorded from epicardial and endocardial regions of coronary-perfused canine left ventricular (LV) wedge preparations, together with a transmural pseudo-electrocardiogram. The Ito agonist NS5806 (7-15 μM) and L-type calcium current (ICa) blocker verapamil (2-3 μM) were used to induce an early repolarization pattern and PVT. After stable induction of arrhythmogenesis, the PDE-3 inhibitors cilostazol and milrinone or isoproterenol were added to the coronary perfusate. All were effective in restoring the AP dome in the LV epicardium, thus abolishing the repolarization defects responsible for phase 2 reentry and PVT. Arrhythmic activity was suppressed in 7 of 8 preparations by cilostazol (10 μM), 6 of 7 by milrinone (2.5 μM), and 7 of 8 by isoproterenol (0.1-1 μM). Using voltage clamp techniques applied to LV epicardial myocytes, both cilostazol (10 μM) and milrinone (2.5 μM) were found to reduce Ito by 44.4% and 40.4%, respectively, in addition to their known effects to augment ICa. Our findings suggest that PDE-3 inhibitors exert an ameliorative effect in the setting of ERS by producing an inward shift in the balance of current during the early phases of the epicardial AP via inhibition of Ito as well as augmentation of ICa, thus reversing the repolarization defects underlying the development of phase 2 reentry and ventricular tachycardia/ventricular fibrillation. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  20. Short-term action potential memory and electrical restitution: A cellular computational study on the stability of cardiac repolarization under dynamic pacing.

    Directory of Open Access Journals (Sweden)

    Massimiliano Zaniboni

    Full Text Available Electrical restitution (ER is a major determinant of repolarization stability and, under fast pacing rate, it reveals memory properties of the cardiac action potential (AP, whose dynamics have never been fully elucidated, nor their ionic mechanisms. Previous studies have looked at ER mainly in terms of changes in AP duration (APD when the preceding diastolic interval (DI changes and described dynamic conditions where this relationship shows hysteresis which, in turn, has been proposed as a marker of short-term AP memory and repolarization stability. By means of numerical simulations of a non-propagated human ventricular AP, we show here that measuring ER as APD versus the preceding cycle length (CL provides additional information on repolarization dynamics which is not contained in the companion formulation. We focus particularly on fast pacing rate conditions with a beat-to-beat variable CL, where memory properties emerge from APD vs CL and not from APD vs DI and should thus be stored in APD and not in DI. We provide an ion-currents characterization of such conditions under periodic and random CL variability, and show that the memory stored in APD plays a stabilizing role on AP repolarization under pacing rate perturbations. The gating kinetics of L-type calcium current seems to be the main determinant of this safety mechanism. We also show that, at fast pacing rate and under otherwise identical pacing conditions, a periodically beat-to-beat changing CL is more effective than a random one in stabilizing repolarization. In summary, we propose a novel view of short-term AP memory, differentially stored between systole and diastole, which opens a number of methodological and theoretical implications for the understanding of arrhythmia development.

  1. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  2. Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol

    DEFF Research Database (Denmark)

    Atanasovska, Tania; Smith, Robert; Graff, Claus

    2018-01-01

    repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min intense rowing exercise and 60 min......-exercise (Peffect). [K+]a was lower after SAL than PLAC, from 2 min pre-exercise until 2.5 min during exercise, and at 50 and 60 min post-exercise (P...-exercise decline in [K+]a was correlated with QT hysteresis (r=0.343, n=112, pooled data, P=0.001). Thus the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Whilst salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery...

  3. Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits.

    Science.gov (United States)

    Zhu, Yujie; Ai, Xun; Oster, Robert A; Bers, Donald M; Pogwizd, Steven M

    2013-06-01

    Slow delayed rectifier potassium current (IKs) is important in action potential (AP) repolarization and repolarization reserve. We tested the hypothesis that there are sex-specific differences in IKs, AP, and their regulation by β-adrenergic receptors (β-AR's) using whole-cell patch-clamp. AP duration (APD90) was significantly longer in control female (F) than in control male (M) myocytes. Isoproterenol (ISO, 500 nM) shortened APD90 comparably in M and F, and was largely reversed by β1-AR blocker CGP 20712A (CGP, 300 nM). Inhibition of IKs with chromanol 293B (10 μM) resulted in less APD prolongation in F at baseline (3.0 vs 8.9 %, p < 0.05 vs M) and even in the presence of ISO (5.4 vs 20.9 %, p < 0.05). This suggests that much of the ISO-induced APD abbreviation in F is independent of IKs. In F, baseline IKs was 42 % less and was more weakly activated by ISO (19 vs 68 % in M, p < 0.01). ISO enhancement of IKs was comparably attenuated by CGP in M and F. After ovariectomy, IKs in F had greater enhancement by ISO (72 %), now comparable to control M. After orchiectomy, IKs in M was only slightly enhanced by ISO (23 %), comparable to control F. Pretreatment with thapsigargin (to block SR Ca release) had bigger impact on ISO-induced APD shortening in F than that in M (p < 0.01). In conclusion, we found that there are sex differences in IKs, AP, and their regulation by β-AR's that are modulated by sex hormones, suggesting the potential for sex-specific antiarrhythmic therapy.

  4. Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

    Directory of Open Access Journals (Sweden)

    Joon Ha

    Full Text Available Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR activation or applied depolarization block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG, which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations

  5. Functional magnetic resonance imaging study of neuronal activation during cognitive tasks related to frontal lobe functions in patients with obsessive-compulsive disorder

    International Nuclear Information System (INIS)

    Koizumi, Hazuki

    2010-01-01

    Previous neurological studies and brain activation studies using functional magnetic resonance imaging (f-MRI) have suggested frontal lobe dysfunctions in patients with obsessive-compulsive disorder (OCD). However, no f-MRI study has used cognitive tasks reflecting fluency of ideas and memory related to frontal lobe functions. The purposes of this study are to assess the neuropsychological examinations and brain activities of OCD patients using f-MRI, as well as, to investigate the relationship between the severity of obsessive-compulsive symptoms and frontal lobe functions. The subjects were 22 right-handed persons consisting of 11 outpatients who had received a diagnosis of OCD based on diagnostic and statistical manual of mental disorders-fourth edition (DMS-IV) and age- and sex-matched 11 healthy controls. All subjects were examined using Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Wechsler Adult Intelligence Scale-3 rd edition (WAIS-III), Wisconsin Card Sorting Test (WCST), Modified Stroop Test (MST), Verbal Fluency Test (VFT), Idea Fluency Test (IFT), and Rey-Auditory Verbal Learning Test (RAVLT). The brain activities were measured with f-MRI during three cognitive tasks; Task 1: idea generation (IFT), Task 2: word generation (VFT), and Task 3: remembrance of words (RAVLT). The block design was used in the trials, in which rest and activating tasks were alternated for five times in each task. The neuropsychological examinations revealed significant differences in the numbers of categories achieved and total errors in WCST, times of Part I in MST, scores of VFT and IFT, and the results of RAVLT between the OCD patients and healthy controls. Using functional brain imaging with f-MRI, noticeable activations were found in the superior, middle, inferior frontal gyri, and the cingulate gyrus during all tasks in both the OCD and control groups. The OCD patients had significantly higher activation in the cingulate gyrus than normal controls during Task 1 (IFT

  6. Action Potential Broadening in Capsaicin-Sensitive DRG Neurons from Frequency-Dependent Reduction of Kv3 Current.

    Science.gov (United States)

    Liu, Pin W; Blair, Nathaniel T; Bean, Bruce P

    2017-10-04

    Action potential (AP) shape is a key determinant of cellular electrophysiological behavior. We found that in small-diameter, capsaicin-sensitive dorsal root ganglia neurons corresponding to nociceptors (from rats of either sex), stimulation at frequencies as low as 1 Hz produced progressive broadening of the APs. Stimulation at 10 Hz for 3 s resulted in an increase in AP width by an average of 76 ± 7% at 22°C and by 38 ± 3% at 35°C. AP clamp experiments showed that spike broadening results from frequency-dependent reduction of potassium current during spike repolarization. The major current responsible for frequency-dependent reduction of overall spike-repolarizing potassium current was identified as Kv3 current by its sensitivity to low concentrations of 4-aminopyridine (IC 50 action potentials of small-diameter rat DRG neurons showed spike broadening at frequencies as low as 1 Hz and that spike broadening resulted predominantly from frequency-dependent inactivation of Kv3 channels. Spike width helps to control transmitter release, conduction velocity, and firing patterns and understanding the role of particular potassium channels can help to guide new pharmacological strategies for targeting pain-sensing neurons selectively. Copyright © 2017 the authors 0270-6474/17/379705-10$15.00/0.

  7. Selective serotonergic excitation of callosal projection neurons

    Directory of Open Access Journals (Sweden)

    Daniel eAvesar

    2012-03-01

    Full Text Available Serotonin (5-HT acting as a neurotransmitter in the cerebral cortex is critical for cognitive function, yet how 5-HT regulates information processing in cortical circuits is not well understood. We tested the serotonergic responsiveness of layer 5 pyramidal neurons (L5PNs of the mouse medial prefrontal cortex (mPFC, and found 3 distinct response types: long-lasting 5-HT1A (1A receptor-dependent inhibitory responses (84% of L5PNs, 5-HT2A (2A receptor-dependent excitatory responses (9%, and biphasic responses in which 2A-dependent excitation followed brief inhibition (5%. Relative to 5-HT-inhibited neurons, those excited by 5-HT had physiological properties characteristic of callosal/commissural (COM neurons that project to the contralateral cortex. We tested whether serotonergic responses in cortical pyramidal neurons are correlated with their axonal projection pattern using retrograde fluorescent labeling of COM and corticopontine-projecting (CPn neurons. 5-HT generated excitatory or biphasic responses in all 5-HT-responsive layer 5 COM neurons. Conversely, CPn neurons were universally inhibited by 5-HT. Serotonergic excitation of COM neurons was blocked by the 2A antagonist MDL 11939, while serotonergic inhibition of CPn neurons was blocked by the 1A antagonist WAY 100635, confirming a role for these two receptor subtypes in regulating pyramidal neuron activity. Selective serotonergic excitation of COM neurons was not layer-specific, as COM neurons in layer 2/3 were also selectively excited by 5-HT relative to their non-labeled pyramidal neuron neighbors. Because neocortical 2A receptors are implicated in the etiology and pathophysiology of schizophrenia, we propose that COM neurons may represent a novel cellular target for intervention in psychiatric disease.

  8. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  9. Mirror Neurons from Associative Learning

    OpenAIRE

    Catmur, Caroline; Press, Clare; Heyes, Cecilia

    2016-01-01

    Mirror neurons fire both when executing actions and observing others perform similar actions. Their sensorimotor matching properties have generally been considered a genetic adaptation for social cognition; however, in the present chapter we argue that the evidence in favor of this account is not compelling. Instead we present evidence supporting an alternative account: that mirror neurons’ matching properties arise from associative learning during individual development. Notably, this proces...

  10. Cellular and Ionic Mechanisms Underlying Effects of Cilostazol, Milrinone and Isoproterenol to Suppress Arrhythmogenesis in an Experimental Model of Early Repolarization Syndrome

    Science.gov (United States)

    Patocskai, Bence; Barajas-Martinez, Hector; Hu, Dan; Gurabi, Zsolt; Koncz, István; Antzelevitch, Charles

    2016-01-01

    Background Early Repolarization Syndrome (ERS) is associated with polymorphic ventricular tachycardia (PVT) and fibrillation (VF), leading to sudden cardiac death. Objective The present study tests the hypothesis that the Ito-blocking effect of phosphodiesterase-3 (PDE-3) inhibitors plays a role in reversing repolarization heterogeneities responsible for arrhythmogenesis in experimental models of ERS. Methods Transmembrane action potentials (AP) were simultaneously recorded from epicardial and endocardial regions of coronary-perfused canine left-ventricular (LV) wedge preparations, together with a transmural pseudo-ECG. The Ito-agonist NS5806 (7–15 μM) and ICa-blocker verapamil (2–3 uM) were used to induce an ER pattern and PVT. Results Following stable induction of arrhythmogenesis, the PDE-3 inhibitors cilostazol and milrinone or isoproterenol were added to the coronary perfusate. All were effective in restoring the AP dome in the LV epicardium, thus abolishing the repolarization defects responsible for phase-2-reentry (P2R) and PVT. Arrhythmic activity was suppressed in 7/8 preparations by cilostazol (10 μM), 6/7 by milrinone (2.5 μM) and 7/8 by isoproterenol (0.1–1μM). Using voltage clamp techniques applied to LV epicardial myocytes, both cilostazol (10 μM) and milrinone (2.5 μM) were found to reduce Ito by 44.4% and 40.4%, respectively, in addition to their known effects to augment ICa. Conclusions Our findings suggest that PDE-3 inhibitors exert an ameliorative effect in the setting of ERS by producing an inward shift in the balance of current in the early phases of the epicardial AP via inhibition of Ito as well as augmentation of ICa, thus reversing the repolarization defects underlying development of P2R and VT/VF. PMID:26820510

  11. Identifying drug-induced repolarization abnormalities from distinct ECG patterns in congenital long QT syndrome: a study of sotalol effects on T-wave morphology

    DEFF Research Database (Denmark)

    Graff, Claus; Andersen, Mads P; Xue, Joel Q

    2009-01-01

    BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal repolariz......BACKGROUND: The electrocardiographic QT interval is used to identify drugs with potential harmful effects on cardiac repolarization in drug trials, but the variability of the measurement can mask drug-induced ECG changes. The use of complementary electrocardiographic indices of abnormal...... are typical ECG patterns in LQT2. Blinded to labels, the new morphology measures were tested in a third group of 39 healthy subjects receiving sotalol. Over 3 days the sotalol group received 0, 160 and 320 mg doses, respectively, and a 12-lead Holter ECG was recorded for 22.5 hours each day. Drug...... with QTcF, p ECG patterns in LQT2 carriers effectively quantified repolarization changes induced by sotalol. Further studies are needed to validate whether this measure has...

  12. "Is all the stuff about neurons necessary?" The development of lay summaries to disseminate findings from the Newcastle Cognitive Function after Stroke (COGFAST) study.

    Science.gov (United States)

    Barnfield, Sarah; Pitts, Alison Clara; Kalaria, Raj; Allan, Louise; Tullo, Ellen

    2017-01-01

    Why did we do this study? It can be difficult for scientists to communicate their research findings to the public. This is partly due to the complexity of translating scientific language into words that the public understand. Further, it may be hard for the public to find out about and locate information about research studies. We aimed to adapt some scientific articles about the links between dementia and stroke into lay summaries to be displayed online for the general public. How did we do it? We collaborated with five people from a volunteer organisation, VOICENorth. They took part in two group discussions about studies reporting on the link between dementia and stroke, and selected four studies to translate into lay summaries and display on a website. We discussed the layout and language of the summaries and made adaptations to make them more understandable to the general public. What did we find? We were able to work with members of the public to translate research findings into lay summaries suitable for a general audience. We made changes to language and layout including the use of 'question and answer' style layouts, the addition of a reference list of scientific terms, and removing certain words. What does this mean? Working with members of the public is a realistic way to create resources that improve the accessibility of research findings to the wider public. Background Scientific research is often poorly understood by the general public and difficult for them to access. This presents a major barrier to disseminating and translating research findings. Stroke and dementia are both major public health issues, and research has shown lifestyle measures help to prevent them. This project aimed to select a series of studies from the Newcastle Cognitive Function after Stroke cohort (COGFAST) and create lay summaries comprehensible and accessible to the public. Methods We used a focus group format to collaborate with five members of the public to review COGFAST

  13. Timing control by redundant inhibitory neuronal circuits

    Energy Technology Data Exchange (ETDEWEB)

    Tristan, I., E-mail: itristan@ucsd.edu; Rulkov, N. F.; Huerta, R.; Rabinovich, M. [BioCircuits Institute, University of California, San Diego, La Jolla, California 92093-0402 (United States)

    2014-03-15

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model.

  14. Chromatin Regulation of Neuronal Maturation and Plasticity.

    Science.gov (United States)

    Gallegos, David A; Chan, Urann; Chen, Liang-Fu; West, Anne E

    2018-05-01

    Neurons are dynamic cells that respond and adapt to stimuli throughout their long postmitotic lives. The structural and functional plasticity of neurons requires the regulated transcription of new gene products, and dysregulation of transcription in either the developing or adult brain impairs cognition. We discuss how mechanisms of chromatin regulation help to orchestrate the transcriptional programs that underlie the maturation of developing neurons and the plasticity of adult neurons. We review how chromatin regulation acts locally to modulate the expression of specific genes and more broadly to coordinate gene expression programs during transitions between cellular states. These data highlight the importance of epigenetic transcriptional mechanisms in postmitotic neurons. We suggest areas where emerging methods may advance understanding in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Timing control by redundant inhibitory neuronal circuits

    International Nuclear Information System (INIS)

    Tristan, I.; Rulkov, N. F.; Huerta, R.; Rabinovich, M.

    2014-01-01

    Rhythms and timing control of sequential activity in the brain is fundamental to cognition and behavior. Although experimental and theoretical studies support the understanding that neuronal circuits are intrinsically capable of generating different time intervals, the dynamical origin of the phenomenon of functionally dependent timing control is still unclear. Here, we consider a new mechanism that is related to the multi-neuronal cooperative dynamics in inhibitory brain motifs consisting of a few clusters. It is shown that redundancy and diversity of neurons within each cluster enhances the sensitivity of the timing control with the level of neuronal excitation of the whole network. The generality of the mechanism is shown to work on two different neuronal models: a conductance-based model and a map-based model

  16. Right precordial-directed electrocardiographical markers identify arrhythmogenic right ventricular cardiomyopathy in the absence of conventional depolarization or repolarization abnormalities.

    Science.gov (United States)

    Cortez, Daniel; Svensson, Anneli; Carlson, Jonas; Graw, Sharon; Sharma, Nandita; Brun, Francesca; Spezzacatene, Anita; Mestroni, Luisa; Platonov, Pyotr G

    2017-10-13

    Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) carries a risk of sudden death. We aimed to assess whether vectorcardiographic (VCG) parameters directed toward the right heart and a measured angle of the S-wave would help differentiate ARVD/C with otherwise normal electrocardiograms from controls. Task Force 2010 definite ARVD/C criteria were met for all patients. Those who did not fulfill Task Force depolarization or repolarization criteria (-ECG) were compared with age and gender-matched control subjects. Electrocardiogram measures of a 3-dimentional spatial QRS-T angle, a right-precordial-directed orthogonal QRS-T (RPD) angle, a root mean square of the right sided depolarizing forces (RtRMS-QRS), QRS duration (QRSd) and the corrected QT interval (QTc), and a measured angle including the upslope and downslope of the S-wave (S-wave angle) were assessed. Definite ARVD/C was present in 155 patients by 2010 Task Force criteria (41.7 ± 17.6 years, 65.2% male). -ECG ARVD/C patients (66 patients) were compared to 66 control patients (41.7 ± 17.6 years, 65.2% male). All parameters tested except the QRSd and QTc significantly differentiated -ECG ARVD/C from control patients (p right-sided VCG or measured angle markers better than the spatial QRS-T angle, the QRSd or QTc, in the absence of Taskforce ECG criteria.

  17. In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes.

    Science.gov (United States)

    Zhou, Xin; Bueno-Orovio, Alfonso; Orini, Michele; Hanson, Ben; Hayward, Martin; Taggart, Peter; Lambiase, Pier D; Burrage, Kevin; Rodriguez, Blanca

    2016-01-22

    Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type; Psilico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation. © 2015 The Authors.

  18. Spectral fingerprints of large-scale neuronal interactions

    NARCIS (Netherlands)

    Siegel, M.; Donner, T.H.; Engel, A.K.

    2012-01-01

    Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the

  19. Mirror neurons: functions, mechanisms and models.

    Science.gov (United States)

    Oztop, Erhan; Kawato, Mitsuo; Arbib, Michael A

    2013-04-12

    Mirror neurons for manipulation fire both when the animal manipulates an object in a specific way and when it sees another animal (or the experimenter) perform an action that is more or less similar. Such neurons were originally found in macaque monkeys, in the ventral premotor cortex, area F5 and later also in the inferior parietal lobule. Recent neuroimaging data indicate that the adult human brain is endowed with a "mirror neuron system," putatively containing mirror neurons and other neurons, for matching the observation and execution of actions. Mirror neurons may serve action recognition in monkeys as well as humans, whereas their putative role in imitation and language may be realized in human but not in monkey. This article shows the important role of computational models in providing sufficient and causal explanations for the observed phenomena involving mirror systems and the learning processes which form them, and underlines the need for additional circuitry to lift up the monkey mirror neuron circuit to sustain the posited cognitive functions attributed to the human mirror neuron system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. Where do mirror neurons come from?

    Science.gov (United States)

    Heyes, Cecilia

    2010-03-01

    Debates about the evolution of the 'mirror neuron system' imply that it is an adaptation for action understanding. Alternatively, mirror neurons may be a byproduct of associative learning. Here I argue that the adaptation and associative hypotheses both offer plausible accounts of the origin of mirror neurons, but the associative hypothesis has three advantages. First, it provides a straightforward, testable explanation for the differences between monkeys and humans that have led some researchers to question the existence of a mirror neuron system. Second, it is consistent with emerging evidence that mirror neurons contribute to a range of social cognitive functions, but do not play a dominant, specialised role in action understanding. Finally, the associative hypothesis is supported by recent data showing that, even in adulthood, the mirror neuron system can be transformed by sensorimotor learning. The associative account implies that mirror neurons come from sensorimotor experience, and that much of this experience is obtained through interaction with others. Therefore, if the associative account is correct, the mirror neuron system is a product, as well as a process, of social interaction. (c) 2009 Elsevier Ltd. All rights reserved.

  1. Coupling Perception with Actions via Mirror Neurons

    Czech Academy of Sciences Publication Activity Database

    Wiedermann, Jiří

    č. 55 (2003), s. 11-12 ISSN 0926-4981 R&D Projects: GA ČR GA201/02/1456 Institutional research plan: AV0Z1030915 Keywords : mirror neurons * cognitive agents * neural nets Subject RIV: BA - General Mathematics http://www.ercim.eu/publication/Ercim_News/enw55/wiedermann.html

  2. Unbroken Mirror Neurons in Autism Spectrum Disorders

    Science.gov (United States)

    Fan, Yang-Teng; Decety, Jean; Yang, Chia-Yen; Liu, Ji-Lin; Cheng, Yawei

    2010-01-01

    Background: The "broken mirror" theory of autism, which proposes that a dysfunction of the human mirror neuron system (MNS) is responsible for the core social and cognitive deficits in individuals with autism spectrum disorders (ASD), has received considerable attention despite weak empirical evidence. Methods: In this electroencephalographic…

  3. The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction.

    Science.gov (United States)

    Jani, Ylber; Kamberi, Ahmet; Xhunga, Sotir; Pocesta, Bekim; Ferati, Fatmir; Lala, Dali; Zeqiri, Agim; Rexhepi, Atila

    2015-01-01

    To assess the influence of type 2 DM and gender, on the QT dispersion, Tpeak-Tend dispersion of ventricular repolarization, in patients with sub-clinic left ventricular diastolic dysfunction of the heart. QT dispersion, that reflects spatial inhomogeneity in ventricular repolarization, Tpeak-Tend dispersion, this on the other hand reflects transmural inhomogeneity in ventricular repolarization, that is increased in an early stage of cardiomyopathy, and in patients with left ventricular diastolic dysfunction, as well. The left ventricular diastolic dysfunction, a basic characteristic of diabetic heart disease (diabetic cardiomyopathy), that developes earlier than systolic dysfunction, suggests that diastolic markers might be sensitive for early cardiac injury. It is also demonstrated that gender has complex influence on indices of myocardial repolarization abnormalities such as QT interval and QT dispersion. We performed an observational study including 300 diabetic patients with similar epidemiological-demographic characteristics recruited in our institution from May 2009 to July 2014, divided into two groups. Demographic and laboratory echocardiographic data were obtained, twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersion, were determined manually, and were compared between various groups. For statistical analysis a t-test, X(2) test, and logistic regression are used according to the type of variables. A p value <0.05 was considered statistically significant for a confidence interval of 95%. QTc max. interval, QTc dispersion and Tpeak-Tend dispersion, were significantly higher in diabetic group with subclinical LV (left ventricular) diastolic dysfunction, than in diabetic group with normal left ventricular diastolic function (445.24±14.7 ms vs. 433.55±14.4 ms, P<0.000; 44.98±18.78 ms vs. 32.05±17.9 ms, P<0.000; 32.60±1.6 ms vs. 17.46±2.0 ms, P<0.02. Prolonged QTc max. interval was found in 33% of patients, indiabetic group

  4. 5-HT modulation of hyperpolarization-activated inward current and calcium- dependent outward current in a crustacean motor neuron

    DEFF Research Database (Denmark)

    Kiehn, O.; Harris-Warrick, R. M.

    1992-01-01

    1. Serotonergic modulation of a hyperpolarization-activated inward current, I(h), and a calcium-dependent outward current, I(o(Ca)), was examined in the dorsal gastric (DG) motor neuron, with the use of intracellular recording techniques in an isolated preparation of the crab stomatogastric....... The time course of activation of I(h) was well fitted by a single exponential function and strongly voltage dependent. 5-HT increased the rate of activation of I(h). 5- HT also slowed the rate of deactivation of the I(h) tail on repolarization to -50 mV. 6. The activation curve for the conductance (G...... reduced or eliminated the 5-HT response in the depolarizing range, suggesting that 5-HT specifically reduces I(o(Ca)). 11. These results demonstrate that 5-HT has dual effects on the DG motor neuron, in the crab stomatogastric ganglion. We suggest that changes in the two conductances are responsible...

  5. Cellular Mechanism Underlying Hypothermia-Induced VT/VF in the Setting of Early Repolarization and the Protective Effect of Quinidine, Cilostazol and Milrinone

    Science.gov (United States)

    Gurabi, Zsolt; Koncz, István; Patocskai, Bence; Nesterenko, Vladislav V.; Antzelevitch, Charles

    2014-01-01

    Background Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome (ERS) and examines the effectiveness of quinidine, cilostazol and milrinone to prevent hypothermia-induced arrhythmias. Method and Results Transmembrane action potentials (AP) were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left-ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3–10 µM) and verapamil (1µM) was used to pharmacologically model the genetic mutations responsible for ERS. Acetylcholine (3µM) was used to simulate increased parasympathetic tone, which is known to promote ER. In control, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C-34°C) resulted in increased J wave area on the ECG and accentuated epicardial AP notch but no arrhythmic activity. In the setting of ER, hypothermia caused further accentuation of the epicardial AP notch, leading to loss of the AP dome at some sites but not others, thus creating the substrate for development of phase-2-reentry and VT/VF. Addition of the Ito antagonist quinidine (5 µM) or the phosphodiesterase III inhibitors cilostazol (10 µM) or milrinone (5 µM), diminished the ER manifestations and prevented the hypothermia-induced phase 2 reentry and VT/VF. Conclusions Hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities, leading to development of phase-2-reentry. Quinidine, cilostazol and milrinone suppress the hypothermia-induced VT/VF by reversing the repolarization abnormalities. PMID:24429494

  6. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone.

    Science.gov (United States)

    Gurabi, Zsolt; Koncz, István; Patocskai, Bence; Nesterenko, Vladislav V; Antzelevitch, Charles

    2014-02-01

    Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome and examines the effectiveness of quinidine, cilostazol, and milrinone to prevent hypothermia-induced arrhythmias. Transmembrane action potentials were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3-10 μmol/L) and verapamil (1 μmol/L) was used to pharmacologically model the genetic mutations responsible for ER syndrome. Acetylcholine (3 μmol/L) was used to simulate increased parasympathetic tone, which is known to promote ER. In controls, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C-34°C) resulted in increased J-wave area on the ECG and accentuated epicardial action potential notch but no arrhythmic activity. In the setting of ER, hypothermia caused further accentuation of the epicardial action potential notch, leading to loss of the action potential dome at some sites but not others, thus creating the substrate for development of phase 2 reentry and VT/VF. Addition of the transient outward current antagonist quinidine (5 μmol/L) or the phosphodiesterase III inhibitors cilostazol (10 μmol/L) or milrinone (5 μmol/L) diminished the ER manifestations and prevented the hypothermia-induced phase 2 reentry and VT/VF. Hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities, leading to development of phase 2 reentry. Quinidine, cilostazol, and milrinone suppress the hypothermia-induced VT/VF by reversing the repolarization abnormalities.

  7. Mirror neurons: from origin to function.

    Science.gov (United States)

    Cook, Richard; Bird, Geoffrey; Catmur, Caroline; Press, Clare; Heyes, Cecilia

    2014-04-01

    This article argues that mirror neurons originate in sensorimotor associative learning and therefore a new approach is needed to investigate their functions. Mirror neurons were discovered about 20 years ago in the monkey brain, and there is now evidence that they are also present in the human brain. The intriguing feature of many mirror neurons is that they fire not only when the animal is performing an action, such as grasping an object using a power grip, but also when the animal passively observes a similar action performed by another agent. It is widely believed that mirror neurons are a genetic adaptation for action understanding; that they were designed by evolution to fulfill a specific socio-cognitive function. In contrast, we argue that mirror neurons are forged by domain-general processes of associative learning in the course of individual development, and, although they may have psychological functions, they do not necessarily have a specific evolutionary purpose or adaptive function. The evidence supporting this view shows that (1) mirror neurons do not consistently encode action "goals"; (2) the contingency- and context-sensitive nature of associative learning explains the full range of mirror neuron properties; (3) human infants receive enough sensorimotor experience to support associative learning of mirror neurons ("wealth of the stimulus"); and (4) mirror neurons can be changed in radical ways by sensorimotor training. The associative account implies that reliable information about the function of mirror neurons can be obtained only by research based on developmental history, system-level theory, and careful experimentation.

  8. Premature Ventricular Contraction Coupling Interval Variability Destabilizes Cardiac Neuronal and Electrophysiological Control: Insights from Simultaneous Cardio-Neural Mapping

    Science.gov (United States)

    Hamon, David; Rajendran, Pradeep S.; Chui, Ray W.; Ajijola, Olujimi A.; Irie, Tadanobu; Talebi, Ramin; Salavatian, Siamak; Vaseghi, Marmar; Bradfield, Jason S.; Armour, J. Andrew; Ardell, Jeffrey L.; Shivkumar, Kalyanam

    2017-01-01

    Background Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system (ICNS), a neural network on the heart, remains unknown. The objective was to determine the effect of PVCs and CI on ICNS function in generating cardiac neuronal and electrical instability using a novel cardio-neural mapping approach. Methods and Results In a porcine model (n=8) neuronal activity was recorded from a ventricular ganglion using a microelectrode array, and cardiac electrophysiological mapping was performed. Neurons were functionally classified based on their response to afferent and efferent cardiovascular stimuli, with neurons that responded to both defined as convergent (local reflex processors). Dynamic changes in neuronal activity were then evaluated in response to right ventricular outflow tract PVCs with fixed short, fixed long, and variable CI. PVC delivery elicited a greater neuronal response than all other stimuli (P<0.001). Compared to fixed short and long CI, PVCs with variable CI had a greater impact on neuronal response (P<0.05 versus short CI), particularly on convergent neurons (P<0.05), as well as neurons receiving sympathetic (P<0.05) and parasympathetic input (P<0.05). The greatest cardiac electrical instability was also observed following variable (short) CI PVCs. Conclusions Variable CI PVCs affect critical populations of ICNS neurons and alter cardiac repolarization. These changes may be critical for arrhythmogenesis and remodeling leading to cardiomyopathy. PMID:28408652

  9. Premature Ventricular Contraction Coupling Interval Variability Destabilizes Cardiac Neuronal and Electrophysiological Control: Insights From Simultaneous Cardioneural Mapping.

    Science.gov (United States)

    Hamon, David; Rajendran, Pradeep S; Chui, Ray W; Ajijola, Olujimi A; Irie, Tadanobu; Talebi, Ramin; Salavatian, Siamak; Vaseghi, Marmar; Bradfield, Jason S; Armour, J Andrew; Ardell, Jeffrey L; Shivkumar, Kalyanam

    2017-04-01

    Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system, a neural network on the heart, remains unknown. The objective was to determine the effect of PVCs and CI on intrinsic cardiac nervous system function in generating cardiac neuronal and electric instability using a novel cardioneural mapping approach. In a porcine model (n=8), neuronal activity was recorded from a ventricular ganglion using a microelectrode array, and cardiac electrophysiological mapping was performed. Neurons were functionally classified based on their response to afferent and efferent cardiovascular stimuli, with neurons that responded to both defined as convergent (local reflex processors). Dynamic changes in neuronal activity were then evaluated in response to right ventricular outflow tract PVCs with fixed short, fixed long, and variable CI. PVC delivery elicited a greater neuronal response than all other stimuli ( P <0.001). Compared with fixed short and long CI, PVCs with variable CI had a greater impact on neuronal response ( P <0.05 versus short CI), particularly on convergent neurons ( P <0.05), as well as neurons receiving sympathetic ( P <0.05) and parasympathetic input ( P <0.05). The greatest cardiac electric instability was also observed after variable (short) CI PVCs. Variable CI PVCs affect critical populations of intrinsic cardiac nervous system neurons and alter cardiac repolarization. These changes may be critical for arrhythmogenesis and remodeling, leading to cardiomyopathy. © 2017 American Heart Association, Inc.

  10. The mirror neuron system and the consequences of its dysfunction.

    Science.gov (United States)

    Iacoboni, Marco; Dapretto, Mirella

    2006-12-01

    The discovery of premotor and parietal cells known as mirror neurons in the macaque brain that fire not only when the animal is in action, but also when it observes others carrying out the same actions provides a plausible neurophysiological mechanism for a variety of important social behaviours, from imitation to empathy. Recent data also show that dysfunction of the mirror neuron system in humans might be a core deficit in autism, a socially isolating condition. Here, we review the neurophysiology of the mirror neuron system and its role in social cognition and discuss the clinical implications of mirror neuron dysfunction.

  11. Six-Year Outcome of Subjects Without Overt Heart Disease With an Early Repolarization/J Wave Electrocardiographic Pattern.

    Science.gov (United States)

    Lanza, Gaetano Antonio; Argirò, Alessia; Mollo, Roberto; De Vita, Antonio; Spera, Francesco; Golino, Michele; Rota, Elisabetta; Filice, Monica; Crea, Filippo

    2017-12-01

    "Early repolarization" (ER) is a frequent finding at standard electrocardiogram (ECG). In this study we assessed whether ER is associated with an increased risk of events, as recently suggested by some studies. We prospectively enrolled 4,176 consecutive subjects without any heart disease who underwent routine ECG recording. ER was diagnosed in case of typical concave ST-segment elevation ≥0.1 mV; a J wave was diagnosed when the QRS showed a notch or a slur in its terminal part. In this study we compared the 6-year outcome of all 687 subjects with ER/J wave and 687 matched subjects without ER/J wave (controls). Both groups included 335 males and 352 females, and age was 48.8 ± 18 years. Overall, 145 deaths occurred (11%), only 11 of which attributed to cardiac causes. No sudden death was reported. Cardiac deaths occurred in 5 (0.8%) and 6 (0.9%) ER/J wave subjects and controls, respectively (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.26 to 2.80, p = 0.79). Both ER (OR 1.68, 95% CI 0.21 to 13.3, p = 0.62) and J wave (OR 0.91, 95% CI 0.28 to 3.00, p = 0.88) showed no association with cardiac death. Total mortality was 11.5% in the ER/J wave group and 10.6% in the control group (OR 1.10, 95% CI 0.78 to 1.56, p = 0.58). Both ER (OR 0.44, 95% CI 0.16 to 1.24, p = 0.12) and J wave (OR 1.20, 95% CI 0.85 to 1.70, p = 0.30) showed also no association with all-cause death. In subjects without any evidence of heart disease, we found no significant association of ER/J wave with the risk of cardiac, as well as all-cause, death at medium-term follow-up. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Tinbergen on mirror neurons

    Science.gov (United States)

    Heyes, Cecilia

    2014-01-01

    Fifty years ago, Niko Tinbergen defined the scope of behavioural biology with his four problems: causation, ontogeny, survival value and evolution. About 20 years ago, there was another highly significant development in behavioural biology—the discovery of mirror neurons (MNs). Here, I use Tinbergen's original four problems (rather than the list that appears in textbooks) to highlight the differences between two prominent accounts of MNs, the genetic and associative accounts; to suggest that the latter provides the defeasible ‘best explanation’ for current data on the causation and ontogeny of MNs; and to argue that functional analysis, of the kind that Tinbergen identified somewhat misleadingly with studies of ‘survival value’, should be a high priority for future research. In this kind of functional analysis, system-level theories would assign MNs a small, but potentially important, role in the achievement of action understanding—or another social cognitive function—by a production line of interacting component processes. These theories would be tested by experimental intervention in human and non-human animal samples with carefully documented and controlled developmental histories. PMID:24778376

  13. Tinbergen on mirror neurons.

    Science.gov (United States)

    Heyes, Cecilia

    2014-01-01

    Fifty years ago, Niko Tinbergen defined the scope of behavioural biology with his four problems: causation, ontogeny, survival value and evolution. About 20 years ago, there was another highly significant development in behavioural biology-the discovery of mirror neurons (MNs). Here, I use Tinbergen's original four problems (rather than the list that appears in textbooks) to highlight the differences between two prominent accounts of MNs, the genetic and associative accounts; to suggest that the latter provides the defeasible 'best explanation' for current data on the causation and ontogeny of MNs; and to argue that functional analysis, of the kind that Tinbergen identified somewhat misleadingly with studies of 'survival value', should be a high priority for future research. In this kind of functional analysis, system-level theories would assign MNs a small, but potentially important, role in the achievement of action understanding-or another social cognitive function-by a production line of interacting component processes. These theories would be tested by experimental intervention in human and non-human animal samples with carefully documented and controlled developmental histories.

  14. Neuronal Migration Disorders

    Science.gov (United States)

    ... Understanding Sleep The Life and Death of a Neuron Genes At Work In The Brain Order Publications ... birth defects caused by the abnormal migration of neurons in the developing brain and nervous system. In ...

  15. Motor Neuron Diseases

    Science.gov (United States)

    ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ... and other neurodegenerative diseases to better understand the function of neurons and other support cells and identify candidate therapeutic ...

  16. [Influence of pacing site on myocardial transmural dispersion of repolarization in intact normal and dilated cardiomyopathy dogs].

    Science.gov (United States)

    Bai, Rong; Pu, Jun; Liu, Nian; Lu, Jia-Gao; Zhou, Qiang; Ruan, Yan-Fei; Niu, Hui-Yan; Wang, Lin

    2003-12-25

    In order to verify the hypothesis that left ventricular epicardial (LV-Epi) pacing and biventricular (BiV) pacing unavoidably influence the myocardial electrophysiological characters and may result in high risk of malignant ventricular arrhythmia, we calculated, in both normal mongrel dogs and dog models with rapid-right-ventricular-pacing induced dilated cardiomyopathy congestive heart failure (DCM-CHF), the monophasic action potential duration (MAPD) and the transmural dispersion of repolarization (TDR) in intracardiac electrogram together with the QT interval and T(peak)-T(end) (T(p(-T(e)) interval in surface electrocardiogram (ECG) during LV-Epi and BiV pacing, compared with those during right ventricular endocardial (RV-Endo) pacing. To prepare the DCM-CHF dog model, rapid right ventricular pacing (250 bpm) was performed for 23.6+/-2.57 days to the dog. All the normal and DCM-CHF dogs were given radio frequency catheter ablation (RFCA) to His bundle with the guide of X-ray fluoroscopy. After the RFCA procedures, the animals were under the situation of complete atrioventricular block so that the canine heart rates could be voluntarily controlled in the following experiments. After a thoracotomy, ECG and monophasic action potentials (MAP) of subendocardial, subepicardial and mid-layer myocardium were recorded synchronously in 8 normal and 5 DCM-CHF dogs during pacing from endocardium of RV apex (RV-Endo), epicardium of LV anterior wall (LV-Epi) and simultaneously both of the above (biventricular, BiV), the later was similar to the ventricular resynchronization therapy to congestive heart failure patients in clinic. The Tp-Te) meant the interval from the peak to the end of T wave, which was a representative index of TDR in surface ECG. The TDR was defined as the difference between the longest and the shortest MAPD of subendocardial, subepicardial and mid-layer myocardium. Our results showed that in normal dogs, pacing participating of LV (LV-Epi, BiV) prolonged

  17. Energy-efficient neural information processing in individual neurons and neuronal networks.

    Science.gov (United States)

    Yu, Lianchun; Yu, Yuguo

    2017-11-01

    Brains are composed of networks of an enormous number of neurons interconnected with synapses. Neural information is carried by the electrical signals within neurons and the chemical signals among neurons. Generating these electrical and chemical signals is metabolically expensive. The fundamental issue raised here is whether brains have evolved efficient ways of developing an energy-efficient neural code from the molecular level to the circuit level. Here, we summarize the factors and biophysical mechanisms that could contribute to the energy-efficient neural code for processing input signals. The factors range from ion channel kinetics, body temperature, axonal propagation of action potentials, low-probability release of synaptic neurotransmitters, optimal input and noise, the size of neurons and neuronal clusters, excitation/inhibition balance, coding strategy, cortical wiring, and the organization of functional connectivity. Both experimental and computational evidence suggests that neural systems may use these factors to maximize the efficiency of energy consumption in processing neural signals. Studies indicate that efficient energy utilization may be universal in neuronal systems as an evolutionary consequence of the pressure of limited energy. As a result, neuronal connections may be wired in a highly economical manner to lower energy costs and space. Individual neurons within a network may encode independent stimulus components to allow a minimal number of neurons to represent whole stimulus characteristics efficiently. This basic principle may fundamentally change our view of how billions of neurons organize themselves into complex circuits to operate and generate the most powerful intelligent cognition in nature. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Relating normalization to neuronal populations across cortical areas.

    Science.gov (United States)

    Ruff, Douglas A; Alberts, Joshua J; Cohen, Marlene R

    2016-09-01

    Normalization, which divisively scales neuronal responses to multiple stimuli, is thought to underlie many sensory, motor, and cognitive processes. In every study where it has been investigated, neurons measured in the same brain area under identical conditions exhibit a range of normalization, ranging from suppression by nonpreferred stimuli (strong normalization) to additive responses to combinations of stimuli (no normalization). Normalization has been hypothesized to arise from interactions between neuronal populations, either in the same or different brain areas, but current models of normalization are not mechanistic and focus on trial-averaged responses. To gain insight into the mechanisms underlying normalization, we examined interactions between neurons that exhibit different degrees of normalization. We recorded from multiple neurons in three cortical areas while rhesus monkeys viewed superimposed drifting gratings. We found that neurons showing strong normalization shared less trial-to-trial variability with other neurons in the same cortical area and more variability with neurons in other cortical areas than did units with weak normalization. Furthermore, the cortical organization of normalization was not random: neurons recorded on nearby electrodes tended to exhibit similar amounts of normalization. Together, our results suggest that normalization reflects a neuron's role in its local network and that modulatory factors like normalization share the topographic organization typical of sensory tuning properties. Copyright © 2016 the American Physiological Society.

  19. Neuro-cognition and social-cognition: application to exercise rehabilitation

    OpenAIRE

    Kim, Sooyeon

    2013-01-01

    The discovery of mirror neurons has been recognized as one of the major developments in neuroscience, with possible implications for the explanation of many important cognitive functions, including action and perception understanding, imitation, and empathy. In the mirror neuron system, action observation, imitation, and empathy are represented in the same basic motor circuit as action execution. The present paper presents basic neurophysiological findings about mirror neuron system and discu...

  20. Mirror Neurons and Mirror-Touch Synesthesia.

    Science.gov (United States)

    Linkovski, Omer; Katzin, Naama; Salti, Moti

    2016-05-30

    Since mirror neurons were introduced to the neuroscientific community more than 20 years ago, they have become an elegant and intuitive account for different cognitive mechanisms (e.g., empathy, goal understanding) and conditions (e.g., autism spectrum disorders). Recently, mirror neurons were suggested to be the mechanism underlying a specific type of synesthesia. Mirror-touch synesthesia is a phenomenon in which individuals experience somatosensory sensations when seeing someone else being touched. Appealing as it is, careful delineation is required when applying this mechanism. Using the mirror-touch synesthesia case, we put forward theoretical and methodological issues that should be addressed before relying on the mirror-neurons account. © The Author(s) 2016.

  1. Quantitative analysis of T-wave morphology increases confidence in drug-induced cardiac repolarization abnormalities: evidence from the investigational IKr inhibitor Lu 35-138

    DEFF Research Database (Denmark)

    Graff, Claus; Matz, Jørgen; Christensen, Ellen B

    2009-01-01

    prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I(Kr)-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used...... to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35-138 increased the QTc interval with corresponding changes in T......-wave morphology as determined by MCS. For subjects taking Lu 35-138, T-wave morphology was a more reliable indicator of I(Kr) inhibition than QTcF (chi(2) = 20.3, P = .001). At 80% study power for identifying a 5-millisecond placebo-adjusted change from baseline for QTcF, the corresponding study power for MCS...

  2. Neuronal network analyses: premises, promises and uncertainties

    OpenAIRE

    Parker, David

    2010-01-01

    Neuronal networks assemble the cellular components needed for sensory, motor and cognitive functions. Any rational intervention in the nervous system will thus require an understanding of network function. Obtaining this understanding is widely considered to be one of the major tasks facing neuroscience today. Network analyses have been performed for some years in relatively simple systems. In addition to the direct insights these systems have provided, they also illustrate some of the diffic...

  3. Cardiac memory in patients with Wolff-Parkinson-White syndrome: noninvasive imaging of activation and repolarization before and after catheter ablation.

    Science.gov (United States)

    Ghosh, Subham; Rhee, Edward K; Avari, Jennifer N; Woodard, Pamela K; Rudy, Yoram

    2008-08-26

    Cardiac memory refers to a change in ventricular repolarization induced by and persisting for minutes to months after cessation of a period of altered ventricular activation (eg, resulting from pacing or preexcitation in patients with Wolff-Parkinson-White syndrome). ECG imaging (ECGI) is a novel imaging modality for noninvasive electroanatomic mapping of epicardial activation and repolarization. Fourteen pediatric patients with Wolff-Parkinson-White syndrome and no other congenital disease, were imaged with ECGI a day before and 45 minutes, 1 week, and 1 month after successful catheter ablation. ECGI determined that preexcitation sites were consistent with sites of successful ablation in all cases to within a 1-hour arc of each atrioventricular annulus. In the preexcited rhythm, activation-recovery interval (ARI) was the longest (349+/-6 ms) in the area of preexcitation leading to high average base-to-apex ARI dispersion of 95+/-9 ms (normal is approximately 40 ms). The ARI dispersion remained the same 45 minutes after ablation, although the activation sequence was restored to normal. ARI dispersion was still high (79+/-9 ms) 1 week later and returned to normal (45+/-6 ms) 1 month after ablation. The study demonstrates that ECGI can noninvasively localize ventricular insertion sites of accessory pathways to guide ablation and evaluate its outcome in pediatric patients with Wolff-Parkinson-White syndrome. Wolff-Parkinson-White is associated with high ARI dispersion in the preexcited rhythm that persists after ablation and gradually returns to normal over a period of 1 month, demonstrating the presence of cardiac memory. The 1-month time course is consistent with transcriptional reprogramming and remodeling of ion channels.

  4. The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction

    Science.gov (United States)

    Jani, Ylber; Kamberi, Ahmet; Xhunga, Sotir; Pocesta, Bekim; Ferati, Fatmir; Lala, Dali; Zeqiri, Agim; Rexhepi, Atila

    2015-01-01

    Objective: To assess the influence of type 2 DM and gender, on the QT dispersion, Tpeak-Tend dispersion of ventricular repolarization, in patients with sub-clinic left ventricular diastolic dysfunction of the heart. Background: QT dispersion, that reflects spatial inhomogeneity in ventricular repolarization, Tpeak-Tend dispersion, this on the other hand reflects transmural inhomogeneity in ventricular repolarization, that is increased in an early stage of cardiomyopathy, and in patients with left ventricular diastolic dysfunction, as well. The left ventricular diastolic dysfunction, a basic characteristic of diabetic heart disease (diabetic cardiomyopathy), that developes earlier than systolic dysfunction, suggests that diastolic markers might be sensitive for early cardiac injury. It is also demonstrated that gender has complex influence on indices of myocardial repolarization abnormalities such as QT interval and QT dispersion. Material and methods: We performed an observational study including 300 diabetic patients with similar epidemiological-demographic characteristics recruited in our institution from May 2009 to July 2014, divided into two groups. Demographic and laboratory echocardiographic data were obtained, twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersion, were determined manually, and were compared between various groups. For statistical analysis a t-test, X2 test, and logistic regression are used according to the type of variables. A p value <0.05 was considered statistically significant for a confidence interval of 95%. Results: QTc max. interval, QTc dispersion and Tpeak-Tend dispersion, were significantly higher in diabetic group with subclinical LV (left ventricular) diastolic dysfunction, than in diabetic group with normal left ventricular diastolic function (445.24±14.7 ms vs. 433.55±14.4 ms, P<0.000; 44.98±18.78 ms vs. 32.05±17.9 ms, P<0.000; 32.60±1.6 ms vs. 17.46±2.0 ms, P<0.02. Prolonged QTc max

  5. Cognitive Changes

    Science.gov (United States)

    ... are here Home › Non-Movement Symptoms › Cognitive Changes Cognitive Changes Some people with Parkinson’s disease (PD) experience mild cognitive impairment. Feelings of distraction or disorganization can accompany ...

  6. Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.

    Science.gov (United States)

    Kimm, Tilia; Khaliq, Zayd M; Bean, Bruce P

    2015-12-16

    Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both

  7. Cognitive Challenges

    Science.gov (United States)

    ... Privacy Policy Sitemap Learn Engage Donate About TSC Cognitive Challenges Approximately 45% to 60% of individuals with TSC develop cognitive challenges (intellectual disabilities), although the degree of intellectual ...

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

    OpenAIRE

    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...

  9. Cognitive Reserve and Alzheimer's Disease Biomarkers Are Independent Determinants of Cognition

    Science.gov (United States)

    Vemuri, Prashanthi; Weigand, Stephen D.; Przybelski, Scott A.; Knopman, David S.; Smith, Glenn E.; Trojanowski, John Q.; Shaw, Leslie M.; Decarli, Charlie S.; Carmichael, Owen; Bernstein, Matt A.; Aisen, Paul S.; Weiner, Michael; Petersen, Ronald C.; Jack, Clifford R., Jr.

    2011-01-01

    The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury…

  10. Cognitive consilience: Primate non-primary neuroanatomical circuits underlying cognition

    Directory of Open Access Journals (Sweden)

    Soren Van Hout Solari

    2011-12-01

    Full Text Available Interactions between the cerebral cortex, thalamus, and basal ganglia form the basis ofcognitive information processing in the mammalian brain. Understanding the principles ofneuroanatomical organization in these structures is critical to understanding the functions theyperform and ultimately how the human brain works. We have manually distilled and synthesizedhundreds of primate neuroanatomy facts into a single interactive visualization. The resultingpicture represents the fundamental neuroanatomical blueprint upon which cognitive functionsmust be implemented. Within this framework we hypothesize and detail 7 functional circuitscorresponding to psychological perspectives on the brain: consolidated long-term declarativememory, short-term declarative memory, working memory/information processing, behavioralmemory selection, behavioral memory output, cognitive control, and cortical information flow regulation. Each circuit is described in terms of distinguishable neuronal groups including thecerebral isocortex (9 pyramidal neuronal groups, parahippocampal gyrus and hippocampus,thalamus (4 neuronal groups, basal ganglia (7 neuronal groups, metencephalon, basal forebrainand other subcortical nuclei. We focus on neuroanatomy related to primate non-primary corticalsystems to elucidate the basis underlying the distinct homotypical cognitive architecture. To dis-play the breadth of this review, we introduce a novel method of integrating and presenting datain multiple independent visualizations: an interactive website (www.cognitiveconsilience.comand standalone iPhone and iPad applications. With these tools we present a unique, annotatedview of neuroanatomical consilience (integration of knowledge.

  11. NEURON and Python.

    Science.gov (United States)

    Hines, Michael L; Davison, Andrew P; Muller, Eilif

    2009-01-01

    The NEURON simulation program now allows Python to be used, alone or in combination with NEURON's traditional Hoc interpreter. Adding Python to NEURON has the immediate benefit of making available a very extensive suite of analysis tools written for engineering and science. It also catalyzes NEURON software development by offering users a modern programming tool that is recognized for its flexibility and power to create and maintain complex programs. At the same time, nothing is lost because all existing models written in Hoc, including graphical user interface tools, continue to work without change and are also available within the Python context. An example of the benefits of Python availability is the use of the xml module in implementing NEURON's Import3D and CellBuild tools to read MorphML and NeuroML model specifications.

  12. Spinal cord: motor neuron diseases.

    Science.gov (United States)

    Rezania, Kourosh; Roos, Raymond P

    2013-02-01

    Spinal cord motor neuron diseases affect lower motor neurons in the ventral horn. This article focuses on the most common spinal cord motor neuron disease, amyotrophic lateral sclerosis, which also affects upper motor neurons. Also discussed are other motor neuron diseases that only affect the lower motor neurons. Despite the identification of several genes associated with familial amyotrophic lateral sclerosis, the pathogenesis of this complex disease remains elusive. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Walk like me, talk like me. The connection between mirror neurons and autism spectrum disorder.

    Science.gov (United States)

    Saffin, Jillian M; Tohid, Hassaan

    2016-04-01

    Understanding social cognition has become a hallmark in deciphering autism spectrum disorder. Neurobiological theories are taking precedence in causation studies as researchers look to abnormalities in brain development as the cause of deficits in social behavior, cognitive processes, and language. Following their discovery in the 1990s, mirror neurons have become a dominant theory for that the mirror neuron system may play a critical role in the pathophysiology of various symptoms of autism. Over the decades, the theory has evolved from the suggestion of a broken mirror neuron system to impairments in mirror neuron circuitry. The mirror neuron system has not gained total support due to inconsistent findings; a comprehensive analysis of the growing body of research could shed light on the benefits, or the disadvantage of continuing to study mirror neurons and their connection to autism.

  14. Shock wave compression and self-generated electric field repolarization in ferroelectric ceramics Pb0.99[(Zr0.90Sn0.10)0.96Ti0.04]0.98Nb0.02O3

    Science.gov (United States)

    Jiang, Dongdong; Du, Jinmei; Gu, Yan; Feng, Yujun

    2012-03-01

    The shock wave induced depoling current of Pb0.99[(Zr0.90Sn0.10)0.96Ti0.04]0.98Nb0.02O3 ceramics was investigated with a system composed of a resistive load and an unpoled ceramic. Disparity in the depoling current was explained by considering the drawing charge effect of unpoled ceramic. The drawing effect for poled ceramics was analysed by developing a model incorporating a time- and electric-field-dependent repolarization. This model predicts that the high-impedance current eventually becomes higher than the short-circuit current, which is consistent with the experimental results in the literature. This work indicates that both the repolarization of uncompressed ceramics caused by the self-generated electric field and depolarization of compressed ceramics caused by the shock wave govern the output current.

  15. Shock wave compression and self-generated electric field repolarization in ferroelectric ceramics Pb0.99[(Zr0.90Sn0.10)0.96Ti0.04]0.98Nb0.02O3

    International Nuclear Information System (INIS)

    Jiang Dongdong; Du Jinmei; Gu Yan; Feng Yujun

    2012-01-01

    The shock wave induced depoling current of Pb 0.99 [(Zr 0.90 Sn 0.10 ) 0.96 Ti 0.04 ] 0.98 Nb 0.02 O 3 ceramics was investigated with a system composed of a resistive load and an unpoled ceramic. Disparity in the depoling current was explained by considering the drawing charge effect of unpoled ceramic. The drawing effect for poled ceramics was analysed by developing a model incorporating a time- and electric-field-dependent repolarization. This model predicts that the high-impedance current eventually becomes higher than the short-circuit current, which is consistent with the experimental results in the literature. This work indicates that both the repolarization of uncompressed ceramics caused by the self-generated electric field and depolarization of compressed ceramics caused by the shock wave govern the output current. (paper)

  16. Neuronal-glial trafficking

    International Nuclear Information System (INIS)

    Bachelard, H.S.

    2001-01-01

    Full text: The name 'glia' originates from the Greek word for glue, because astro glia (or astrocytes) were thought only to provide an anatomical framework for the electrically-excitable neurones. However, awareness that astrocytes perform vital roles in protecting the neurones, which they surround, emerged from evidence that they act as neuroprotective K + -sinks, and that they remove potentially toxic extracellular glutamate from the vicinity of the neurones. The astrocytes convert the glutamate to non-toxic glutamine which is returned to the neurones and used to replenish transmitter glutamate. This 'glutamate-glutamine cycle' (established in the 1960s by Berl and his colleagues) also contributes to protecting the neurones against a build-up of toxic ammonia. Glial cells also supply the neurones with components for free-radical scavenging glutathione. Recent studies have revealed that glial cells play a more positive interactive role in furnishing the neurones with fuels. Studies using radioactive 14 C, 13 C-MRS and 15 N-GCMS have revealed that glia produce alanine, lactate and proline for consumption by neurones, with increased formation of neurotransmitter glutamate. On neuronal activation the release of NH 4 + and glutamate from the neurones stimulates glucose uptake and glycolysis in the glia to produce more alanine, which can be regarded as an 'alanine-glutamate cycle' Use of 14 C-labelled precursors provided early evidence that neurotransmitter GABA may be partly derived from glial glutamine, and this has been confirmed recently in vivo by MRS isotopomer analysis of the GABA and glutamine labelled from 13 C-acetate. Relative rates of intermediary metabolism in glia and neurones can be calculated using a combination of [1- 13 C] glucose and [1,2- 13 C] acetate. When glutamate is released by neurones there is a net neuronal loss of TCA intermediates which have to be replenished. Part of this is derived from carboxylation of pyruvate, (pyruvate carboxylase

  17. Prenatal Ontogeny as a Susceptibility Period for Cortical GABA Neuron Disturbances in Schizophrenia

    OpenAIRE

    Volk, David W.; Lewis, David A.

    2013-01-01

    Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex. Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny...

  18. Central Artery Stiffness, Baroreflex Sensitivity, and Brain White Matter Neuronal Fiber Integrity in Older Adults

    OpenAIRE

    Tarumi, Takashi; de Jong, Daan L.K.; Zhu, David C.; Tseng, Benjamin Y.; Liu, Jie; Hill, Candace; Riley, Jonathan; Womack, Kyle B.; Kerwin, Diana R.; Lu, Hanzhang; Cullum, C. Munro; Zhang, Rong

    2015-01-01

    Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65±6 years) with normal cognitive function or mild cog...

  19. Single neuron computation

    CERN Document Server

    McKenna, Thomas M; Zornetzer, Steven F

    1992-01-01

    This book contains twenty-two original contributions that provide a comprehensive overview of computational approaches to understanding a single neuron structure. The focus on cellular-level processes is twofold. From a computational neuroscience perspective, a thorough understanding of the information processing performed by single neurons leads to an understanding of circuit- and systems-level activity. From the standpoint of artificial neural networks (ANNs), a single real neuron is as complex an operational unit as an entire ANN, and formalizing the complex computations performed by real n

  20. The mirror neuron system.

    Science.gov (United States)

    Cattaneo, Luigi; Rizzolatti, Giacomo

    2009-05-01

    Mirror neurons are a class of neurons, originally discovered in the premotor cortex of monkeys, that discharge both when individuals perform a given motor act and when they observe others perform that same motor act. Ample evidence demonstrates the existence of a cortical network with the properties of mirror neurons (mirror system) in humans. The human mirror system is involved in understanding others' actions and their intentions behind them, and it underlies mechanisms of observational learning. Herein, we will discuss the clinical implications of the mirror system.

  1. Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture*

    Science.gov (United States)

    Mauceri, Daniela; Hagenston, Anna M.; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar

    2015-01-01

    Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. PMID:26231212

  2. Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture.

    Science.gov (United States)

    Mauceri, Daniela; Hagenston, Anna M; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar

    2015-09-18

    Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Modeling the Development of Goal-Specificity in Mirror Neurons.

    Science.gov (United States)

    Thill, Serge; Svensson, Henrik; Ziemke, Tom

    2011-12-01

    Neurophysiological studies have shown that parietal mirror neurons encode not only actions but also the goal of these actions. Although some mirror neurons will fire whenever a certain action is perceived (goal-independently), most will only fire if the motion is perceived as part of an action with a specific goal. This result is important for the action-understanding hypothesis as it provides a potential neurological basis for such a cognitive ability. It is also relevant for the design of artificial cognitive systems, in particular robotic systems that rely on computational models of the mirror system in their interaction with other agents. Yet, to date, no computational model has explicitly addressed the mechanisms that give rise to both goal-specific and goal-independent parietal mirror neurons. In the present paper, we present a computational model based on a self-organizing map, which receives artificial inputs representing information about both the observed or executed actions and the context in which they were executed. We show that the map develops a biologically plausible organization in which goal-specific mirror neurons emerge. We further show that the fundamental cause for both the appearance and the number of goal-specific neurons can be found in geometric relationships between the different inputs to the map. The results are important to the action-understanding hypothesis as they provide a mechanism for the emergence of goal-specific parietal mirror neurons and lead to a number of predictions: (1) Learning of new goals may mostly reassign existing goal-specific neurons rather than recruit new ones; (2) input differences between executed and observed actions can explain observed corresponding differences in the number of goal-specific neurons; and (3) the percentage of goal-specific neurons may differ between motion primitives.

  4. Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

    Science.gov (United States)

    Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

    2017-11-01

    Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Postnatal Gene Therapy Improves Spatial Learning Despite the Presence of Neuronal Ectopia in a Model of Neuronal Migration Disorder

    Directory of Open Access Journals (Sweden)

    Huaiyu Hu

    2016-11-01

    Full Text Available Patients with type II lissencephaly, a neuronal migration disorder with ectopic neurons, suffer from severe mental retardation, including learning deficits. There is no effective therapy to prevent or correct the formation of neuronal ectopia, which is presumed to cause cognitive deficits. We hypothesized that learning deficits were not solely caused by neuronal ectopia and that postnatal gene therapy could improve learning without correcting the neuronal ectopia formed during fetal development. To test this hypothesis, we evaluated spatial learning of cerebral cortex-specific protein O-mannosyltransferase 2 (POMT2, an enzyme required for O-mannosyl glycosylation knockout mice and compared to the knockout mice that were injected with an adeno-associated viral vector (AAV encoding POMT2 into the postnatal brains with Barnes maze. The data showed that the knockout mice exhibited reduced glycosylation in the cerebral cortex, reduced dendritic spine density on CA1 neurons, and increased latency to the target hole in the Barnes maze, indicating learning deficits. Postnatal gene therapy restored functional glycosylation, rescued dendritic spine defects, and improved performance on the Barnes maze by the knockout mice even though neuronal ectopia was not corrected. These results indicate that postnatal gene therapy improves spatial learning despite the presence of neuronal ectopia.

  6. Neuromorphic Silicon Neuron Circuits

    Science.gov (United States)

    Indiveri, Giacomo; Linares-Barranco, Bernabé; Hamilton, Tara Julia; van Schaik, André; Etienne-Cummings, Ralph; Delbruck, Tobi; Liu, Shih-Chii; Dudek, Piotr; Häfliger, Philipp; Renaud, Sylvie; Schemmel, Johannes; Cauwenberghs, Gert; Arthur, John; Hynna, Kai; Folowosele, Fopefolu; Saighi, Sylvain; Serrano-Gotarredona, Teresa; Wijekoon, Jayawan; Wang, Yingxue; Boahen, Kwabena

    2011-01-01

    Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain–machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance-based Hodgkin–Huxley models to bi-dimensional generalized adaptive integrate and fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips. PMID:21747754

  7. Neuromorphic silicon neuron circuits

    Directory of Open Access Journals (Sweden)

    Giacomo eIndiveri

    2011-05-01

    Full Text Available Hardware implementations of spiking neurons can be extremely useful for a large variety of applications, ranging from high-speed modeling of large-scale neural systems to real-time behaving systems, to bidirectional brain-machine interfaces. The specific circuit solutions used to implement silicon neurons depend on the application requirements. In this paper we describe the most common building blocks and techniques used to implement these circuits, and present an overview of a wide range of neuromorphic silicon neurons, which implement different computational models, ranging from biophysically realistic and conductance based Hodgkin-Huxley models to bi-dimensional generalized adaptive Integrate and Fire models. We compare the different design methodologies used for each silicon neuron design described, and demonstrate their features with experimental results, measured from a wide range of fabricated VLSI chips.

  8. Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex

    Science.gov (United States)

    Joshi, Ankur; Kalappa, Bopanna I.; Anderson, Charles T.

    2016-01-01

    The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. SIGNIFICANCE STATEMENT Acetylcholine (ACh) is crucial for cognitive

  9. The Effects of Motor Neurone Disease on Language: Further Evidence

    Science.gov (United States)

    Bak, Thomas H.; Hodges, John R.

    2004-01-01

    It might sound surprising that Motor Neurone Disease (MND), regarded still by many as the very example of a neurodegenerative disease affecting selectively the motor system and sparing the sensory functions as well as cognition, can have a significant influence on language. In this article we hope to demonstrate that language dysfunction is not…

  10. NeuronBank: a tool for cataloging neuronal circuitry

    Directory of Open Access Journals (Sweden)

    Paul S Katz

    2010-04-01

    Full Text Available The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models.

  11. The Effects of Nicorandil and Nifekalant, Which Were Injected into the Pericardial Space, for Transmural Dispersion of Repolarization in the Pig

    Directory of Open Access Journals (Sweden)

    Hiroyuki Ito, MD

    2007-01-01

    Full Text Available Introduction: Some studies have reported that transmural dispersion of repolarization (TDR is involved in the onset of ventricular arrhythmia. We investigated the effects of nicorandil (NIC and nifekalant (NIF injected into the pericardial space, on TDR and T waves in the pig. Methods and Results: We injected NIC 4 or 8 mg and NIF 50 or 100 mg at intervals into the pericardial space for eleven pigs. The effects of these drugs were investigated on the effective refractory period (ERP between the endocardial and epicardial myocardial cells, as well as on QT time, QT peak-end (QTcpe as an index of TDR, and T waveforms, respectively. QTcpe increased from 91 ± 21 to 116 ± 19 msec, 2.8 min after injection of NIC (p < 0.01, although corrected QT (QTc interval did not changed. But 5.5 min after injection, QTc decreased while QTcpe recovered. T wave amplitude significantly increased, and epicardium ERP decreased. When NIF was injected, TDR decreased from 55 ± 10 msec to 44 ± 8 msec (p < 0.01 although QTc did not change. In a later phase, QTc increased (p < 0.01 and QTcpe recovered. T wave amplitude rapidly decreased and became negative. Conclusion: Injected into the pericardial space, NIC and NIF brought about certain changes in ERP, QT and T waveform. Furthermore, NIC increased TDR while NIF decreased TDR.

  12. A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.

    Science.gov (United States)

    Hug, Bruce; Abbas, Richat; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

    2010-08-01

    Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance. This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo. Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were neratinib. Pharmacokinetic/pharmacodynamic analysis revealed no relationship between neratinib concentrations and QTc interval. No subjects had QTcI, QTcF, or QTcN intervals >450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P neratinib do not prolong the QTc interval in healthy subjects. (c) 2010 AACR.

  13. Language comprehension warps the mirror neuron system

    Directory of Open Access Journals (Sweden)

    Noah eZarr

    2013-12-01

    Full Text Available Is the mirror neuron system (MNS used in language understanding? According to embodied accounts of language comprehension, understanding sentences describing actions makes use of neural mechanisms of action control, including the MNS. Consequently, repeatedly comprehending sentences describing similar actions should induce adaptation of the MNS thereby warping its use in other cognitive processes such as action recognition and prediction. To test this prediction, participants read blocks of multiple sentences where each sentence in the block described transfer of objects in a direction away or toward the reader. Following each block, adaptation was measured by having participants predict the end-point of videotaped actions. The adapting sentences disrupted prediction of actions in the same direction, but a only for videos of biological motion, and b only when the effector implied by the language (e.g., the hand matched the videos. These findings are signatures of the mirror neuron system.

  14. [Effect of intermittent hypoxia of sleep apnea on embryonic rat cortical neurons in vitro].

    Science.gov (United States)

    Zhang, Chanjuan; Li, Yanzhong; Wang, Yan

    2015-05-01

    To investigate the effects of different pattens of intermittent hypoxia on the activity and apoptosis of primary cultured rat embryonic cortical neurons, and to evaluate the role of intermittent hypoxia in the mechanism of obstructive sleep syndrom induced cognitive function loss. The embryonic cerebral cortical neurons were cultured in vitro and were identified by immunofluorescence. Cultured neurons were randomly divided into intermittent hypoxia group, intermittent normal oxygen group, persistent hypoxia group and the control group, and intermittent hypoxia group was divided into five subgroups according to different frequency and time-bound. Neurons were exposed in different modes of hypoxia. MTT colorimetry was used to detect the viability of the neurons, and DAPI colorated measurement was used to calculate the percentages of neuron apoptosis. There were significantly different effects between all subgroups of intermittent hypoxia and the continued hypoxia group on neuronal activity and apoptosis (P Intermittent hypoxia groups with different frequency and time had no difference in neuronal activity and apoptosis (P > 0.05). The effect of intermittent hypoxia was more serious than that of continued hypoxia on neuronal activity and apoptosis; The impact of intermittent hypoxia on neuronal activity and apoptosis may be an important factor in obstructive sleep apnea related cognitive impairment.

  15. Assessing neuronal networks: understanding Alzheimer's disease.

    LENUS (Irish Health Repository)

    Bokde, Arun L W

    2012-02-01

    Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer\\'s disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.

  16. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    Science.gov (United States)

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

  17. Sleep for cognitive enhancement

    Directory of Open Access Journals (Sweden)

    Susanne eDiekelmann

    2014-04-01

    Full Text Available Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i cueing memory reactivation during sleep, (ii stimulating sleep-specific brain oscillations, and (iii targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications.

  18. Novel transcriptional networks regulated by CLOCK in human neurons.

    Science.gov (United States)

    Fontenot, Miles R; Berto, Stefano; Liu, Yuxiang; Werthmann, Gordon; Douglas, Connor; Usui, Noriyoshi; Gleason, Kelly; Tamminga, Carol A; Takahashi, Joseph S; Konopka, Genevieve

    2017-11-01

    The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function. © 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.

  19. The neuronal identity bias behind neocortical GABAergic plasticity.

    Science.gov (United States)

    Allene, Camille; Lourenço, Joana; Bacci, Alberto

    2015-09-01

    In the neocortex, different types of excitatory and inhibitory neurons connect to one another following a detailed blueprint, defining functionally-distinct subnetworks, whose activity and modulation underlie complex cognitive functions. We review the cell-autonomous plasticity of perisomatic inhibition onto principal excitatory neurons. We propose that the tendency of different cortical layers to exhibit depression or potentiation of perisomatic inhibition is dictated by the specific identities of principal neurons (PNs). These are mainly defined by their projection targets and by their preference to be innervated by specific perisomatic-targeting basket cell types. Therefore, principal neurons responsible for relaying information to subcortical nuclei are differentially inhibited and show specific forms of plasticity compared to other PNs that are specialized in more associative functions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Prevention of hypoglycemia-induced neuronal death by minocycline

    Science.gov (United States)

    2012-01-01

    Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients. PMID:22998689

  1. Neuromorphic cognitive systems a learning and memory centered approach

    CERN Document Server

    Yu, Qiang; Hu, Jun; Tan Chen, Kay

    2017-01-01

    This book presents neuromorphic cognitive systems from a learning and memory-centered perspective. It illustrates how to build a system network of neurons to perform spike-based information processing, computing, and high-level cognitive tasks. It is beneficial to a wide spectrum of readers, including undergraduate and postgraduate students and researchers who are interested in neuromorphic computing and neuromorphic engineering, as well as engineers and professionals in industry who are involved in the design and applications of neuromorphic cognitive systems, neuromorphic sensors and processors, and cognitive robotics. The book formulates a systematic framework, from the basic mathematical and computational methods in spike-based neural encoding, learning in both single and multi-layered networks, to a near cognitive level composed of memory and cognition. Since the mechanisms for integrating spiking neurons integrate to formulate cognitive functions as in the brain are little understood, studies of neuromo...

  2. Neuronal avalanches and learning

    Energy Technology Data Exchange (ETDEWEB)

    Arcangelis, Lucilla de, E-mail: dearcangelis@na.infn.it [Department of Information Engineering and CNISM, Second University of Naples, 81031 Aversa (Italy)

    2011-05-01

    Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

  3. Neuronal avalanches and learning

    International Nuclear Information System (INIS)

    Arcangelis, Lucilla de

    2011-01-01

    Networks of living neurons represent one of the most fascinating systems of biology. If the physical and chemical mechanisms at the basis of the functioning of a single neuron are quite well understood, the collective behaviour of a system of many neurons is an extremely intriguing subject. Crucial ingredient of this complex behaviour is the plasticity property of the network, namely the capacity to adapt and evolve depending on the level of activity. This plastic ability is believed, nowadays, to be at the basis of learning and memory in real brains. Spontaneous neuronal activity has recently shown features in common to other complex systems. Experimental data have, in fact, shown that electrical information propagates in a cortex slice via an avalanche mode. These avalanches are characterized by a power law distribution for the size and duration, features found in other problems in the context of the physics of complex systems and successful models have been developed to describe their behaviour. In this contribution we discuss a statistical mechanical model for the complex activity in a neuronal network. The model implements the main physiological properties of living neurons and is able to reproduce recent experimental results. Then, we discuss the learning abilities of this neuronal network. Learning occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. The system is able to learn all the tested rules, in particular the exclusive OR (XOR) and a random rule with three inputs. The learning dynamics exhibits universal features as function of the strength of plastic adaptation. Any rule could be learned provided that the plastic adaptation is sufficiently slow.

  4. Brain Signal Variability Differentially Affects Cognitive Flexibility and Cognitive Stability.

    Science.gov (United States)

    Armbruster-Genç, Diana J N; Ueltzhöffer, Kai; Fiebach, Christian J

    2016-04-06

    Recent research yielded the intriguing conclusion that, in healthy adults, higher levels of variability in neuronal processes are beneficial for cognitive functioning. Beneficial effects of variability in neuronal processing can also be inferred from neurocomputational theories of working memory, albeit this holds only for tasks requiring cognitive flexibility. However, cognitive stability, i.e., the ability to maintain a task goal in the face of irrelevant distractors, should suffer under high levels of brain signal variability. To directly test this prediction, we studied both behavioral and brain signal variability during cognitive flexibility (i.e., task switching) and cognitive stability (i.e., distractor inhibition) in a sample of healthy human subjects and developed an efficient and easy-to-implement analysis approach to assess BOLD-signal variability in event-related fMRI task paradigms. Results show a general positive effect of neural variability on task performance as assessed by accuracy measures. However, higher levels of BOLD-signal variability in the left inferior frontal junction area result in reduced error rate costs during task switching and thus facilitate cognitive flexibility. In contrast, variability in the same area has a detrimental effect on cognitive stability, as shown in a negative effect of variability on response time costs during distractor inhibition. This pattern was mirrored at the behavioral level, with higher behavioral variability predicting better task switching but worse distractor inhibition performance. Our data extend previous results on brain signal variability by showing a differential effect of brain signal variability that depends on task context, in line with predictions from computational theories. Recent neuroscientific research showed that the human brain signal is intrinsically variable and suggested that this variability improves performance. Computational models of prefrontal neural networks predict differential

  5. [Mirror neurons: from anatomy to pathophysiological and therapeutic implications].

    Science.gov (United States)

    Mathon, B

    2013-04-01

    Mirror neurons are a special class of neurons discovered in the 1990s. They respond when we perform an action and also when we see someone else perform that action. They play a role in the pathophysiology of some neuropsychiatric diseases. Mirror neurons have been identified in humans: in Broca's area and the inferior parietal cortex. Their responses are qualitative and selective depending on the observed action. Emotions (including disgust) and empathy seem to operate according to a mirror mechanism. Indeed, the mirror system allows us to encode the sensory experience and to simulate the emotional state of others. This results in our improved identification of the emotions in others. Additionally, mirror neurons can encode an observed action in motor stimuli and allow its reproduction; thus, they are involved in imitation and learning. Current studies are assessing the role of mirror neurons in the pathopysiology of social-behavior disorders, including autism and schizophrenia. Understanding this mirror system will allow us to develop psychotherapy practices based on empathic resonance between the patient and the therapist. Also, some authors report that a passive rehabilitation technique, based on stimulation of the mirror-neuron system, has a beneficial effect in the treatment of patients with post-stroke motor deficits. Mirror neurons are an anatomical entity that enables improved understanding of behavior and emotions, and serves as a base for developing new cognitive therapies. Additional studies are needed to clarify the exact role of this neuronal system in social cognition and its role in the development of some neuropsychiatric diseases. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  6. Reconciling genetic evolution and the associative learning account of mirror neurons through data-acquisition mechanisms.

    Science.gov (United States)

    Lotem, Arnon; Kolodny, Oren

    2014-04-01

    An associative learning account of mirror neurons should not preclude genetic evolution of its underlying mechanisms. On the contrary, an associative learning framework for cognitive development should seek heritable variation in the learning rules and in the data-acquisition mechanisms that construct associative networks, demonstrating how small genetic modifications of associative elements can give rise to the evolution of complex cognition.

  7. ALS and other motor neuron diseases.

    Science.gov (United States)

    Tiryaki, Ezgi; Horak, Holli A

    2014-10-01

    This review describes the most common motor neuron disease, ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its pathophysiology, including new genetic underpinnings of the disease. This article also covers other motor neuron diseases, reviews how to distinguish them from ALS, and discusses their pathophysiology. In this article, the spectrum of cognitive involvement in ALS, new concepts about protein synthesis pathology in the etiology of ALS, and new genetic associations will be covered. This concept has changed over the past 3 to 4 years with the discovery of new genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. The anterior horn cells control all voluntary movement: motor activity, respiratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a "medical home" for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them.

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

    Science.gov (United States)

    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.

  9. Spontaneous Cognition and Epistemic Agency in the Cognitive Niche

    Science.gov (United States)

    Fabry, Regina E.

    2018-01-01

    According to Thomas Metzinger, many human cognitive processes in the waking state are spontaneous and are deprived of the experience of epistemic agency. He considers mind wandering as a paradigm example of our recurring loss of epistemic agency. I will enrich this view by extending the scope of the concept of epistemic agency to include cases of depressive rumination and creative cognition, which are additional types of spontaneous cognition. Like mind wandering, they are characterized by unique phenomenal and functional properties that give rise to varying degrees of epistemic agency. The main claim of this paper will be that the experience of being an epistemic agent within a certain time frame is a relational phenomenon that emerges from the organism’s capacity to interact with its cognitive niche. To explore this relation, I develop a new framework that integrates phenomenological considerations on epistemic agency with a functional account of the reciprocal coupling of the embodied organism with its cognitive niche. This account rests upon dynamical accounts of strong embodied and embedded cognition and recent work on cognitive niche construction. Importantly, epistemic agency and organism-niche coupling are gradual phenomena ranging from weak to strong realizations. The emerging framework will be employed to analyze mind wandering, depressive rumination, and creative cognition as well as their commonalities and differences. Mind wandering and depressive rumination are cases of weak epistemic agency and organism-niche coupling. However, there are also important phenomenological, functional, and neuronal differences. In contrast, creative cognition is a case of strong epistemic agency and organism-niche coupling. By providing a phenomenological and functional analysis of these distinct types of spontaneous cognition, we can gain a better understanding of the importance of organism-niche interaction for the realization of epistemic agency.

  10. Stochastic neuron models

    CERN Document Server

    Greenwood, Priscilla E

    2016-01-01

    This book describes a large number of open problems in the theory of stochastic neural systems, with the aim of enticing probabilists to work on them. This includes problems arising from stochastic models of individual neurons as well as those arising from stochastic models of the activities of small and large networks of interconnected neurons. The necessary neuroscience background to these problems is outlined within the text, so readers can grasp the context in which they arise. This book will be useful for graduate students and instructors providing material and references for applying probability to stochastic neuron modeling. Methods and results are presented, but the emphasis is on questions where additional stochastic analysis may contribute neuroscience insight. An extensive bibliography is included. Dr. Priscilla E. Greenwood is a Professor Emerita in the Department of Mathematics at the University of British Columbia. Dr. Lawrence M. Ward is a Professor in the Department of Psychology and the Brain...

  11. Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

    Directory of Open Access Journals (Sweden)

    Henry James L

    2009-09-01

    Full Text Available Abstract Background Clinical data on osteoarthritis (OA suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons. Results At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. Conclusion These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.

  12. Neuronal Migration and Neuronal Migration Disorder in Cerebral Cortex

    OpenAIRE

    SUN, Xue-Zhi; TAKAHASHI, Sentaro; GUI, Chun; ZHANG, Rui; KOGA, Kazuo; NOUYE, Minoru; MURATA, Yoshiharu

    2002-01-01

    Neuronal cell migration is one of the most significant features during cortical development. After final mitosis, neurons migrate from the ventricular zone into the cortical plate, and then establish neuronal lamina and settle onto the outermost layer, forming an "inside-out" gradient of maturation. Neuronal migration is guided by radial glial fibers and also needs proper receptors, ligands, and other unknown extracellular factors, requests local signaling (e.g. some emitted by the Cajal-Retz...

  13. Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM) and GBM Stem Cells.

    Science.gov (United States)

    Mukherjee, Sumit; Baidoo, Juliet N E; Sampat, Samay; Mancuso, Andrew; David, Lovena; Cohen, Leah S; Zhou, Shuiqin; Banerjee, Probal

    2018-01-18

    Glioblastoma (GBM) is a deadly brain tumor with a current mean survival of 12-15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C) has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E) from green tea and resveratrol (R) from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin) to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM): 32:8:100 (termed 32 μM+ TriCurin). We have now prepared liposomal TriCurin (TrLp) and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM)-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

  14. Safety of transvenous low energy cardioversion of atrial fibrillation in patients with a history of ventricular tachycardia: effects of rate and repolarization time on proarrhythmic risk.

    Science.gov (United States)

    Simons, G R; Newby, K H; Kearney, M M; Brandon, M J; Natale, A

    1998-02-01

    The objective of this study was to assess the safety and efficacy of transvenous low energy cardioversion of atrial fibrillation in patients with ventricular tachycardia and atrial fibrillation and to study the mechanisms of proarrhythmia. Previous studies have demonstrated that cardioversion of atrial fibrillation using low energy, R wave synchronized, direct current shocks applied between catheters in the coronary sinus and right atrium is feasible. However, few data are available regarding the risk of ventricular proarrhythmia posed by internal atrial defibrillation shocks among patients with ventricular arrhythmias or structural heart disease. Atrial defibrillation was performed on 32 patients with monomorphic ventricular tachycardia and left ventricular dysfunction. Shocks were administered during atrial fibrillation (baseline shocks), isoproterenol infusion, ventricular pacing, ventricular tachycardia, and atrial pacing. Baseline shocks were also administered to 29 patients with a history of atrial fibrillation but no ventricular arrhythmias. A total of 932 baseline shocks were administered. No ventricular proarrhythmia was observed after well-synchronized baseline shocks, although rare inductions of ventricular fibrillation occurred after inappropriate T wave sensing. Shocks administered during wide-complex rhythms (ventricular pacing or ventricular tachycardia) frequently induced ventricular arrhythmias, but shocks administered during atrial pacing at identical ventricular rates did not cause proarrhythmia. The risk of ventricular proarrhythmia after well-synchronized atrial defibrillation shocks administered during narrow-complex rhythms is low, even in patients with a history of ventricular tachycardia. The mechanism of proarrhythmia during wide-complex rhythms appears not to be related to ventricular rate per se, but rather to the temporal relationship between shock delivery and the repolarization time of the previous QRS complex.

  15. Liposomal TriCurin, A Synergistic Combination of Curcumin, Epicatechin Gallate and Resveratrol, Repolarizes Tumor-Associated Microglia/Macrophages, and Eliminates Glioblastoma (GBM and GBM Stem Cells

    Directory of Open Access Journals (Sweden)

    Sumit Mukherjee

    2018-01-01

    Full Text Available Glioblastoma (GBM is a deadly brain tumor with a current mean survival of 12–15 months. Despite being a potent anti-cancer agent, the turmeric ingredient curcumin (C has limited anti-tumor efficacy in vivo due to its low bioavailability. We have reported earlier a strategy involving the use two other polyphenols, epicatechin gallate (E from green tea and resveratrol (R from red grapes at a unique, synergistic molar ratio with C (C:E:R: 4:1:12.5, termed TriCurin to achieve superior potency against HPV+ tumors than C alone at C:E:R (μM: 32:8:100 (termed 32 μM+ TriCurin. We have now prepared liposomal TriCurin (TrLp and demonstrated that TrLp boosts activated p53 in cultured GL261 mouse GBM cells to trigger apoptosis of GBM and GBM stem cells in vitro. TrLp administration into mice yielded a stable plasma concentration of 210 nM C for 60 min, which, though sub-lethal for cultured GL261 cells, was able to cause repolarization of M2-like tumor (GBM-associated microglia/macrophages to the tumoricidal M1-like phenotype and intra-GBM recruitment of activated natural killer cells. The intratumor presence of such tumoricidal immune cells was associated with concomitant suppression of tumor-load, and apoptosis of GBM and GBM stem cells. Thus, TrLp is a potential onco-immunotherapeutic agent against GBM tumors.

  16. Changes in prefrontal neuronal activity after learning to perform a spatial working memory task.

    Science.gov (United States)

    Qi, Xue-Lian; Meyer, Travis; Stanford, Terrence R; Constantinidis, Christos

    2011-12-01

    The prefrontal cortex is considered essential for learning to perform cognitive tasks though little is known about how the representation of stimulus properties is altered by learning. To address this issue, we recorded neuronal activity in monkeys before and after training on a task that required visual working memory. After the subjects learned to perform the task, we observed activation of more prefrontal neurons and increased activity during working memory maintenance. The working memory-related increase in firing rate was due mostly to regular-spiking putative pyramidal neurons. Unexpectedly, the selectivity of neurons for stimulus properties and the ability of neurons to discriminate between stimuli decreased as the information about stimulus properties was apparently present in neural firing prior to training and neuronal selectivity degraded after training in the task. The effect was robust and could not be accounted for by differences in sampling sites, selection of neurons, level of performance, or merely the elapse of time. The results indicate that, in contrast to the effects of perceptual learning, mastery of a cognitive task degrades the apparent stimulus selectivity as neurons represent more abstract information related to the task. This effect is countered by the recruitment of more neurons after training.

  17. Mirror neurons and the social nature of language: the neural exploitation hypothesis.

    Science.gov (United States)

    Gallese, Vittorio

    2008-01-01

    This paper discusses the relevance of the discovery of mirror neurons in monkeys and of the mirror neuron system in humans to a neuroscientific account of primates' social cognition and its evolution. It is proposed that mirror neurons and the functional mechanism they underpin, embodied simulation, can ground within a unitary neurophysiological explanatory framework important aspects of human social cognition. In particular, the main focus is on language, here conceived according to a neurophenomenological perspective, grounding meaning on the social experience of action. A neurophysiological hypothesis--the "neural exploitation hypothesis"--is introduced to explain how key aspects of human social cognition are underpinned by brain mechanisms originally evolved for sensorimotor integration. It is proposed that these mechanisms were later on adapted as new neurofunctional architecture for thought and language, while retaining their original functions as well. By neural exploitation, social cognition and language can be linked to the experiential domain of action.

  18. Neuropeptide Y-immunoreactive neurons in the cerebral cortex of humans and other haplorrhine primates

    Science.gov (United States)

    Raghanti, Mary Ann; Conley, Tiffini; Sudduth, Jessica; Erwin, Joseph M.; Stimpson, Cheryl D.; Hof, Patrick R.; Sherwood, Chet C.

    2012-01-01

    We examined the distribution of neurons immunoreactive for neuropeptide Y (NPY) in the posterior part of the superior temporal cortex (Brodmann's area 22 or area Tpt) of humans and nonhuman haplorrhine primates. NPY has been implicated in learning and memory and the density of NPY-expressing cortical neurons and axons is reduced in depression, bipolar disorder, schizophrenia, and Alzheimer's disease. Due to the role that NPY plays in both cognition and neurodegenerative diseases, we tested the hypothesis that the density of cortical and interstitial neurons expressing NPY was increased in humans relative to other primate species. The study sample included great apes (chimpanzee and gorilla), Old World monkeys (pigtailed macaque, moor macaque, and baboon) and New World monkeys (squirrel monkey and capuchin). Stereologic methods were used to estimate the density of NPY-immunoreactive (-ir) neurons in layers I-VI of area Tpt and the subjacent white matter. Adjacent Nissl-stained sections were used to calculate local densities of all neurons. The ratio of NPY-ir neurons to total neurons within area Tpt and the total density of NPY-ir neurons within the white matter were compared among species. Overall, NPY-ir neurons represented only an average of 0.006% of the total neuron population. While there were significant differences among species, phylogenetic trends in NPY-ir neuron distributions were not observed and humans did not differ from other primates. However, variation among species warrants further investigation into the distribution of this neuromodulator system. PMID:23042407

  19. Learning Recruits Neurons Representing Previously Established Associations in the Corvid Endbrain.

    Science.gov (United States)

    Veit, Lena; Pidpruzhnykova, Galyna; Nieder, Andreas

    2017-10-01

    Crows quickly learn arbitrary associations. As a neuronal correlate of this behavior, single neurons in the corvid endbrain area nidopallium caudolaterale (NCL) change their response properties during association learning. In crows performing a delayed association task that required them to map both familiar and novel sample pictures to the same two choice pictures, NCL neurons established a common, prospective code for associations. Here, we report that neuronal tuning changes during learning were not distributed equally in the recorded population of NCL neurons. Instead, such learning-related changes relied almost exclusively on neurons which were already encoding familiar associations. Only in such neurons did behavioral improvements during learning of novel associations coincide with increasing selectivity over the learning process. The size and direction of selectivity for familiar and newly learned associations were highly correlated. These increases in selectivity for novel associations occurred only late in the delay period. Moreover, NCL neurons discriminated correct from erroneous trial outcome based on feedback signals at the end of the trial, particularly in newly learned associations. Our results indicate that task-relevant changes during association learning are not distributed within the population of corvid NCL neurons but rather are restricted to a specific group of association-selective neurons. Such association neurons in the multimodal cognitive integration area NCL likely play an important role during highly flexible behavior in corvids.

  20. Early Visual Cortex as a Multiscale Cognitive Blackboard

    NARCIS (Netherlands)

    Roelfsema, Pieter R.; de Lange, Floris P.

    2016-01-01

    Neurons in early visual cortical areas not only represent incoming visual information but are also engaged by higher level cognitive processes, including attention, working memory, imagery, and decision-making. Are these cognitive effects an epiphenomenon or are they functionally relevant for these

  1. Early visual cortex as a multiscale cognitive blackboard.

    NARCIS (Netherlands)

    Roelfsema, P.R.; De Lange, Floris

    2016-01-01

    Neurons in early visual cortical areas not only represent incoming visual information but are also engaged by higher level cognitive processes, including attention, working memory, imagery, and decision-making. Are these cognitive effects an epiphenomenon or are they functionally relevant for these

  2. Dynamical modeling of the moth pheromone-sensitive olfactory receptor neuron within its sensillar environment.

    Directory of Open Access Journals (Sweden)

    Yuqiao Gu

    Full Text Available In insects, olfactory receptor neurons (ORNs, surrounded with auxiliary cells and protected by a cuticular wall, form small discrete sensory organs--the sensilla. The moth pheromone-sensitive sensillum is a well studied example of hair-like sensillum that is favorable to both experimental and modeling investigations. The model presented takes into account both the molecular processes of ORNs, i.e. the biochemical reactions and ionic currents giving rise to the receptor potential, and the cellular organization and compartmentalization of the organ represented by an electrical circuit. The number of isopotential compartments needed to describe the long dendrite bearing pheromone receptors was determined. The transduction parameters that must be modified when the number of compartments is increased were identified. This model reproduces the amplitude and time course of the experimentally recorded receptor potential. A first complete version of the model was analyzed in response to pheromone pulses of various strengths. It provided a quantitative description of the spatial and temporal evolution of the pheromone-dependent conductances, currents and potentials along the outer dendrite and served to determine the contribution of the various steps in the cascade to its global sensitivity. A second simplified version of the model, utilizing a single depolarizing conductance and leak conductances for repolarizing the ORN, was derived from the first version. It served to analyze the effects on the sensory properties of varying the electrical parameters and the size of the main sensillum parts. The consequences of the results obtained on the still uncertain mechanisms of olfactory transduction in moth ORNs--involvement or not of G-proteins, role of chloride and potassium currents--are discussed as well as the optimality of the sensillum organization, the dependence of biochemical parameters on the neuron spatial extension and the respective contributions

  3. Motor cognition-motor semantics: action perception theory of cognition and communication.

    Science.gov (United States)

    Pulvermüller, Friedemann; Moseley, Rachel L; Egorova, Natalia; Shebani, Zubaida; Boulenger, Véronique

    2014-03-01

    A new perspective on cognition views cortical cell assemblies linking together knowledge about actions and perceptions not only as the vehicles of integrated action and perception processing but, furthermore, as a brain basis for a wide range of higher cortical functions, including attention, meaning and concepts, sequences, goals and intentions, and even communicative social interaction. This article explains mechanisms relevant to mechanistic action perception theory, points to concrete neuronal circuits in brains along with artificial neuronal network simulations, and summarizes recent brain imaging and other experimental data documenting the role of action perception circuits in cognition, language and communication. © 2013 Published by Elsevier Ltd.

  4. Neuronal nets in robotics

    International Nuclear Information System (INIS)

    Jimenez Sanchez, Raul

    1999-01-01

    The paper gives a generic idea of the solutions that the neuronal nets contribute to the robotics. The advantages and the inconveniences are exposed that have regarding the conventional techniques. It also describe the more excellent applications as the pursuit of trajectories, the positioning based on images, the force control or of the mobile robots management, among others

  5. Cognitive Control Signals in Posterior Cingulate Cortex

    Directory of Open Access Journals (Sweden)

    Benjamin eHayden

    2010-12-01

    Full Text Available Efficiently shifting between tasks is a central function of cognitive control. The role of the default network—a constellation of areas with high baseline activity that declines during task performance—in cognitive control remains poorly understood. We hypothesized that task switching demands cognitive control to shift the balance of processing towards the external world, and therefore predicted that switching between the two tasks would require suppression of activity of neurons within the CGp. To test this idea, we recorded the activity of single neurons in posterior cingulate cortex (CGp, a central node in the default network, in monkeys performing two interleaved tasks. As predicted, we found that basal levels of neuronal activity were reduced following a switch from one task to another and gradually returned to pre-switch baseline on subsequent trials. We failed to observe these effects in lateral intraparietal cortex (LIP, part of the dorsal fronto-parietal cortical attention network directly connected to CGp. These findings indicate that suppression of neuronal activity in CGp facilitates cognitive control, and suggest that activity in the default network reflects processes that directly compete with control processes elsewhere in the brain..

  6. Visual cognition

    Energy Technology Data Exchange (ETDEWEB)

    Pinker, S.

    1985-01-01

    This book consists of essays covering issues in visual cognition presenting experimental techniques from cognitive psychology, methods of modeling cognitive processes on computers from artificial intelligence, and methods of studying brain organization from neuropsychology. Topics considered include: parts of recognition; visual routines; upward direction; mental rotation, and discrimination of left and right turns in maps; individual differences in mental imagery, computational analysis and the neurological basis of mental imagery: componental analysis.

  7. Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory.

    Science.gov (United States)

    Benn, Abigail; Barker, Gareth R I; Stuart, Sarah A; Roloff, Eva V L; Teschemacher, Anja G; Warburton, E Clea; Robinson, Emma S J

    2016-05-04

    Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance. These results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal activity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments that enhance the amplitude of EPSPs; however, drugs that alter the duration of the EPSP or increase glutamate release lack efficacy. This suggests that both neural and temporal specificity are needed to achieve cognitive enhancement. Copyright © 2016 Benn et al.

  8. Cognitive Readiness

    National Research Council Canada - National Science Library

    Morrison, John

    2002-01-01

    Cognitive readiness is described as the mental preparation an individual needs to establish and sustain competent performance in the complex and unpredictable environment of modern military operations...

  9. Vasculo-Neuronal Coupling: Retrograde Vascular Communication to Brain Neurons.

    Science.gov (United States)

    Kim, Ki Jung; Ramiro Diaz, Juan; Iddings, Jennifer A; Filosa, Jessica A

    2016-12-14

    Continuous cerebral blood flow is essential for neuronal survival, but whether vascular tone influences resting neuronal function is not known. Using a multidisciplinary approach in both rat and mice brain slices, we determined whether flow/pressure-evoked increases or decreases in parenchymal arteriole vascular tone, which result in arteriole constriction and dilation, respectively, altered resting cortical pyramidal neuron activity. We present evidence for intercellular communication in the brain involving a flow of information from vessel to astrocyte to neuron, a direction opposite to that of classic neurovascular coupling and referred to here as vasculo-neuronal coupling (VNC). Flow/pressure increases within parenchymal arterioles increased vascular tone and simultaneously decreased resting pyramidal neuron firing activity. On the other hand, flow/pressure decreases evoke parenchymal arteriole dilation and increased resting pyramidal neuron firing activity. In GLAST-CreERT2; R26-lsl-GCaMP3 mice, we demonstrate that increased parenchymal arteriole tone significantly increased intracellular calcium in perivascular astrocyte processes, the onset of astrocyte calcium changes preceded the inhibition of cortical pyramidal neuronal firing activity. During increases in parenchymal arteriole tone, the pyramidal neuron response was unaffected by blockers of nitric oxide, GABA A , glutamate, or ecto-ATPase. However, VNC was abrogated by TRPV4 channel, GABA B , as well as an adenosine A 1 receptor blocker. Differently to pyramidal neuron responses, increases in flow/pressure within parenchymal arterioles increased the firing activity of a subtype of interneuron. Together, these data suggest that VNC is a complex constitutive active process that enables neurons to efficiently adjust their resting activity according to brain perfusion levels, thus safeguarding cellular homeostasis by preventing mismatches between energy supply and demand. We present evidence for vessel-to-neuron

  10. [Chewing and cognitive function].

    Science.gov (United States)

    Hirano, Yoshiyuki; Onozuka, Minoru

    2014-01-01

    Chewing does not only crush food to aid swallowing and digestion; it also helps to relieve stress and regulate cognitive functions, including alertness and executive function. It is well known that chewing gum is used for sleepiness prevention during work, learning, and driving. In addition, it has been shown in the elderly that a decrease in the number of residual teeth is related to dementia onset. These findings suggest a link between chewing and maintaining memory and attention. Recently, many studies regarding the effects of chewing on memory and attention were conducted using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). When a working memory task was used, the middle frontal gyrus in the dorsolateral prefrontal cortex showed greater activation in addition to producing higher alertness after chewing. Furthermore, using an attentional network test, reaction time shortened, and the anterior cingulate cortex and left frontal gyrus were both activated for the executive network. From these results, it is suggested that chewing elevates alertness, consequently leading to improvements in cognitive performance. In this review, we introduce findings concerning the effects of chewing on cognitive performance, and discuss the neuronal mechanisms underlying these effects.

  11. Cognitive anthropology is a cognitive science.

    Science.gov (United States)

    Boster, James S

    2012-07-01

    Cognitive anthropology contributes to cognitive science as a complement to cognitive psychology. The chief threat to its survival has not been rejection by other cognitive scientists but by other cultural anthropologists. It will remain a part of cognitive science as long as cognitive anthropologists research, teach, and publish. Copyright © 2012 Cognitive Science Society, Inc.

  12. Adult hippocampal neurogenesis and cognitive aging

    Directory of Open Access Journals (Sweden)

    Román Darío Moreno Fernández

    2013-12-01

    Full Text Available Aging is a normal developmental process associated with neurobiological changes leading to cognitive alterations with preserved, impaired, and enhanced functions. Evidence from animal and human studies is reviewed to explore the potential role of hippocampal plasticity on age-related cognitive changes with special attention to adult hippocampal neurogenesis. Results from lesion and stimulation strategies, as well as correlation data, support either a direct or modulatory role for adult newborn neurons in cognition at advanced ages. Further research on this topic may help to develop new treatments and to improve the quality of life of older people.

  13. Neuronal survival in the brain: neuron type-specific mechanisms

    DEFF Research Database (Denmark)

    Pfisterer, Ulrich Gottfried; Khodosevich, Konstantin

    2017-01-01

    Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial...... numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether...... for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various...

  14. Subtype-Specific Corticostriatal Projection Neuron Developmental Gene Expression and Corticospinal Expression of the Paroxysmal Nonkinesigenic Dyskinesia Gene

    OpenAIRE

    Xu, Zhaoying

    2016-01-01

    The mammalian neocortex is responsible for motor control, integration of sensory information, perception, cognitive function, and consciousness. It is complex, yet highly organized, with six layers containing broad classes of excitatory projection neurons (along with interneurons) with diverse subtype and area identities. Corticostriatal projection neurons (CStrPN) are the major cortical efferent neurons connecting the cerebral cortex to the striatum of the basal ganglia, and are critically i...

  15. Coordinated scaling of cortical and cerebellar numbers of neurons

    Directory of Open Access Journals (Sweden)

    Suzana Herculano-Houzel

    2010-03-01

    Full Text Available While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of 4 different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora, Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.

  16. The infant mirror neuron system studied with high density EEG.

    Science.gov (United States)

    Nyström, Pär

    2008-01-01

    The mirror neuron system has been suggested to play a role in many social capabilities such as action understanding, imitation, language and empathy. These are all capabilities that develop during infancy and childhood, but the human mirror neuron system has been poorly studied using neurophysiological measures. This study measured the brain activity of 6-month-old infants and adults using a high-density EEG net with the aim of identifying mirror neuron activity. The subjects viewed both goal-directed movements and non-goal-directed movements. An independent component analysis was used to extract the sources of cognitive processes. The desynchronization of the mu rhythm in adults has been shown to be a marker for activation of the mirror neuron system and was used as a criterion to categorize independent components between subjects. The results showed significant mu desynchronization in the adult group and significantly higher ERP activation in both adults and 6-month-olds for the goal-directed action observation condition. This study demonstrate that infants as young as 6 months display mirror neuron activity and is the first to present a direct ERP measure of the mirror neuron system in infants.

  17. Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy.

    Directory of Open Access Journals (Sweden)

    Franziska Altmüller

    2017-03-01

    Full Text Available Noonan syndrome (NS is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity

  18. Neuronal synchrony: peculiarity and generality.

    Science.gov (United States)

    Nowotny, Thomas; Huerta, Ramon; Rabinovich, Mikhail I

    2008-09-01

    Synchronization in neuronal systems is a new and intriguing application of dynamical systems theory. Why are neuronal systems different as a subject for synchronization? (1) Neurons in themselves are multidimensional nonlinear systems that are able to exhibit a wide variety of different activity patterns. Their "dynamical repertoire" includes regular or chaotic spiking, regular or chaotic bursting, multistability, and complex transient regimes. (2) Usually, neuronal oscillations are the result of the cooperative activity of many synaptically connected neurons (a neuronal circuit). Thus, it is necessary to consider synchronization between different neuronal circuits as well. (3) The synapses that implement the coupling between neurons are also dynamical elements and their intrinsic dynamics influences the process of synchronization or entrainment significantly. In this review we will focus on four new problems: (i) the synchronization in minimal neuronal networks with plastic synapses (synchronization with activity dependent coupling), (ii) synchronization of bursts that are generated by a group of nonsymmetrically coupled inhibitory neurons (heteroclinic synchronization), (iii) the coordination of activities of two coupled neuronal networks (partial synchronization of small composite structures), and (iv) coarse grained synchronization in larger systems (synchronization on a mesoscopic scale). (c) 2008 American Institute of Physics.

  19. Visual cognition

    Energy Technology Data Exchange (ETDEWEB)

    Pinker, S.

    1985-01-01

    This collection of research papers on visual cognition first appeared as a special issue of Cognition: International Journal of Cognitive Science. The study of visual cognition has seen enormous progress in the past decade, bringing important advances in our understanding of shape perception, visual imagery, and mental maps. Many of these discoveries are the result of converging investigations in different areas, such as cognitive and perceptual psychology, artificial intelligence, and neuropsychology. This volume is intended to highlight a sample of work at the cutting edge of this research area for the benefit of students and researchers in a variety of disciplines. The tutorial introduction that begins the volume is designed to help the nonspecialist reader bridge the gap between the contemporary research reported here and earlier textbook introductions or literature reviews.

  20. Cognitive Systems

    DEFF Research Database (Denmark)

    The tutorial will discuss the definition of cognitive systems as the possibilities to extend the current systems engineering paradigm in order to perceive, learn, reason and interact robustly in open-ended changing environments. I will also address cognitive systems in a historical perspective...... to be modeled within a limited set of predefined specifications. There will inevitably be a need for robust decisions and behaviors in novel situations that include handling of conflicts and ambiguities based on the capability and knowledge of the artificial cognitive system. Further, there is a need...... in cognitive systems include e.g. personalized information systems, sensor network systems, social dynamics system and Web2.0, and cognitive components analysis. I will use example from our own research and link to other research activities....

  1. Cognitive remission

    DEFF Research Database (Denmark)

    Bortolato, Beatrice; Miskowiak, Kamilla W; Köhler, Cristiano A

    2016-01-01

    BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted...... phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD....... DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal...

  2. From Neurons to Newtons

    DEFF Research Database (Denmark)

    Nielsen, Bjørn Gilbert

    2001-01-01

    proteins generate forces, to the macroscopic levels where overt arm movements are vol- untarily controlled within an unpredictable environment by legions of neurons¯ring in orderly fashion. An extensive computer simulation system has been developed for this thesis, which at present contains a neural...... network scripting language for specifying arbitrary neural architectures, de¯nition ¯les for detailed spinal networks, various biologically realistic models of neurons, and dynamic synapses. Also included are structurally accurate models of intrafusal and extra-fusal muscle ¯bers and a general body...... that an explicit function may be derived which expresses the force that the spindle contractile elements must produce to exactly counter spindle unloading during muscle shortening. This information was used to calculate the corresponding "optimal" °-motoneuronal activity level. For some simple arm movement tasks...

  3. Criticality in Neuronal Networks

    Science.gov (United States)

    Friedman, Nir; Ito, Shinya; Brinkman, Braden A. W.; Shimono, Masanori; Deville, R. E. Lee; Beggs, John M.; Dahmen, Karin A.; Butler, Tom C.

    2012-02-01

    In recent years, experiments detecting the electrical firing patterns in slices of in vitro brain tissue have been analyzed to suggest the presence of scale invariance and possibly criticality in the brain. Much of the work done however has been limited in two ways: 1) the data collected is from local field potentials that do not represent the firing of individual neurons; 2) the analysis has been primarily limited to histograms. In our work we examine data based on the firing of individual neurons (spike data), and greatly extend the analysis by considering shape collapse and exponents. Our results strongly suggest that the brain operates near a tuned critical point of a highly distinctive universality class.

  4. Actions of the pyrethroid insecticide bifenthrin on sodium channels expressed in rat cerebral cortical neurons.

    Science.gov (United States)

    Yang, Lin; Li, Li

    2015-01-01

    Voltage-gated sodium channels are important sites for the neurotoxic actions of pyrethroid insecticides in mammals. Here, we studied the mode of action of bifenthrin on the native sodium channels in cerebral cortical neurons prepared from newborn rat brain, where the toxic effects are largely generated. Bifenthrin caused a pronounced late current that persisted at the end of a depolarizing pulse, a slowly-decaying tail current following repolarization and significant resting modification (25.3% modification at 10 μM). No significant bifenthrin-induced effect was observed at the peak current. Bifenthrin also caused a concentration-dependent hyperpolarizing shift in steady-state activation and inactivation as well as slowed recovery from channel inactivation. Repetitive depolarization increased the potency of bifenthrin with high frequency. There was approximately 64% inhibition of modification upon repetitive activation by 10-Hz trains of depolarizing pulses. These results suggest that bifenthrin binds to and modifies sodium channels in both the closed and open states and exhibits the behavior between type I and type II.

  5. Cognitive Effects and Sedation.

    Science.gov (United States)

    Dhingra, Lara; Ahmed, Ebtesam; Shin, Jae; Scharaga, Elyssa; Magun, Maximilian

    2015-10-01

    Cognitive effects and sedation (CES) are prevalent in chronic nonmalignant pain populations receiving long-term opioid therapy and are among the most common reasons patients discontinue opioid use. In this narrative review, we describe the phenomenology, epidemiology, mechanisms, assessment, and management of opioid-related CES. We reviewed the empirical and theoretical literature on CES in opioid-treated populations with chronic pain. Data on long-term opioid therapy (≥ 3 months in duration) in chronic nonmalignant pain patients were sought. The phenomenology of CES includes: inattention, concentration difficulties, memory deficits, psychomotor dysfunction, perceptual distortions, and executive dysfunction and somnolence, sleep disorders, and lethargy. Deficits may be caused by unrelieved pain or opioid therapy alone, or from a combination of these and other factors. Mechanisms include central nervous system effects, for example, direct toxic effects on neurons resulting in decreased consciousness; direct effects on processing and reaction resulting in cognitive or psychomotor impairment, and inhibitory effects on cholinergic activity. Pharmacological management approaches may include opioid dose reduction and rotation or psychostimulant use. Nonpharmacological approaches may include cognitive-behavioral therapy, mindfulness-based stress reduction, acupuncture, exercise, and yoga. The most prevalent CES include: memory deficits (73-81%), sleep disturbance (35-57%), and fatigue (10%). At its most severe, extreme cognitive dysfunction can result in frank delirium and decreased alertness can result in coma. Emotional distress, sleep disorders, and other comorbidities and treatments can worsen CES, particularly among the elderly. Conclusions about the neuropsychological domains affected by opioids are limited due to the heterogeneity of studies and methodological issues. Wiley Periodicals, Inc.

  6. Orexin receptor activation generates gamma band input to cholinergic and serotonergic arousal system neurons and drives an intrinsic Ca2+-dependent resonance in LDT and PPT cholinergic neurons.

    Directory of Open Access Journals (Sweden)

    Masaru eIshibashi

    2015-06-01

    Full Text Available A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT and pedunculopontine (PPT tegmental neurons and serotonergic dorsal raphe (DR neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca2+-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal targets. Since key arousal input arises from hypothalamic orexin (hypocretin neurons, we investigated whether the unusually noisy, depolarizing orexin current could provide significant gamma input to cholinergic and serotonergic neurons, and whether such input could drive Ca2+-dependent oscillations. Whole-cell recordings in brain slices were obtained from mice expressing Cre-induced fluorescence in cholinergic LDT and PPT, and serotonergic DR neurons. After first quantifying reporter expression accuracy in cholinergic and serotonergic neurons, we found that the orexin current produced significant high frequency, including gamma, input to both cholinergic and serotonergic neurons. Then, by using a dynamic clamp, we found that adding a noisy orexin conductance to cholinergic neurons induced a Ca2+-dependent resonance that peaked in the theta and alpha frequency range (4 - 14 Hz and extended up to 100 Hz. We propose that this orexin current noise and the Ca2+ dependent resonance work synergistically to boost the encoding of high-frequency synaptic inputs into action potentials and to help ensure cholinergic neurons fire during EEG activation. This activity could reinforce thalamocortical states supporting arousal, REM sleep and intracortical

  7. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

    Science.gov (United States)

    Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling; Kelver, Daniel A; Fiske, Michael P; Glajch, Kelly E; Pitt, Jason E; Huang, Tina Y; Justice, Nicholas J; Chan, C Savio

    2015-08-26

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the

  8. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

    Science.gov (United States)

    Hernández, Vivian M.; Hegeman, Daniel J.; Cui, Qiaoling; Kelver, Daniel A.; Fiske, Michael P.; Glajch, Kelly E.; Pitt, Jason E.; Huang, Tina Y.; Justice, Nicholas J.

    2015-01-01

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping

  9. Metabolic reprogramming during neuronal differentiation.

    Science.gov (United States)

    Agostini, M; Romeo, F; Inoue, S; Niklison-Chirou, M V; Elia, A J; Dinsdale, D; Morone, N; Knight, R A; Mak, T W; Melino, G

    2016-09-01

    Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.

  10. Morphological differences in the mirror neuron system in Williams Syndrome

    OpenAIRE

    Ng, Rowena; Brown, Timothy T.; Erhart, Matthew; Järvinen, Anna M.; Korenberg, Julie R.; Bellugi, Ursula; Halgren, Eric

    2015-01-01

    Williams syndrome (WS) is a genetic condition characterized by an overly gregarious personality, including high empathetic concern for others. Although seemingly disparate from the profile of autism spectrum disorder (ASD), both are associated with deficits in social communication/cognition. Notably, the mirror neuron system (MNS) has been implicated in social dysfunction for ASD; yet, the integrity of this network and its association with social functioning in WS remains unknown. Magnetic re...

  11. α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons.

    Science.gov (United States)

    Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos; Vaden, Jada H; Mclean, John W; Wu, Yumei; Banumurthy, Gokulakrishna; Overstreet-Wadiche, Linda; Herskowitz, Jeremy H; Volpicelli-Daley, Laura A

    2018-05-01

    Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca 2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.

  12. Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice

    Directory of Open Access Journals (Sweden)

    Li Xiang-Yao

    2012-07-01

    Full Text Available Abstract The neurons in neocortex layer I (LI provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies were reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC, a key cortical area for sensory and cognitive functions, by using whole-cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all of the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay-sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP, named ADP1 and ADP2, respectively. Using pharmacological approaches, we found that LI neurons received both excitatory (mediated by AMPA, kainate and NMDA receptors, and inhibitory inputs (which were mediated by GABAA receptors. Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice.

  13. Embodying cognition

    DEFF Research Database (Denmark)

    Martiny, Kristian Møller Moltke; Aggerholm, Kenneth

    2016-01-01

    During the last decades, research on cognition has undergone a reformation, which is necessary to take into account when evaluating the cognitive and behavioural aspects of therapy. This reformation is due to the research programme called Embodied Cognition (EC). Although EC may have become...... the theoretical authority in current cognitive science, there are only sporadic examples of EC-based therapy, and no established framework. We aim to build such a framework on the aims, methods and techniques of the current third-wave of CBT. There appears to be a possibility for cross-fertilization between EC...... and CBT that could contribute to the development of theory and practice for both of them. We present a case-study of an EC-based model of intervention for working with self-control in cerebral palsy.We centre the results of the study and its discussion on how we should understand and work with self...

  14. Environmental Cognition.

    Science.gov (United States)

    Evans, Gary W.

    1980-01-01

    Research is reviewed on human spatial cognition in real, everyday settings and is organized into five empirical categories: age, familiarity, gender, class and culture, and physical components of settings. (Author/DB)

  15. Moral Cognition

    NARCIS (Netherlands)

    Schleim, Stephan; Clausen, Jens; Levy, Neil

    2015-01-01

    Research on moral cognition is a growing and heavily multidisciplinary field. This section contains chapters addressing foundational psychological, neuroscientific, and philosophical issues of research on moral decision-making. Further- more, beyond summarizing the state of the art of their

  16. Cognitive Function

    Science.gov (United States)

    Because chemicals can adversely affect cognitive function in humans, considerable effort has been made to characterize their effects using animal models. Information from such models will be necessary to: evaluate whether chemicals identified as potentially neurotoxic by screenin...

  17. Cognitive Challenges

    Science.gov (United States)

    ... Alliance Our Story Our Vision Our Team Our Leadership Our Results Our Corporate Policies FAQs Careers Contact Us Media Store Privacy Policy Sitemap Learn Engage Donate About TSC Cognitive Challenges Approximately 45% to 60% of individuals with TSC ...

  18. Cognitive technologies

    CERN Document Server

    Mello, Alan; Figueiredo, Fabrício; Figueiredo, Rafael

    2017-01-01

    This book focuses on the next generation optical networks as well as mobile communication technologies. The reader will find chapters on Cognitive Optical Network, 5G Cognitive Wireless, LTE, Data Analysis and Natural Language Processing. It also presents a comprehensive view of the enhancements and requirements foreseen for Machine Type Communication. Moreover, some data analysis techniques and Brazilian Portuguese natural language processing technologies are also described here. .

  19. Fish cognition

    OpenAIRE

    Bshary, Redouan; Brown, Culum

    2017-01-01

    The central nervous system, and the brain in particular, is one of the most remarkable products of evolution. This system allows an individual to acquire, process, store and act on information gathered from the environment. The resulting flexibility in behavior beyond genetically coded strategies is a prime adaptation in animals. The field of animal cognition examines the underlying processes and mechanisms. Fishes are a particularly interesting group of vertebrates to study cognition for two...

  20. Associative learning alone is insufficient for the evolution and maintenance of the human mirror neuron system.

    Science.gov (United States)

    Oberman, Lindsay M; Hubbard, Edward M; McCleery, Joseph P

    2014-04-01

    Cook et al. argue that mirror neurons originate from associative learning processes, without evolutionary influence from social-cognitive mechanisms. We disagree with this claim and present arguments based upon cross-species comparisons, EEG findings, and developmental neuroscience that the evolution of mirror neurons is most likely driven simultaneously and interactively by evolutionarily adaptive psychological mechanisms and lower-level biological mechanisms that support them.

  1. Visual cognition.

    Science.gov (United States)

    Cavanagh, Patrick

    2011-07-01

    Visual cognition, high-level vision, mid-level vision and top-down processing all refer to decision-based scene analyses that combine prior knowledge with retinal input to generate representations. The label "visual cognition" is little used at present, but research and experiments on mid- and high-level, inference-based vision have flourished, becoming in the 21st century a significant, if often understated part, of current vision research. How does visual cognition work? What are its moving parts? This paper reviews the origins and architecture of visual cognition and briefly describes some work in the areas of routines, attention, surfaces, objects, and events (motion, causality, and agency). Most vision scientists avoid being too explicit when presenting concepts about visual cognition, having learned that explicit models invite easy criticism. What we see in the literature is ample evidence for visual cognition, but few or only cautious attempts to detail how it might work. This is the great unfinished business of vision research: at some point we will be done with characterizing how the visual system measures the world and we will have to return to the question of how vision constructs models of objects, surfaces, scenes, and events. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. The biophysics of neuronal growth

    International Nuclear Information System (INIS)

    Franze, Kristian; Guck, Jochen

    2010-01-01

    For a long time, neuroscience has focused on biochemical, molecular biological and electrophysiological aspects of neuronal physiology and pathology. However, there is a growing body of evidence indicating the importance of physical stimuli for neuronal growth and development. In this review we briefly summarize the historical background of neurobiophysics and give an overview over the current understanding of neuronal growth from a physics perspective. We show how biophysics has so far contributed to a better understanding of neuronal growth and discuss current inconsistencies. Finally, we speculate how biophysics may contribute to the successful treatment of lesions to the central nervous system, which have been considered incurable until very recently.

  3. Vitamin C Status and Cognitive Function: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Nikolaj Travica

    2017-08-01

    Full Text Available Vitamin C plays a role in neuronal differentiation, maturation, myelin formation and modulation of the cholinergic, catecholinergic, and glutaminergic systems. This review evaluates the link between vitamin C status and cognitive performance, in both cognitively intact and impaired individuals. We searched the PUBMED, SCOPUS, SciSearch and the Cochrane Library from 1980 to January 2017, finding 50 studies, with randomised controlled trials (RCTs, n = 5, prospective (n = 24, cross-sectional (n = 17 and case-control (n = 4 studies. Of these, 36 studies were conducted in healthy participants and 14 on cognitively impaired individuals (including Alzheimer’s and dementia. Vitamin C status was measured using food frequency questionnaires or plasma vitamin C. Cognition was assessed using a variety of tests, mostly the Mini-Mental-State-Examination (MMSE. In summary, studies demonstrated higher mean vitamin C concentrations in the cognitively intact groups of participants compared to cognitively impaired groups. No correlation between vitamin C concentrations and MMSE cognitive function was apparent in the cognitively impaired individuals. The MMSE was not suitable to detect a variance in cognition in the healthy group. Analysis of the studies that used a variety of cognitive assessments in the cognitively intact was beyond the scope of this review; however, qualitative assessment revealed a potential association between plasma vitamin C concentrations and cognition. Due to a number of limitations in these studies, further research is needed, utilizing plasma vitamin C concentrations and sensitive cognitive assessments that are suitable for cognitively intact adults.

  4. Neuron-microglia interactions in mental health disorders: 'For better, and for worse'

    Directory of Open Access Journals (Sweden)

    Eric S Wohleb

    2016-11-01

    Full Text Available Persistent cognitive and behavioral symptoms that characterize many mental health disorders arise from impaired neuroplasticity in several key corticolimbic brain regions. Recent evidence suggest that reciprocal neuron-microglia interactions shape neuroplasticity during physiological conditions, implicating microglia in the neurobiology of mental health disorders. Neuron-microglia interactions are modulated by several molecular and cellular pathways and dysregulation of these pathways often have neurobiological consequences, including aberrant neuronal responses and microglia activation. The interactions between neurons and microglia have implications for mental health disorders as rodent stress models cause concomitant neuronal dystrophy and alterations in microglia morphology and function. In this context, functional changes in microglia may be indicative of an immune state termed parainflammation in which tissue-resident macrophages (i.e., microglia respond to malfunctioning cells by initiating modest inflammation in an attempt to restore homeostasis. Thus, aberrant neuronal activity and release of damage-associated signals during repeated stress exposure may contribute to functional changes in microglia and resultant parainflammation. Furthermore, accumulating evidence shows that uncoupling neuron-microglia interactions may contribute to altered neuroplasticity and associated anxiety- or depressive-like behaviors. Additional work shows that microglia have varied phenotypes in specific brain regions, which may underlie divergent neuroplasticity observed in corticolimbic structures following stress exposure. These findings indicate that neuron-microglia interactions are critical mediators of the interface between adaptive, homeostatic neuronal function and the neurobiology of mental health disorders.

  5. Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

    Science.gov (United States)

    Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

    2017-11-17

    The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. All-memristive neuromorphic computing with level-tuned neurons

    Science.gov (United States)

    Pantazi, Angeliki; Woźniak, Stanisław; Tuma, Tomas; Eleftheriou, Evangelos

    2016-09-01

    In the new era of cognitive computing, systems will be able to learn and interact with the environment in ways that will drastically enhance the capabilities of current processors, especially in extracting knowledge from vast amount of data obtained from many sources. Brain-inspired neuromorphic computing systems increasingly attract research interest as an alternative to the classical von Neumann processor architecture, mainly because of the coexistence of memory and processing units. In these systems, the basic components are neurons interconnected by synapses. The neurons, based on their nonlinear dynamics, generate spikes that provide the main communication mechanism. The computational tasks are distributed across the neural network, where synapses implement both the memory and the computational units, by means of learning mechanisms such as spike-timing-dependent plasticity. In this work, we present an all-memristive neuromorphic architecture comprising neurons and synapses realized by using the physical properties and state dynamics of phase-change memristors. The architecture employs a novel concept of interconnecting the neurons in the same layer, resulting in level-tuned neuronal characteristics that preferentially process input information. We demonstrate the proposed architecture in the tasks of unsupervised learning and detection of multiple temporal correlations in parallel input streams. The efficiency of the neuromorphic architecture along with the homogenous neuro-synaptic dynamics implemented with nanoscale phase-change memristors represent a significant step towards the development of ultrahigh-density neuromorphic co-processors.

  7. All-memristive neuromorphic computing with level-tuned neurons.

    Science.gov (United States)

    Pantazi, Angeliki; Woźniak, Stanisław; Tuma, Tomas; Eleftheriou, Evangelos

    2016-09-02

    In the new era of cognitive computing, systems will be able to learn and interact with the environment in ways that will drastically enhance the capabilities of current processors, especially in extracting knowledge from vast amount of data obtained from many sources. Brain-inspired neuromorphic computing systems increasingly attract research interest as an alternative to the classical von Neumann processor architecture, mainly because of the coexistence of memory and processing units. In these systems, the basic components are neurons interconnected by synapses. The neurons, based on their nonlinear dynamics, generate spikes that provide the main communication mechanism. The computational tasks are distributed across the neural network, where synapses implement both the memory and the computational units, by means of learning mechanisms such as spike-timing-dependent plasticity. In this work, we present an all-memristive neuromorphic architecture comprising neurons and synapses realized by using the physical properties and state dynamics of phase-change memristors. The architecture employs a novel concept of interconnecting the neurons in the same layer, resulting in level-tuned neuronal characteristics that preferentially process input information. We demonstrate the proposed architecture in the tasks of unsupervised learning and detection of multiple temporal correlations in parallel input streams. The efficiency of the neuromorphic architecture along with the homogenous neuro-synaptic dynamics implemented with nanoscale phase-change memristors represent a significant step towards the development of ultrahigh-density neuromorphic co-processors.

  8. The pairwise phase consistency in cortical network and its relationship with neuronal activation

    Directory of Open Access Journals (Sweden)

    Wang Daming

    2017-01-01

    Full Text Available Gamma-band neuronal oscillation and synchronization with the range of 30-90 Hz are ubiquitous phenomenon across numerous brain areas and various species, and correlated with plenty of cognitive functions. The phase of the oscillation, as one aspect of CTC (Communication through Coherence hypothesis, underlies various functions for feature coding, memory processing and behaviour performing. The PPC (Pairwise Phase Consistency, an improved coherence measure, statistically quantifies the strength of phase synchronization. In order to evaluate the PPC and its relationships with input stimulus, neuronal activation and firing rate, a simplified spiking neuronal network is constructed to simulate orientation columns in primary visual cortex. If the input orientation stimulus is preferred for a certain orientation column, neurons within this corresponding column will obtain higher firing rate and stronger neuronal activation, which consequently engender higher PPC values, with higher PPC corresponding to higher firing rate. In addition, we investigate the PPC in time resolved analysis with a sliding window.

  9. Mirror neurons and their clinical relevance.

    Science.gov (United States)

    Rizzolatti, Giacomo; Fabbri-Destro, Maddalena; Cattaneo, Luigi

    2009-01-01

    One of the most exciting events in neurosciences over the past few years has been the discovery of a mechanism that unifies action perception and action execution. The essence of this 'mirror' mechanism is as follows: whenever individuals observe an action being done by someone else, a set of neurons that code for that action is activated in the observers' motor system. Since the observers are aware of the outcome of their motor acts, they also understand what the other individual is doing without the need for intermediate cognitive mediation. In this Review, after discussing the most pertinent data concerning the mirror mechanism, we examine the clinical relevance of this mechanism. We first discuss the relationship between mirror mechanism impairment and some core symptoms of autism. We then outline the theoretical principles of neurorehabilitation strategies based on the mirror mechanism. We conclude by examining the relationship between the mirror mechanism and some features of the environmental dependency syndromes.

  10. Language comprehension warps the mirror neuron system.

    Science.gov (United States)

    Zarr, Noah; Ferguson, Ryan; Glenberg, Arthur M

    2013-01-01

    Is the mirror neuron system (MNS) used in language understanding? According to embodied accounts of language comprehension, understanding sentences describing actions makes use of neural mechanisms of action control, including the MNS. Consequently, repeatedly comprehending sentences describing similar actions should induce adaptation of the MNS thereby warping its use in other cognitive processes such as action recognition and prediction. To test this prediction, participants read blocks of multiple sentences where each sentence in the block described transfer of objects in a direction away or toward the reader. Following each block, adaptation was measured by having participants predict the end-point of videotaped actions. The adapting sentences disrupted prediction of actions in the same direction, but (a) only for videos of biological motion, and (b) only when the effector implied by the language (e.g., the hand) matched the videos. These findings are signatures of the MNS.

  11. Connecting mirror neurons and forward models.

    Science.gov (United States)

    Miall, R C

    2003-12-02

    Two recent developments in motor neuroscience are promising the extension of theoretical concepts from motor control towards cognitive processes, including human social interactions and understanding the intentions of others. The first of these is the discovery of what are now called mirror neurons, which code for both observed and executed actions. The second is the concept of internal models, and in particular recent proposals that forward and inverse models operate in paired modules. These two ideas will be briefly introduced, and a recent suggestion linking between the two processes of mirroring and modelling will be described which may underlie our abilities for imitating actions, for cooperation between two actors, and possibly for communication via gesture and language.

  12. Insulin reduces neuronal excitability by turning on GABA(A channels that generate tonic current.

    Directory of Open Access Journals (Sweden)

    Zhe Jin

    Full Text Available Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid decreases neuronal excitability by activating GABA(A channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocampal slices that insulin (1 nM "turns on" new extrasynaptic GABA(A channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50 in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

  13. Human cognition

    International Nuclear Information System (INIS)

    Norman, D.A.

    1982-01-01

    The study of human cognition encompasses the study of all mental phenomena, from the receipt and interpretation of sensory information to the final control of the motor system in the performance of action. The cognitive scientist examines all intermediary processes, including thought, decision making, and memory and including the effects of motivation, states of arousal and stress, the study of language, and the effects of social factors. The field therefore ranges over an enormous territory, covering all that is known or that should be known about human behavior. It is not possible to summarize the current state of knowledge about cognition with any great confidence that we know the correct answer about any aspect of the work. Nontheless, models provide good characterizations of certain aspects of the data and situations. Even if these models should prove to be incorrect, they do provide good approximate descriptions of people's behavior in some situations, and these approximations will still apply even when the underlying theories have changed. A quick description is provided of models within a number of areas of human cognition and skill and some general theoretical frameworks with which to view human cognition. The frameworks are qualitative descriptions that provide a way to view the development of more detailed, quantitative models and, most important, a way of thinking about human performance and skill

  14. Visual cognition

    Science.gov (United States)

    Cavanagh, Patrick

    2011-01-01

    Visual cognition, high-level vision, mid-level vision and top-down processing all refer to decision-based scene analyses that combine prior knowledge with retinal input to generate representations. The label “visual cognition” is little used at present, but research and experiments on mid- and high-level, inference-based vision have flourished, becoming in the 21st century a significant, if often understated part, of current vision research. How does visual cognition work? What are its moving parts? This paper reviews the origins and architecture of visual cognition and briefly describes some work in the areas of routines, attention, surfaces, objects, and events (motion, causality, and agency). Most vision scientists avoid being too explicit when presenting concepts about visual cognition, having learned that explicit models invite easy criticism. What we see in the literature is ample evidence for visual cognition, but few or only cautious attempts to detail how it might work. This is the great unfinished business of vision research: at some point we will be done with characterizing how the visual system measures the world and we will have to return to the question of how vision constructs models of objects, surfaces, scenes, and events. PMID:21329719

  15. Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

    Science.gov (United States)

    Toriumi, Kazuya; Mouri, Akihiro; Narusawa, Shiho; Aoyama, Yuki; Ikawa, Natsumi; Lu, Lingling; Nagai, Taku; Mamiya, Takayoshi; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2012-01-01

    N-methyl--aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression. PMID:22257896

  16. Activation of the Basal Forebrain by the Orexin/Hypocretin Neurons: Orexin International Symposium

    Science.gov (United States)

    Arrigoni, Elda; Mochizuki, Takatoshi; Scammell, Thomas E.

    2010-01-01

    The orexin neurons play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurons promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurons may promote arousal by exciting cortically-projecting neurons of the BF. Orexin fibers synapse on BF cholinergic neurons and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurons, induces cortical release of acetylcholine, and promotes wakefulness. The orexin neurons also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurons that project to the cortex. Cholinergic neurons were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurons that project to the cortex seem to comprise at least two populations with some directly excited by orexin that may represent wake-active, GABAergic neurons, whereas others did not respond to orexin but were inhibited by dynorphin and may be sleep-active, GABAergic neurons. This evidence suggests that the BF is a key site through which orexins activate the cortex and promotes behavioral arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance. PMID:19723027

  17. Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic and Parvalbumin Neurons in mice

    Directory of Open Access Journals (Sweden)

    Chun eYang

    2013-06-01

    Full Text Available Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV neurons to determine the effect of adenosine. Whole-cell recordings were made BF cholinergic neurons and from BF GABAergic & PV neurons with the size (>20 µm and intrinsic membrane properties (prominent H-currents corresponding to cortically projecting neurons. A brief (2 min bath application of adenosine (100 μM decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents in all groups of BF cholinergic, GABAergic and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM. Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1-receptor mediated inhibition of glutamatergic inputs to cortically-projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for

  18. Cognitive linguistics.

    Science.gov (United States)

    Evans, Vyvyan

    2012-03-01

    Cognitive linguistics is one of the fastest growing and influential perspectives on the nature of language, the mind, and their relationship with sociophysical (embodied) experience. It is a broad theoretical and methodological enterprise, rather than a single, closely articulated theory. Its primary commitments are outlined. These are the Cognitive Commitment-a commitment to providing a characterization of language that accords with what is known about the mind and brain from other disciplines-and the Generalization Commitment-which represents a dedication to characterizing general principles that apply to all aspects of human language. The article also outlines the assumptions and worldview which arises from these commitments, as represented in the work of leading cognitive linguists. WIREs Cogn Sci 2012, 3:129-141. doi: 10.1002/wcs.1163 For further resources related to this article, please visit the WIREs website. Copyright © 2012 John Wiley & Sons, Inc.

  19. Entrepreneurial Cognition

    DEFF Research Database (Denmark)

    Zichella, Giulio

    entrepreneurs and nonentrepreneurs differ in their behavioral susceptibility to prior outcomes, increasing degrees of risk, risk perception, and predictive information. The empirical analyses are based on data from a laboratory experiment that I designed and conducted in October 2014. Individuals participating......Research in decision making and cognition has a long tradition in economics and management and represents a substantial stream of research in entrepreneurship. Risk and uncertainty are two characteristics of the decision environment. It has long been believed that entrepreneurs who need to make...... business judgments in such environments are less risk- and uncertainty-averse than non-entrepreneurs. However, this theoretical prediction has not been supported by empirical evidence. Instead, entrepreneurs have been found to be more susceptible to cognitive biases and heuristics. These cognitive...

  20. The straintronic spin-neuron

    International Nuclear Information System (INIS)

    Biswas, Ayan K; Bandyopadhyay, Supriyo; Atulasimha, Jayasimha

    2015-01-01

    In artificial neural networks, neurons are usually implemented with highly dissipative CMOS-based operational amplifiers. A more energy-efficient implementation is a ‘spin-neuron’ realized with a magneto-tunneling junction (MTJ) that is switched with a spin-polarized current (representing weighted sum of input currents) that either delivers a spin transfer torque or induces domain wall motion in the soft layer of the MTJ to mimic neuron firing. Here, we propose and analyze a different type of spin-neuron in which the soft layer of the MTJ is switched with mechanical strain generated by a voltage (representing weighted sum of input voltages) and term it straintronic spin-neuron. It dissipates orders of magnitude less energy in threshold operations than the traditional current-driven spin neuron at 0 K temperature and may even be faster. We have also studied the room-temperature firing behaviors of both types of spin neurons and find that thermal noise degrades the performance of both types, but the current-driven type is degraded much more than the straintronic type if both are optimized for maximum energy-efficiency. On the other hand, if both are designed to have the same level of thermal degradation, then the current-driven version will dissipate orders of magnitude more energy than the straintronic version. Thus, the straintronic spin-neuron is superior to current-driven spin neurons. (paper)

  1. Neuronal discrimination capacity

    International Nuclear Information System (INIS)

    Deng Yingchun; Williams, Peter; Feng Jianfeng; Liu Feng

    2003-01-01

    We explore neuronal mechanisms of discriminating between masked signals. It is found that when the correlation between input signals is zero, the output signals are separable if and only if input signals are separable. With positively (negatively) correlated signals, the output signals are separable (mixed) even when input signals are mixed (separable). Exact values of discrimination capacity are obtained for two most interesting cases: the exactly balanced inhibitory and excitatory input case and the uncorrelated input case. Interestingly, the discrimination capacity obtained in these cases is independent of model parameters, input distribution and is universal. Our results also suggest a functional role of inhibitory inputs and correlated inputs or, more generally, the large variability of efferent spike trains observed in in vivo experiments: the larger the variability of efferent spike trains, the easier it is to discriminate between masked input signals

  2. Neuronal discrimination capacity

    Energy Technology Data Exchange (ETDEWEB)

    Deng Yingchun [Department of Mathematics, Hunan Normal University 410081, Changsha (China); COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Williams, Peter; Feng Jianfeng [COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Liu Feng [COGS, University of Sussex at Brighton, BN1 9QH (United Kingdom); Physics Department, Nanjing University (China)

    2003-12-19

    We explore neuronal mechanisms of discriminating between masked signals. It is found that when the correlation between input signals is zero, the output signals are separable if and only if input signals are separable. With positively (negatively) correlated signals, the output signals are separable (mixed) even when input signals are mixed (separable). Exact values of discrimination capacity are obtained for two most interesting cases: the exactly balanced inhibitory and excitatory input case and the uncorrelated input case. Interestingly, the discrimination capacity obtained in these cases is independent of model parameters, input distribution and is universal. Our results also suggest a functional role of inhibitory inputs and correlated inputs or, more generally, the large variability of efferent spike trains observed in in vivo experiments: the larger the variability of efferent spike trains, the easier it is to discriminate between masked input signals.

  3. Orexin neurons receive glycinergic innervations.

    Directory of Open Access Journals (Sweden)

    Mari Hondo

    Full Text Available Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.

  4. Enhancing Endogenous Nitric Oxide by Whole Body Periodic Acceleration Elicits Neuroprotective Effects in Dystrophic Neurons.

    Science.gov (United States)

    Lopez, Jose R; Uryash, A; Kolster, J; Estève, E; Zhang, R; Adams, J A

    2018-03-26

    We have previously shown that inadequate dystrophin in cortical neurons in mdx mice is associated with age-dependent dyshomeostasis of resting intracellular Ca 2+ ([Ca 2+ ] i ) and Na + ([Na + ] i ), elevated reactive oxygen species (ROS) production, increase in neuronal damage and cognitive deficit. In this study, we assessed the potential therapeutic properties of the whole body periodic acceleration (pGz) to ameliorate the pathology observed in cortical neurons from the mdx mouse. pGz adds small pulses to the circulation, thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of nitric oxide (NO). We found [Ca 2+ ] i and [Na + ] i overload along with reactive oxygen species (ROS) overproduction in mdx neurons and cognitive dysfunction. mdx neurons showed increased activity of superoxide dismutase, glutathione peroxidase, malondialdehyde, and calpain as well as decreased cell viability. mdx neurons were more susceptible to hypoxia-reoxygenation injury than WT. pGz ameliorated the [Ca 2+ ] i , and [Na + ] i elevation and ROS overproduction and further increased the activities of superoxide dismutase, glutathione peroxidase and reduced the malondialdehyde and calpains. pGz diminished cell damage and elevated [Ca 2+ ] i during hypoxia-reoxygenation and improved cognitive function in mdx mice. Moreover, pGz upregulated the expression of utrophin, dystroglycan-β and CAPON, constitutive nitric oxide synthases, prosaposin, brain-derived neurotrophic, and glial cell line-derived neurotrophic factors. The present study demonstrated that pGz is an effective therapeutic approach to improve mdx neurons function, including cognitive functions.

  5. Cumulative impact of axial, structural, and repolarization ECG findings on long-term cardiovascular mortality among healthy individuals in Japan: National Integrated Project for Prospective Observation of Non-Communicable Disease and its Trends in the Aged, 1980 and 1990.

    Science.gov (United States)

    Inohara, Taku; Kohsaka, Shun; Okamura, Tomonori; Watanabe, Makoto; Nakamura, Yasuyuki; Higashiyama, Aya; Kadota, Aya; Okuda, Nagako; Murakami, Yoshitaka; Ohkubo, Takayoshi; Miura, Katsuyuki; Okayama, Akira; Ueshima, Hirotsugu

    2014-12-01

    Various cohort studies have shown a close association between long-term cardiovascular disease (CVD) outcomes and individual electrocardiographic (ECG) abnormalities such as axial, structural, and repolarization changes. The combined effect of these ECG abnormalities, each assumed to be benign, has not been thoroughly investigated. Community-dwelling Japanese residents from the National Integrated Project for Perspective Observation of Non-Communicable Disease and its Trends in the Aged, 1980-2004 and 1990-2005 (NIPPON DATA80 and 90), were included in this study. Baseline ECG findings were classified using the Minnesota Code and categorized into axial (left axis deviation, clockwise rotation), structural (left ventricular hypertrophy, atrial enlargement), and repolarization (minor and major ST-T changes) abnormalities. The hazard ratios of the cumulative impacts of ECG findings on long-term CVD death were estimated by stratified Cox proportional hazard models, including adjustments for cohort strata. In all, 16,816 participants were evaluated. The average age was 51.2 ± 13.5 years; 42.7% participants were male. The duration of follow up was 300,924 person-years (mean 17.9 ± 5.8 years); there were 1218 CVD deaths during that time. Overall, 4203 participants (25.0%) had one or more categorical ECG abnormalities: 3648 (21.7%) had a single abnormality, and 555 (3.3%) had two or more. The risk of CVD mortality increased as the number of abnormalities accumulated (single abnormality HR 1.29, 95% CI 1.13-1.48; ≥2 abnormalities HR 2.10, 95% CI 1.73-2.53). Individual ECG abnormalities had an additive effect in predicting CVD outcome risk in our large-scale cohort study. © The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  6. Cognitive Variability

    Science.gov (United States)

    Siegler, Robert S.

    2007-01-01

    Children's thinking is highly variable at every level of analysis, from neural and associative levels to the level of strategies, theories, and other aspects of high-level cognition. This variability exists within people as well as between them; individual children often rely on different strategies or representations on closely related problems…

  7. Cognitive Fingerprints

    Science.gov (United States)

    2015-03-25

    is another cognitive fingerprint that has been used extensively for authorship . This work has been ex- tended to authentication by relating keyboard...this work is the inference of high-level features such as personality, gender , and dominant hand but those features have not been integrated to date

  8. Cognitive Science.

    Science.gov (United States)

    Cocking, Rodney R.; Mestre, Jose P.

    The focus of this paper is on cognitive science as a model for understanding the application of human skills toward effective problem-solving. Sections include: (1) "Introduction" (discussing information processing framework, expert-novice distinctions, schema theory, and learning process); (2) "Application: The Expert-Novice…

  9. Bcl-2 over-expression fails to prevent age-related loss of calretinin positive neurons in the mouse dentate gyrus

    Directory of Open Access Journals (Sweden)

    Han Mingbo

    2006-08-01

    Full Text Available Abstract Background Cognitive performance declines with increasing age. Possible cellular mechanisms underlying this age-related functional decline remain incompletely understood. Early studies attributed this functional decline to age-related neuronal loss. Subsequent studies using unbiased stereological techniques found little or no neuronal loss during aging. However, studies using specific cellular markers found age-related loss of specific neuronal types. To test whether there is age-related loss of specific neuronal populations in the hippocampus, and subsequently, whether over-expression of the B-cell lymphoma protein-2 (Bcl-2 in these neurons could delay possible age-related neuronal loss, we examined calretinin (CR positive neurons in the mouse dentate gyrus during aging. Result In normal mice, there was an age-related loss of CR positive cells in the dentate gyrus. At the same region, there was no significant decrease of total numbers of neurons, which suggested that age-related loss of CR positive cells was due to the decrease of CR expression in these cells instead of cell death. In the transgenic mouse line over-expressing Bcl-2 in neurons, there was an age-related loss of CR positive cells. Interestingly, there was also an age-related neuronal loss in this transgenic mouse line. Conclusion These data suggest an age-related loss of CR positive neurons but not total neuronal loss in normal mice and this age-related neuronal change is not prevented by Bcl-2 over-expression.

  10. Pathogenesis of motor neuron disease

    Institute of Scientific and Technical Information of China (English)

    Xuefei Wang

    2006-01-01

    OBJECTIVE: To summarize and analyze the factors and theories related to the attack of motor neuron disease, and comprehensively investigate the pathogenesis of motor neuron disease.DATA SOURCES: A search of Pubmed database was undertaken to identify articles about motor neuron disease published in English from January 1994 to June 2006 by using the keywords of "neurodegenerative diseases". Other literatures were collected by retrieving specific journals and articles.STUDY SELECTION: The data were checked primarily, articles related to the pathogenesis of motor neuron disease were involved, and those obviously irrelated to the articles were excluded.DATA EXTRACTION: Totally 54 articles were collected, 30 of them were involved, and the other 24 were excluded.DATA SYNTHESIS: The pathogenesis of motor neuron disease has multiple factors, and the present related theories included free radical oxidation, excitotoxicity, genetic and immune factors, lack of neurotrophic factor,injury of neurofilament, etc. The studies mainly come from transgenic animal models, cell culture in vitro and patients with familial motor neuron disease, but there are still many restrictions and disadvantages.CONCLUSION: It is necessary to try to find whether there is internal association among different mechanisms,comprehensively investigate the pathogenesis of motor neuron diseases, in order to provide reliable evidence for the clinical treatment.

  11. Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose.

    Science.gov (United States)

    Amaral, Ana I

    2013-07-01

    Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes.

  12. CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice.

    Science.gov (United States)

    Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A; Zhao, Haitian; Chandakkar, Pallavi; Adrien, Leslie; Strohl, Joshua J; Gibson, Elizabeth L; Ohmoto, Makoto; Matsumoto, Ichiro; Huerta, Patricio T; Marambaud, Philippe

    2016-04-12

    CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1(-/-)) mice and investigate CALHM1 role in neuronal and cognitive functions. Structural analysis revealed that Calhm1(-/-) brains had normal regional and cellular architecture, and showed no evidence of neuronal or synaptic loss, indicating that CALHM1 deficiency does not affect brain development or brain integrity in adulthood. However, Calhm1(-/-) mice showed a severe impairment in memory flexibility, assessed in the Morris water maze, and a significant disruption of long-term potentiation without alteration of long-term depression, measured in ex vivo hippocampal slices. Importantly, in primary neurons and hippocampal slices, CALHM1 activation facilitated the phosphorylation of NMDA and AMPA receptors by protein kinase A. Furthermore, neuronal CALHM1 activation potentiated the effect of glutamate on the expression of c-Fos and C/EBPβ, two immediate-early gene markers of neuronal activity. Thus, CALHM1 controls synaptic activity in cerebral neurons and is required for the flexible processing of memory in mice. These results shed light on CALHM1 physiology in the mammalian brain.

  13. Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons.

    Science.gov (United States)

    Zemel, Benjamin M; Muqeem, Tanziyah; Brown, Eric V; Goulão, Miguel; Urban, Mark W; Tymanskyj, Stephen R; Lepore, Angelo C; Covarrubias, Manuel

    2017-08-23

    Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have

  14. Self-other relations in social development and autism: multiple roles for mirror neurons and other brain bases.

    Science.gov (United States)

    Williams, Justin H G

    2008-04-01

    Mirror neuron system dysfunction may underlie a self-other matching impairment, which has previously been suggested to account for autism. Embodied Cognition Theory, which proposes that action provides a foundation for cognition has lent further credence to these ideas. The hypotheses of a self-other matching deficit and impaired mirror neuron function in autism have now been well supported by studies employing a range of methodologies. However, underlying mechanisms require further exploration to explain how mirror neurons may be involved in attentional and mentalizing processes. Impairments in self-other matching and mirror neuron function are not necessarily inextricably linked and it seems possible that different sub-populations of mirror neurons, located in several regions, contribute differentially to social cognitive functions. It is hypothesized that mirror neuron coding for action-direction may be required for developing attentional sensitivity to self-directed actions, and consequently for person-oriented, stimulus-driven attention. Mirror neuron networks may vary for different types of social learning such as "automatic" imitation and imitation learning. Imitation learning may be more reliant on self-other comparison processes (based on mirror neurons) that identify differences as well as similarities between actions. Differential connectivity with the amygdala-orbitofrontal system may also be important. This could have implications for developing "theory of mind," with intentional self-other comparison being relevant to meta-representational abilities, and "automatic" imitation being more relevant to empathy. While it seems clear that autism is associated with impaired development of embodied aspects of cognition, the ways that mirror neurons contribute to these brain-behavior links are likely to be complex.

  15. Simulating synchronization in neuronal networks

    Science.gov (United States)

    Fink, Christian G.

    2016-06-01

    We discuss several techniques used in simulating neuronal networks by exploring how a network's connectivity structure affects its propensity for synchronous spiking. Network connectivity is generated using the Watts-Strogatz small-world algorithm, and two key measures of network structure are described. These measures quantify structural characteristics that influence collective neuronal spiking, which is simulated using the leaky integrate-and-fire model. Simulations show that adding a small number of random connections to an otherwise lattice-like connectivity structure leads to a dramatic increase in neuronal synchronization.

  16. Glial tumors with neuronal differentiation.

    Science.gov (United States)

    Park, Chul-Kee; Phi, Ji Hoon; Park, Sung-Hye

    2015-01-01

    Immunohistochemical studies for neuronal differentiation in glial tumors revealed subsets of tumors having both characteristics of glial and neuronal lineages. Glial tumors with neuronal differentiation can be observed with diverse phenotypes and histologic grades. The rosette-forming glioneuronal tumor of the fourth ventricle and papillary glioneuronal tumor have been newly classified as distinct disease entities. There are other candidates for classification, such as the glioneuronal tumor without pseudopapillary architecture, glioneuronal tumor with neuropil-like islands, and the malignant glioneuronal tumor. The clinical significance of these previously unclassified tumors should be confirmed. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Mechanosensing in hypothalamic osmosensory neurons.

    Science.gov (United States)

    Prager-Khoutorsky, Masha

    2017-11-01

    Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. From Neurons to Brain: Adaptive Self-Wiring of Neurons

    OpenAIRE

    Segev, Ronen; Ben-Jacob, Eshel

    1998-01-01

    During embryonic morpho-genesis, a collection of individual neurons turns into a functioning network with unique capabilities. Only recently has this most staggering example of emergent process in the natural world, began to be studied. Here we propose a navigational strategy for neurites growth cones, based on sophisticated chemical signaling. We further propose that the embryonic environment (the neurons and the glia cells) acts as an excitable media in which concentric and spiral chemical ...

  19. Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging.

    Science.gov (United States)

    Albayram, Onder; Alferink, Judith; Pitsch, Julika; Piyanova, Anastasia; Neitzert, Kim; Poppensieker, Karola; Mauer, Daniela; Michel, Kerstin; Legler, Anne; Becker, Albert; Monory, Krisztina; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras

    2011-07-05

    Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1(-/-)), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1(-/-) mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1(-/-) mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.

  20. Imaging of intracranial neuronal and mixed neuronal-glial tumours

    International Nuclear Information System (INIS)

    Cui Shimin; Qin Jinxi; Zhang Leili; Liu Meili; Jin Song; Yan Shixin; Liu Li; Dai Weiying; Li Tao; Gao Man

    2001-01-01

    Objective: To investigate the characteristic clinical, imaging , and pathologic findings of intracranial neuronal and mixed neuronal-glial tumours. Methods: The imaging findings of surgery and pathobiology proved intracranial neuronal and mixed neuronal-glial tumours in 14 cases (7 male and 7 female, ranging in age from 6-56 years; mean age 33.8 years) were retrospectively analyzed. Results: Eight gangliogliomas were located in the frontal lobe (4 cases), temporal lobe (1 case), front- temporal lobe (2 cases), and pons (1 case). They appeared as iso-or low density on CT, iso-or low signal intensity on T 1 WI, and high signal intensity on T 2 WI on MR imaging. Two central neurocytomas were located in the supratentorial ventricles. Four desmoplastic gangliogliomas were seen as cystic masses, appearing as low signal intensity on T 1 WI and high signal intensity on T 2 WI. Conclusion: Intracranial neuronal and mixed neuronal-glial tumours had imaging characteristics. Combined with clinical history, it was possible to make a tendency preoperative diagnosis using CT or MR

  1. Potential of Cognitive Computing and Cognitive Systems

    Science.gov (United States)

    Noor, Ahmed K.

    2015-01-01

    Cognitive computing and cognitive technologies are game changers for future engineering systems, as well as for engineering practice and training. They are major drivers for knowledge automation work, and the creation of cognitive products with higher levels of intelligence than current smart products. This paper gives a brief review of cognitive computing and some of the cognitive engineering systems activities. The potential of cognitive technologies is outlined, along with a brief description of future cognitive environments, incorporating cognitive assistants - specialized proactive intelligent software agents designed to follow and interact with humans and other cognitive assistants across the environments. The cognitive assistants engage, individually or collectively, with humans through a combination of adaptive multimodal interfaces, and advanced visualization and navigation techniques. The realization of future cognitive environments requires the development of a cognitive innovation ecosystem for the engineering workforce. The continuously expanding major components of the ecosystem include integrated knowledge discovery and exploitation facilities (incorporating predictive and prescriptive big data analytics); novel cognitive modeling and visual simulation facilities; cognitive multimodal interfaces; and cognitive mobile and wearable devices. The ecosystem will provide timely, engaging, personalized / collaborative, learning and effective decision making. It will stimulate creativity and innovation, and prepare the participants to work in future cognitive enterprises and develop new cognitive products of increasing complexity. http://www.aee.odu.edu/cognitivecomp

  2. Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.

    Science.gov (United States)

    Alp, Murat; Cucinotta, Francis A

    2018-03-01

    Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors. We represented dendrites as cylindrical segments of varying diameter with unit aspect ratios, and developed a fast sampling method to consider the stochastic distribution of ED by δ rays (secondary electrons) around the path of heavy ions, to reduce computational times. We introduce probabilistic models with a small number of parameters to describe the induction of precursor lesions that precede dendritic snipping, denoted as snip sites. Predictions for oxygen ( 16 O, 600 MeV/n) and titanium ( 48 Ti, 600 MeV/n) particles with LET of 16.3 and 129 keV/μm, respectively, are considered. Morphometric parameters to quantify changes in neuron morphology are described, including reduction in total dendritic length, number of branch points and branch numbers. Sholl analysis is applied for single neurons to elucidate dose-dependent reductions in dendritic complexity. We predict important differences in measurements from imaging of tissues from brain slices with single neuron cell observations due to the role of neuron death through both soma apoptosis and excessive dendritic length reduction. To further elucidate the role of track structure, random segment excision (snips) models are introduced and a sensitivity study of the effects of the modes of neuron death in predictions

  3. Neurons on the couch.

    Science.gov (United States)

    Marić, Nadja P; Jašović-Gašić, Miroslava

    2010-12-01

    A hundred years after psychoanalysis was introduced, neuroscience has taken a giant step forward. It seems nowadays that effects of psychotherapy could be monitored and measured by state-of-the art brain imaging techniques. Today, the psychotherapy is considered as a strategic and purposeful environmental influence intended to enhance learning. Since gene expression is regulated by environmental influences throughout life and these processes create brain architecture and influence the strength of synaptic connections, psychotherapy (as a kind of learning) should be explored in the context of aforementioned paradigm. In other words, when placing a client on the couch, therapist actually placed client's neuronal network; while listening and talking, expressing and analyzing, experiencing transference and counter transference, therapist tends to stabilize synaptic connections and influence dendritic growth by regulating gene-transcriptional activity. Therefore, we strongly believe that, in the near future, an increasing knowledge on cellular and molecular interactions and mechanisms of action of different psycho- and pharmaco-therapeutic procedures will enable us to tailor a sophisticated therapeutic approach toward a person, by combining major therapeutic strategies in psychiatry on the basis of rational goals and evidence-based therapeutic expectations.

  4. Laser capture microdissection of enriched populations of neurons or single neurons for gene expression analysis after traumatic brain injury.

    Science.gov (United States)

    Boone, Deborah R; Sell, Stacy L; Hellmich, Helen Lee

    2013-04-10

    Long-term cognitive disability after TBI is associated with injury-induced neurodegeneration in the hippocampus-a region in the medial temporal lobe that is critical for learning, memory and executive function. Hence our studies focus on gene expression analysis of specific neuronal populations in distinct subregions of the hippocampus. The technique of laser capture microdissection (LCM), introduced in 1996 by Emmert-Buck, et al., has allowed for significant advances in gene expression analysis of single cells and enriched populations of cells from heterogeneous tissues such as the mammalian brain that contains thousands of functional cell types. We use LCM and a well established rat model of traumatic brain injury (TBI) to investigate the molecular mechanisms that underlie the pathogenesis of TBI. Following fluid-percussion TBI, brains are removed at pre-determined times post-injury, immediately frozen on dry ice, and prepared for sectioning in a cryostat. The rat brains can be embedded in OCT and sectioned immediately, or stored several months at -80 °C before sectioning for laser capture microdissection. Additionally, we use LCM to study the effects of TBI on circadian rhythms. For this, we capture neurons from the suprachiasmatic nuclei that contain the master clock of the mammalian brain. Here, we demonstrate the use of LCM to obtain single identified neurons (injured and degenerating, Fluoro-Jade-positive, or uninjured, Fluoro-Jade-negative) and enriched populations of hippocampal neurons for subsequent gene expression analysis by real time PCR and/or whole-genome microarrays. These LCM-enabled studies have revealed that the selective vulnerability of anatomically distinct regions of the rat hippocampus are reflected in the different gene expression profiles of different populations of neurons obtained by LCM from these distinct regions. The results from our single-cell studies, where we compare the transcriptional profiles of dying and adjacent surviving

  5. Understanding Neuronal Mechanisms of Epilepsy ...

    Indian Academy of Sciences (India)

    Admin

    α subunit of Rat Brain type IIA Voltage Gated Sodium Channel and geneticin selection ..... scaling the mother wavelet. Scale = 1/ .... through dynamic clamp. Dynamic Clamp ... It has been shown that like in vivo neurons, cortical networks in.

  6. Information processing by neuronal populations

    National Research Council Canada - National Science Library

    Hölscher, Christian; Munk, Matthias

    2009-01-01

    ... simultaneously recorded spike trains 120 Mark Laubach, Nandakumar S. Narayanan, and Eyal Y. Kimchi Part III Neuronal population information coding and plasticity in specific brain areas 149 7 F...

  7. Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate Features of Autism Spectrum Disorders

    OpenAIRE

    Zhao, Yuanzi; Fung, Camille; Shin, Don; Shin, Bo-Chul; Thamotharan, Shanthie; Sankar, Raman; Ehninger, Dan; Silva, Alcino; Devaskar, Sherin U.

    2009-01-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristic...

  8. Forebrain mineralocorticoid receptor overexpression enhances memory, reduces anxiety and attenuates neuronal loss in cerebral ischaemia

    NARCIS (Netherlands)

    Lai, Maggie; Horsburgh, Karen; Bae, Sung-Eun; Carter, Roderick N.; Stenvers, Dirk J.; Fowler, Jill H.; Yau, Joyce L.; Gomez-Sanchez, Celso E.; Holmes, Megan C.; Kenyon, Christopher J.; Seckl, Jonathan R.; Macleod, Malcolm R.

    2007-01-01

    The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in

  9. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia

    DEFF Research Database (Denmark)

    Ejlerskov, Patrick; Hultberg, Jeanette Göransdotter; Wang, JunYang

    2015-01-01

    -causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused...

  10. Differential Patterns of Dysconnectivity in Mirror Neuron and Mentalizing Networks in Schizophrenia

    NARCIS (Netherlands)

    Schilbach, Leonhard; Derntl, Birgit; Aleman, Andre; Caspers, Svenja; Clos, Mareike; Diederen, Kelly M J; Gruber, Oliver; Kogler, Lydia; Liemburg, Edith J; Sommer, Iris E; Müller, Veronika I; Cieslik, Edna C; Eickhoff, Simon B

    Impairments of social cognition are well documented in patients with schizophrenia (SCZ), but the neural basis remains poorly understood. In light of evidence that suggests that the "mirror neuron system" (MNS) and the "mentalizing network" (MENT) are key substrates of intersubjectivity and joint

  11. Emotion processing fails to modulate putative mirror neuron response to trained visuomotor associations.

    Science.gov (United States)

    Fitzgibbon, Bernadette M; Kirkovski, Melissa; Fornito, Alex; Paton, Bryan; Fitzgerald, Paul B; Enticott, Peter G

    2016-04-01

    Recent neuroimaging studies have demonstrated that activation of the putative human mirror neuron system (MNS) can be elicited via visuomotor training. This is generally interpreted as supporting an associative learning account of the mirror neuron system (MNS) that argues against the ontogeny of the MNS to be an evolutionary adaptation for social cognition. The current study assessed whether a central component of social cognition, emotion processing, would influence the MNS activity to trained visuomotor associations, which could support a broader role of the MNS in social cognition. Using functional magnetic resonance imaging (fMRI), we assessed repetition suppression to the presentation of stimulus pairs involving a simple hand action and a geometric shape that was either congruent or incongruent with earlier association training. Each pair was preceded by an image of positive, negative, or neutral emotionality. In support of an associative learning account of the MNS, repetition suppression was greater for trained pairs compared with untrained pairs in several regions, primarily supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). This response, however, was not modulated by the valence of the emotional images. These findings argue against a fundamental role of emotion processing in the mirror neuron response, and are inconsistent with theoretical accounts linking mirror neurons to social cognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Language and Cognition Interaction Neural Mechanisms

    Directory of Open Access Journals (Sweden)

    Leonid Perlovsky

    2011-01-01

    Full Text Available How language and cognition interact in thinking? Is language just used for communication of completed thoughts, or is it fundamental for thinking? Existing approaches have not led to a computational theory. We develop a hypothesis that language and cognition are two separate but closely interacting mechanisms. Language accumulates cultural wisdom; cognition develops mental representations modeling surrounding world and adapts cultural knowledge to concrete circumstances of life. Language is acquired from surrounding language “ready-made” and therefore can be acquired early in life. This early acquisition of language in childhood encompasses the entire hierarchy from sounds to words, to phrases, and to highest concepts existing in culture. Cognition is developed from experience. Yet cognition cannot be acquired from experience alone; language is a necessary intermediary, a “teacher.” A mathematical model is developed; it overcomes previous difficulties and leads to a computational theory. This model is consistent with Arbib's “language prewired brain” built on top of mirror neuron system. It models recent neuroimaging data about cognition, remaining unnoticed by other theories. A number of properties of language and cognition are explained, which previously seemed mysterious, including influence of language grammar on cultural evolution, which may explain specifics of English and Arabic cultures.

  13. Language and cognition interaction neural mechanisms.

    Science.gov (United States)

    Perlovsky, Leonid

    2011-01-01

    How language and cognition interact in thinking? Is language just used for communication of completed thoughts, or is it fundamental for thinking? Existing approaches have not led to a computational theory. We develop a hypothesis that language and cognition are two separate but closely interacting mechanisms. Language accumulates cultural wisdom; cognition develops mental representations modeling surrounding world and adapts cultural knowledge to concrete circumstances of life. Language is acquired from surrounding language "ready-made" and therefore can be acquired early in life. This early acquisition of language in childhood encompasses the entire hierarchy from sounds to words, to phrases, and to highest concepts existing in culture. Cognition is developed from experience. Yet cognition cannot be acquired from experience alone; language is a necessary intermediary, a "teacher." A mathematical model is developed; it overcomes previous difficulties and leads to a computational theory. This model is consistent with Arbib's "language prewired brain" built on top of mirror neuron system. It models recent neuroimaging data about cognition, remaining unnoticed by other theories. A number of properties of language and cognition are explained, which previously seemed mysterious, including influence of language grammar on cultural evolution, which may explain specifics of English and Arabic cultures.

  14. Language and Cognition Interaction Neural Mechanisms

    Science.gov (United States)

    Perlovsky, Leonid

    2011-01-01

    How language and cognition interact in thinking? Is language just used for communication of completed thoughts, or is it fundamental for thinking? Existing approaches have not led to a computational theory. We develop a hypothesis that language and cognition are two separate but closely interacting mechanisms. Language accumulates cultural wisdom; cognition develops mental representations modeling surrounding world and adapts cultural knowledge to concrete circumstances of life. Language is acquired from surrounding language “ready-made” and therefore can be acquired early in life. This early acquisition of language in childhood encompasses the entire hierarchy from sounds to words, to phrases, and to highest concepts existing in culture. Cognition is developed from experience. Yet cognition cannot be acquired from experience alone; language is a necessary intermediary, a “teacher.” A mathematical model is developed; it overcomes previous difficulties and leads to a computational theory. This model is consistent with Arbib's “language prewired brain” built on top of mirror neuron system. It models recent neuroimaging data about cognition, remaining unnoticed by other theories. A number of properties of language and cognition are explained, which previously seemed mysterious, including influence of language grammar on cultural evolution, which may explain specifics of English and Arabic cultures. PMID:21876687

  15. Alterations of cortical GABA neurons and network oscillations in schizophrenia.

    Science.gov (United States)

    Gonzalez-Burgos, Guillermo; Hashimoto, Takanori; Lewis, David A

    2010-08-01

    The hypothesis that alterations of cortical inhibitory gamma-aminobutyric acid (GABA) neurons are a central element in the pathology of schizophrenia has emerged from a series of postmortem studies. How such abnormalities may contribute to the clinical features of schizophrenia has been substantially informed by a convergence with basic neuroscience studies revealing complex details of GABA neuron function in the healthy brain. Importantly, activity of the parvalbumin-containing class of GABA neurons has been linked to the production of cortical network oscillations. Furthermore, growing knowledge supports the concept that gamma band oscillations (30-80 Hz) are an essential mechanism for cortical information transmission and processing. Herein we review recent studies further indicating that inhibition from parvalbumin-positive GABA neurons is necessary to produce gamma oscillations in cortical circuits; provide an update on postmortem studies documenting that deficits in the expression of glutamic acid decarboxylase67, which accounts for most GABA synthesis in the cortex, are widely observed in schizophrenia; and describe studies using novel, noninvasive approaches directly assessing potential relations between alterations in GABA, oscillations, and cognitive function in schizophrenia.

  16. Chimera states in bursting neurons

    OpenAIRE

    Bera, Bidesh K.; Ghosh, Dibakar; Lakshmanan, M.

    2015-01-01

    We study the existence of chimera states in pulse-coupled networks of bursting Hindmarsh-Rose neurons with nonlocal, global and local (nearest neighbor) couplings. Through a linear stability analysis, we discuss the behavior of stability function in the incoherent (i.e. disorder), coherent, chimera and multi-chimera states. Surprisingly, we find that chimera and multi-chimera states occur even using local nearest neighbor interaction in a network of identical bursting neurons alone. This is i...

  17. Cognitive memory.

    Science.gov (United States)

    Widrow, Bernard; Aragon, Juan Carlos

    2013-05-01

    Regarding the workings of the human mind, memory and pattern recognition seem to be intertwined. You generally do not have one without the other. Taking inspiration from life experience, a new form of computer memory has been devised. Certain conjectures about human memory are keys to the central idea. The design of a practical and useful "cognitive" memory system is contemplated, a memory system that may also serve as a model for many aspects of human memory. The new memory does not function like a computer memory where specific data is stored in specific numbered registers and retrieval is done by reading the contents of the specified memory register, or done by matching key words as with a document search. Incoming sensory data would be stored at the next available empty memory location, and indeed could be stored redundantly at several empty locations. The stored sensory data would neither have key words nor would it be located in known or specified memory locations. Sensory inputs concerning a single object or subject are stored together as patterns in a single "file folder" or "memory folder". When the contents of the folder are retrieved, sights, sounds, tactile feel, smell, etc., are obtained all at the same time. Retrieval would be initiated by a query or a prompt signal from a current set of sensory inputs or patterns. A search through the memory would be made to locate stored data that correlates with or relates to the prompt input. The search would be done by a retrieval system whose first stage makes use of autoassociative artificial neural networks and whose second stage relies on exhaustive search. Applications of cognitive memory systems have been made to visual aircraft identification, aircraft navigation, and human facial recognition. Concerning human memory, reasons are given why it is unlikely that long-term memory is stored in the synapses of the brain's neural networks. Reasons are given suggesting that long-term memory is stored in DNA or RNA

  18. Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

    Science.gov (United States)

    Aoyama, Yuki; Toriumi, Kazuya; Mouri, Akihiro; Hattori, Tomoya; Ueda, Eriko; Shimato, Akane; Sakakibara, Nami; Soh, Yuka; Mamiya, Takayoshi; Nagai, Taku; Kim, Hyoung-Chun; Hiramatsu, Masayuki; Nabeshima, Toshitaka; Yamada, Kiyofumi

    2016-01-01

    Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2′-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring. PMID:26105135

  19. Communication among neurons.

    Science.gov (United States)

    Marner, Lisbeth

    2012-04-01

    The communication among neurons is the prerequisite for the working brain. To understand the cellular, neurochemical, and structural basis of this communication, and the impacts of aging and disease on brain function, quantitative measures are necessary. This thesis evaluates several quantitative neurobiological methods with respect to possible bias and methodological issues. Stereological methods are suited for the unbiased estimation of number, length, and volumes of components of the nervous system. Stereological estimates of the total length of myelinated nerve fibers were made in white matter of post mortem brains, and the impact of aging and diseases as Schizophrenia and Alzheimer's disease were evaluated. Although stereological methods are in principle unbiased, shrinkage artifacts are difficult to account for. Positron emission tomography (PET) recordings, in conjunction with kinetic modeling, permit the quantitation of radioligand binding in brain. The novel serotonin 5-HT4 antagonist [11C]SB207145 was used as an example of the validation process for quantitative PET receptor imaging. Methods based on reference tissue as well as methods based on an arterial plasma input function were evaluated with respect to precision and accuracy. It was shown that [11C]SB207145 binding had high sensitivity to occupancy by unlabeled ligand, necessitating high specific activity in the radiosynthesis to avoid bias. The established serotonin 5-HT2A ligand [18F]altanersin was evaluated in a two-year follow-up study in elderly subjects. Application of partial volume correction of the PET data diminished the reliability of the measures, but allowed for the correct distinction between changes due to brain atrophy and receptor availability. Furthermore, a PET study of patients with Alzheimer's disease with the serotonin transporter ligand [11C]DASB showed relatively preserved serotonergic projections, despite a marked decrease in 5-HT2A receptor binding. Possible confounders are

  20. Individual mediodorsal thalamic neurons project to multiple areas of the rat prefrontal cortex: A single neuron-tracing study using virus vectors.

    Science.gov (United States)

    Kuramoto, Eriko; Pan, Shixiu; Furuta, Takahiro; Tanaka, Yasuhiro R; Iwai, Haruki; Yamanaka, Atsushi; Ohno, Sachi; Kaneko, Takeshi; Goto, Tetsuya; Hioki, Hiroyuki

    2017-01-01

    The prefrontal cortex has an important role in a variety of cognitive and executive processes, and is generally defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD). The rat MD is mainly subdivided into three segments, the medial (MDm), central (MDc), and lateral (MDl) divisions, on the basis of the cytoarchitecture and chemoarchitecture. The MD segments are known to topographically project to multiple prefrontal areas at the population level: the MDm mainly to the prelimbic, infralimbic, and agranular insular areas; the MDc to the orbital and agranular insular areas; and the MDl to the prelimbic and anterior cingulate areas. However, it is unknown whether individual MD neurons project to single or multiple prefrontal cortical areas. In the present study, we visualized individual MD neurons with Sindbis virus vectors, and reconstructed whole structures of MD neurons. While the main cortical projection targets of MDm, MDc, and MDl neurons were generally consistent with those of previous results, it was found that individual MD neurons sent their axon fibers to multiple prefrontal areas, and displayed various projection patterns in the target areas. Furthermore, the axons of single MD neurons were not homogeneously spread, but were rather distributed to form patchy axon arbors approximately 1 mm in diameter. The multiple-area projections and patchy axon arbors of single MD neurons might be able to coactivate cortical neuron groups in distant prefrontal areas simultaneously. Furthermore, considerable heterogeneity of the projection patterns is likely, to recruit the different sets of cortical neurons, and thus contributes to a variety of prefrontal functions. J. Comp. Neurol. 525:166-185, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Interferon-γ increases neuronal death in response to amyloid-β1-42

    Directory of Open Access Journals (Sweden)

    Williams Alun

    2006-03-01

    Full Text Available Abstract Background Alzheimer's disease is a neurodegenerative disorder characterized by a progressive cognitive impairment, the consequence of neuronal dysfunction and ultimately the death of neurons. The amyloid hypothesis proposes that neuronal damage results from the accumulation of insoluble, hydrophobic, fibrillar peptides such as amyloid-β1-42. These peptides activate enzymes resulting in a cascade of second messengers including prostaglandins and platelet-activating factor. Apoptosis of neurons is thought to follow as a consequence of the uncontrolled release of second messengers. Biochemical, histopathological and genetic studies suggest that pro-inflammatory cytokines play a role in neurodegeneration during Alzheimer's disease. In the current study we examined the effects of interferon (IFN-γ, tumour necrosis factor (TNFα, interleukin (IL-1β and IL-6 on neurons. Methods Primary murine cortical or cerebellar neurons, or human SH-SY5Y neuroblastoma cells, were grown in vitro. Neurons were treated with cytokines prior to incubation with different neuronal insults. Cell survival, caspase-3 activity (a measure of apoptosis and prostaglandin production were measured. Immunoblots were used to determine the effects of cytokines on the levels of cytoplasmic phospholipase A2 or phospholipase C γ-1. Results While none of the cytokines tested were directly neurotoxic, pre-treatment with IFN-γ sensitised neurons to the toxic effects of amyloid-β1-42 or HuPrP82-146 (a neurotoxic peptide found in prion diseases. The effects of IFN-γ were seen on cortical and cerebellar neurons, and on SH-SY5Y neuroblastoma cells. However, pre-treatment with IFN-γ did not affect the sensitivity to neurons treated with staurosporine or hydrogen peroxide. Pre-treatment with IFN-γ increased the levels of cytoplasmic phospholipase A2 in SH-SY5Y cells and increased prostaglandin E2 production in response to amyloid-β1-42. Conclusion Treatment of neuronal cells

  2. APPLICATION OF UKRAINIAN GRID INFRASTRUCTURE FOR INVESTIGATION OF NONLINEAR DYNAMICS IN LARGE NEURONAL NETWORKS

    Directory of Open Access Journals (Sweden)

    O. О. Sudakov

    2015-12-01

    Full Text Available In present work the Ukrainian National Grid (UNG infrastructure was applied for investigation of synchronization in large networks of interacting neurons. This application is important for solving of modern neuroscience problems related to mechanisms of nervous system activities (memory, cognition etc. and nervous pathologies (epilepsy, Parkinsonism, etc.. Modern non-linear dynamics theories and applications provides powerful basis for computer simulations of biological neuronal networks and investigation of phenomena which mechanisms hardly could be clarified by other approaches. Cubic millimeter of brain tissue contains about 105 neurons, so realistic (Hodgkin-Huxley model and phenomenological (Kuramoto-Sakaguchi, FitzHugh-Nagumo, etc. models simulations require consideration of large neurons numbers.

  3. Ephaptic Coupling of Cortical Neurons: Possible Contribution of Astroglial Magnetic Fields?

    Science.gov (United States)

    Martinez-Banaclocha, Marcos

    2018-02-01

    The close anatomical and functional relationship between neuronal circuits and the astroglial network in the neocortex has been demonstrated at several organization levels supporting the idea that neuron-astroglial crosstalk can play a key role in information processing. In addition to chemical and electrical neurotransmission, other non-synaptic mechanisms called ephaptic interactions seem to be important to understand neuronal coupling and cognitive functions. Recent interest in this issue comes from the fact that extra-cranial electric and magnetic field stimulations have shown therapeutic actions in the clinical practice. The present paper reviews the current knowledge regarding the ephaptic effects in mammalian neocortex and proposes that astroglial bio-magnetic fields associated with Ca 2+ transients could be implicated in the ephaptic coupling of neurons by a direct magnetic modulation of the intercellular local field potentials. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons.

    Science.gov (United States)

    Cuesto, Germán; Enriquez-Barreto, Lilian; Caramés, Cristina; Cantarero, Marta; Gasull, Xavier; Sandi, Carmen; Ferrús, Alberto; Acebes, Ángel; Morales, Miguel

    2011-02-23

    The possibility of changing the number of synapses may be an important asset in the treatment of neurological diseases. In this context, the synaptogenic role of the phosphoinositide-3-kinase (PI3K) signaling cascade has been previously demonstrated in Drosophila. This study shows that treatment with a PI3K-activating transduction peptide is able to promote synaptogenesis and spinogenesis in primary cultures of rat hippocampal neurons, as well as in CA1 hippocampal neurons in vivo. In culture, the peptide increases synapse density independently of cell density, culture age, dendritic complexity, or synapse type. The induced synapses also increase neurotransmitter release from cultured neurons. The synaptogenic signaling pathway includes PI3K-Akt. Furthermore, the treatment is effective on adult neurons, where it induces spinogenesis and enhances the cognitive behavior of treated animals in a fear-conditioning assay. These findings demonstrate that functional synaptogenesis can be induced in mature mammalian brains through PI3K activation.

  5. Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons.

    Science.gov (United States)

    Lobanova, Anastasia; She, Robert; Pieraut, Simon; Clapp, Charlie; Maximov, Anton; Denchi, Eros Lazzerini

    2017-04-01

    Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans. © 2017 Lobanova et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Neuron activity in rat hippocampus and motor cortex during discrimination reversal.

    Science.gov (United States)

    Disterhoft, J F; Segal, M

    1978-01-01

    Chronic unit activity and gross movement were recorded from rats during two discrimination reversals in a classical appetitive conditioning situation. The anticipatory movement decreased in response to the former CS+ tone and increased to the previous CS- tone after each reversal. Hippocampus and motor cortex were differently related to these two kinds of behavioral change. Response rates of hippocampal neurons were more closely related to the increased movement response to the former CS- which now signaled food. Motor cortex neuron responses were more closely correlated with the decrease in movement responses to the former CS+ which became neutral after the reversal. It appeared that hippocampal neurons could have been involved in one cognitive aspect of the situation, motor cortex neurons in another. The data were related to current functional concepts of these brain regions.

  7. Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development

    Directory of Open Access Journals (Sweden)

    Xiaoning Chen

    2015-01-01

    Full Text Available Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERTGluΔ mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

  8. The diverging force of imitation: integrating cognitive science and hermeneutics

    NARCIS (Netherlands)

    Keestra, M.

    2008-01-01

    Recent research on infant and animal imitation and on mirror neuron systems has brought imitation back in focus in psychology and cognitive science. This topic has always been important for philosophical hermeneutics as well, focusing on theory and method of understanding. Unfortunately, relations

  9. Computational approaches to cognition: the bottom-up view.

    Science.gov (United States)

    Koch, C

    1993-04-01

    How can higher level aspects of cognition, such as figure-ground segregation, object recognition, selective focal attention and ultimately even awareness, be implemented at the level of synapses and neurons? A number of theoretical studies emerging out of the connectionist and the computational neuroscience communities are starting to address these issues using neural plausible models.

  10. Cerebral metabolism in HIV infected patients with non-cognitive disorder using single voxel magnetic resonance spectroscopy

    Directory of Open Access Journals (Sweden)

    Shi Qi

    2015-09-01

    Conclusion: HIV infection induces inflammation in basal ganglia region, frontal lobe and parietal lobe before non-cognitive disorder occurs after HIV infection. However, the basal ganga region sees more neurons loss.

  11. Learning of time series through neuron-to-neuron instruction

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Y [Department of Physics, Kyoto University, Kyoto 606-8502, (Japan); Kinzel, W [Institut fuer Theoretische Physik, Universitaet Wurzburg, 97074 Wurzburg (Germany); Shinomoto, S [Department of Physics, Kyoto University, Kyoto (Japan)

    2003-02-07

    A model neuron with delayline feedback connections can learn a time series generated by another model neuron. It has been known that some student neurons that have completed such learning under the instruction of a teacher's quasi-periodic sequence mimic the teacher's time series over a long interval, even after instruction has ceased. We found that in addition to such faithful students, there are unfaithful students whose time series eventually diverge exponentially from that of the teacher. In order to understand the circumstances that allow for such a variety of students, the orbit dimension was estimated numerically. The quasi-periodic orbits in question were found to be confined in spaces with dimensions significantly smaller than that of the full phase space.

  12. Learning of time series through neuron-to-neuron instruction

    International Nuclear Information System (INIS)

    Miyazaki, Y; Kinzel, W; Shinomoto, S

    2003-01-01

    A model neuron with delayline feedback connections can learn a time series generated by another model neuron. It has been known that some student neurons that have completed such learning under the instruction of a teacher's quasi-periodic sequence mimic the teacher's time series over a long interval, even after instruction has ceased. We found that in addition to such faithful students, there are unfaithful students whose time series eventually diverge exponentially from that of the teacher. In order to understand the circumstances that allow for such a variety of students, the orbit dimension was estimated numerically. The quasi-periodic orbits in question were found to be confined in spaces with dimensions significantly smaller than that of the full phase space

  13. Neuronal oscillations enhance stimulus discrimination by ensuring action potential precision

    DEFF Research Database (Denmark)

    Schaefer, Andreas T; Angelo, Kamilla; Spors, Hartwig

    2006-01-01

    generated membrane potential oscillations dramatically improve action potential (AP) precision by removing the membrane potential variance associated with jitter-accumulating trains of APs. This increased AP precision occurred irrespective of cell type and--at oscillation frequencies ranging from 3 to 65 Hz......Although oscillations in membrane potential are a prominent feature of sensory, motor, and cognitive function, their precise role in signal processing remains elusive. Here we show, using a combination of in vivo, in vitro, and theoretical approaches, that both synaptically and intrinsically......, membrane potential oscillations dramatically enhance the discriminatory capabilities of individual neurons and networks of cells and provide one attractive explanation for their abundance in neurophysiological systems....

  14. Focusing on neuronal cell-type specific mechanisms for brain circuit organization, function and dysfunction

    Institute of Scientific and Technical Information of China (English)

    Lu Li

    2017-01-01

    Mammalian brain circuits consist of dynamically interconnected neurons with characteristic morphology, physiology, connectivity and genetics which are often called neuronal cell types. Neuronal cell types have been considered as building blocks of brain circuits, but knowledge of how neuron types or subtypes connect to and interact with each other to perform neural computation is still lacking. Such mechanistic insights are critical not only to our understanding of normal brain functions, such as perception, motion and cognition, but also to brain disorders including Alzheimer's disease, Schizophrenia and epilepsy, to name a few. Thus it is necessary to carry out systematic and standardized studies on neuronal cell-type specific mechanisms for brain circuit organization and function, which will provide good opportunities to bridge basic and clinical research. Here based on recent technology advancements, we discuss the strategy to target and manipulate specific populations of neuronsin vivo to provide unique insights on how neuron types or subtypes behave, interact, and generate emergent properties in a fully connected brain network. Our approach is highlighted by combining transgenic animal models, targeted electrophysiology and imaging with robotics, thus complete and standardized mapping ofin vivo properties of genetically defined neuron populations can be achieved in transgenic mouse models, which will facilitate the development of novel therapeutic strategies for brain disorders.

  15. Cognition in plants

    NARCIS (Netherlands)

    Calvo, P.; Keijzer, F.A.

    2009-01-01

    To what extent can plants be considered cognitive from the perspective of embodied cognition? Cognition is interpreted very broadly within embodied cognition, and the current evidence for plant intelligence might find an important theoretical background here. However, embodied cognition does stress

  16. The mirror-neuron system.

    Science.gov (United States)

    Rizzolatti, Giacomo; Craighero, Laila

    2004-01-01

    A category of stimuli of great importance for primates, humans in particular, is that formed by actions done by other individuals. If we want to survive, we must understand the actions of others. Furthermore, without action understanding, social organization is impossible. In the case of humans, there is another faculty that depends on the observation of others' actions: imitation learning. Unlike most species, we are able to learn by imitation, and this faculty is at the basis of human culture. In this review we present data on a neurophysiological mechanism--the mirror-neuron mechanism--that appears to play a fundamental role in both action understanding and imitation. We describe first the functional properties of mirror neurons in monkeys. We review next the characteristics of the mirror-neuron system in humans. We stress, in particular, those properties specific to the human mirror-neuron system that might explain the human capacity to learn by imitation. We conclude by discussing the relationship between the mirror-neuron system and language.

  17. Neuronal factors determining high intelligence.

    Science.gov (United States)

    Dicke, Ursula; Roth, Gerhard

    2016-01-05

    Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity--factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. © 2015 The Author(s).

  18. Energy Model of Neuron Activation.

    Science.gov (United States)

    Romanyshyn, Yuriy; Smerdov, Andriy; Petrytska, Svitlana

    2017-02-01

    On the basis of the neurophysiological strength-duration (amplitude-duration) curve of neuron activation (which relates the threshold amplitude of a rectangular current pulse of neuron activation to the pulse duration), as well as with the use of activation energy constraint (the threshold curve corresponds to the energy threshold of neuron activation by a rectangular current pulse), an energy model of neuron activation by a single current pulse has been constructed. The constructed model of activation, which determines its spectral properties, is a bandpass filter. Under the condition of minimum-phase feature of the neuron activation model, on the basis of Hilbert transform, the possibilities of phase-frequency response calculation from its amplitude-frequency response have been considered. Approximation to the amplitude-frequency response by the response of the Butterworth filter of the first order, as well as obtaining the pulse response corresponding to this approximation, give us the possibility of analyzing the efficiency of activating current pulses of various shapes, including analysis in accordance with the energy constraint.

  19. A supplementary circuit rule-set for the neuronal wiring

    Directory of Open Access Journals (Sweden)

    Kunjumon I Vadakkan

    2013-05-01

    Full Text Available Limitations of known anatomical circuit rules necessitate the identification of supplementary rules. This is essential for explaining how associative sensory stimuli induce nervous system changes that generate internal sensations of memory, concurrent with triggering specific motor activities in response to specific cue stimuli. A candidate mechanism is rapidly reversible, yet stabilizable membrane hemi-fusion formed between the closely apposed postsynaptic membranes of different neurons at locations of convergence of sensory inputs during associative learning. The lateral entry of activity from the cue stimulus-activated postsynapse re-activates the opposite postsynapse through the hemi-fused area and induces the basic units of internal sensation (namely, semblions as a systems property. Working, short-term and long-term memories can be viewed as functions of the number of re-activatible hemi-fusions present at the time of memory retrieval. Blocking membrane hemi-fusion either by the insertion of the herpes simplex virus glycoproteins or by the deposition of insoluble intermediates of amyloid and tau proteins in the inter-postsynaptic extracellular matrix space leads to cognitive impairments, supporting this mechanism. The introduction of membrane fusion blockers into the postsynaptic cell cytoplasm that attenuates long-term potentiation, a correlate of behavioral motor activities in response to memory retrieval, provides further support. The lateral spread of activity through the inter-postsynaptic membrane is capable of contributing to oscillating neuronal activity at certain neuronal orders. At the resting state these oscillations provide sub-threshold activation to many neurons at higher orders, including motor neurons maintaining them at a low initiation threshold for motor activity.

  20. Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability

    Directory of Open Access Journals (Sweden)

    Christina R. Muratore

    2017-12-01

    Full Text Available Summary: Alzheimer's disease (AD induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aβ, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aβ plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable and caudal fates (relatively spared in AD. We find that both the generation of Aβ and the responsiveness of TAU to Aβ are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD. : In this article, Muratore et al. examine differential vulnerability of neuronal subtypes in AD by directing iPSC lines from control and familial AD subjects to different regional neuronal fates. APP processing and TAU proteostasis are differentially affected between regional fates, such that neuronal cell type dictates generation of and responsiveness to Aβ. Keywords: Alzheimer's disease, disease modeling, iPSCs, neural stem cells, Abeta, Tau, selective vulnerability, amyloid, familial AD, differential susceptibility

  1. Turning skin into dopamine neurons

    Institute of Scientific and Technical Information of China (English)

    Malin Parmar; Johan Jakobsson

    2011-01-01

    The possibility to generate neurons from fibroblasts became a reality with the development of iPS technology a few years ago.By reprogramming somatic cells using transcription factor (TF) overexpression,it is possible to generate pluripotent stem cells that then can be differentiated into any somatic cell type including various subtypes of neurons.This raises the possibility of using donor-matched or even patientspecific cells for cell therapy of neurological disorders such as Parkinson's disease (PD),Huntington's disease and stroke.Supporting this idea,dopamine neurons,which are the cells dying in PD,derived from human iPS cells have been demonstrated to survive transplantation and reverse motor symptoms in animal models of PD [1].

  2. Dogs Have the Most Neurons, Though Not the Largest Brain: Trade-Off between Body Mass and Number of Neurons in the Cerebral Cortex of Large Carnivoran Species

    Directory of Open Access Journals (Sweden)

    Débora Jardim-Messeder

    2017-12-01

    Full Text Available Carnivorans are a diverse group of mammals that includes carnivorous, omnivorous and herbivorous, domesticated and wild species, with a large range of brain sizes. Carnivory is one of several factors expected to be cognitively demanding for carnivorans due to a requirement to outsmart larger prey. On the other hand, large carnivoran species have high hunting costs and unreliable feeding patterns, which, given the high metabolic cost of brain neurons, might put them at risk of metabolic constraints regarding how many brain neurons they can afford, especially in the cerebral cortex. For a given cortical size, do carnivoran species have more cortical neurons than the herbivorous species they prey upon? We find they do not; carnivorans (cat, mongoose, dog, hyena, lion share with non-primates, including artiodactyls (the typical prey of large carnivorans, roughly the same relationship between cortical mass and number of neurons, which suggests that carnivorans are subject to the same evolutionary scaling rules as other non-primate clades. However, there are a few important exceptions. Carnivorans stand out in that the usual relationship between larger body, larger cortical mass and larger number of cortical neurons only applies to small and medium-sized species, and not beyond dogs: we find that the golden retriever dog has more cortical neurons than the striped hyena, African lion and even brown bear, even though the latter species have up to three times larger cortices than dogs. Remarkably, the brown bear cerebral cortex, the largest examined, only has as many neurons as the ten times smaller cat cerebral cortex, although it does have the expected ten times as many non-neuronal cells in the cerebral cortex compared to the cat. We also find that raccoons have dog-like numbers of neurons in their cat-sized brain, which makes them comparable to primates in neuronal density. Comparison of domestic and wild species suggests that the neuronal

  3. Cognitive processes in CBT

    NARCIS (Netherlands)

    Becker, E.S.; Vrijsen, J.N.; Hofmann, S.G.; Asmundson, G.J.G.

    2017-01-01

    Automatic cognitive processing helps us navigate the world. However, if the emotional and cognitive interplay becomes skewed, those cognitive processes can become maladaptive and result in psychopathology. Although biases are present in most mental disorders, different disorders are characterized by

  4. Mild Cognitive Impairment (MCI)

    Science.gov (United States)

    Mild cognitive impairment (MCI) Overview Mild cognitive impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and the more-serious decline of dementia. It ...

  5. Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species.

    Science.gov (United States)

    Ghosh, Debolina; LeVault, Kelsey R; Brewer, Gregory J

    2014-01-01

    To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. COGNITIVE COMPETENCE COMPARED TO COGNITIVE INDEPENDENCE AND COGNITIVE ACTIVITY

    Directory of Open Access Journals (Sweden)

    Irina B. Shmigirilova

    2014-01-01

    Full Text Available The research is aimed at identifying the essence of the cognitive competence concept in comparison with the concepts of cognitive independence and activity.Methods: The methodology implies a theoretical analysis of psychopedagogical and methodological materials on the cognitive competence formation; generalized teaching experience; empirical methods of direct observations of educational process in the secondary school classrooms; interviews with school teachers and pupils.Results: The research outcomes reveal a semantic intersection between the cognitive competence, independence and activity, and their distinctive features. The paper emphasizes the importance of cognitive competence as an adaptive mechanism in situations of uncertainty and instability.Scientific novelty: The author clarifies the concept of cognitive competence regarding it as a multi-component and systematic characteristic of a personality.Practical significance: The research findings can be used by specialists in didactics developing the teaching techniques of cognitive competence formation for schoolchildren.

  7. 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......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...

  8. Calcium signals in olfactory neurons.

    Science.gov (United States)

    Tareilus, E; Noé, J; Breer, H

    1995-11-09

    Laser scanning confocal microscopy in combination with the fluorescent calcium indicators Fluo-3 and Fura-Red was employed to estimate the intracellular concentration of free calcium ions in individual olfactory receptor neurons and to monitor temporal and spatial changes in the Ca(2+)-level upon stimulation. The chemosensory cells responded to odorants with a significant increase in the calcium concentration, preferentially in the dendritic knob. Applying various stimulation paradigma, it was found that in a population of isolated cells, subsets of receptor neurons display distinct patterns of responsiveness.

  9. Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

    Directory of Open Access Journals (Sweden)

    Grammas Paula

    2009-03-01

    Full Text Available Abstract Background Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD, have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress. Methods Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 μM. Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots. Results Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p Conclusion These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.

  10. Acute dosing of vortioxetine strengthens event-related brain activity associated with engagement of attention and cognitive functioning in rats

    DEFF Research Database (Denmark)

    Laursen, Bettina; Bundgaard, Cecilie H; Graversen, Carina

    2017-01-01

    Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10 mg/kg) in rats performin...... synchronization during attentive and cognitive processing.......Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10 mg/kg) in rats performing...... increased EEG power in all regions. Additionally, neuronal synchronization was increased in vehicle-treated rats during both early and late ERP responses to target tones. This indicates a significant consistency of local phases across trials during high attentional load. During early sensory processing...

  11. Conceptions of cognition for cognitive engineering

    DEFF Research Database (Denmark)

    Blomberg, Olle

    2011-01-01

    Cognitive processes, cognitive psychology tells us, unfold in our heads. In contrast, several approaches in cognitive engineering argue for a shift of unit of analysis from what is going on in the heads of operators to the workings of whole socio-technical systems. This shift is sometimes presented...... as part of the development of a new understanding of what cognition is and where the boundaries of cognitive systems are. Cognition, it is claimed, is not just situated or embedded, but extended and distributed in the world. My main question in this article is what the practical significance...... is of this framing of an expanded unit of analysis in a cognitive vocabulary. I focus on possible consequences for how cognitive engineering practitioners think about function allocation in system design, and on what the relative benefits and costs are of having a common framework and vocabulary for talking about...

  12. Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease.

    Science.gov (United States)

    Kwakowsky, Andrea; Milne, Michael R; Waldvogel, Henry J; Faull, Richard L

    2016-12-17

    The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

  13. Can cognitive science create a cognitive economics?

    Science.gov (United States)

    Chater, Nick

    2015-02-01

    Cognitive science can intersect with economics in at least three productive ways: by providing richer models of individual behaviour for use in economic analysis; by drawing from economic theory in order to model distributed cognition; and jointly to create more powerful 'rational' models of cognitive processes and social interaction. There is the prospect of moving from behavioural economics to a genuinely cognitive economics. Copyright © 2014. Published by Elsevier B.V.

  14. Integrating cognitive (neuroscience using mechanisms

    Directory of Open Access Journals (Sweden)

    Marcin Miłkowski

    2016-11-01

    Full Text Available In this paper, an account of theoretical integration in cognitive (neuroscience from the mechanistic perspective is defended. It is argued that mechanistic patterns of integration can be better understood in terms of constraints on representations of mechanisms, not just on the space of possible mechanisms, as previous accounts of integration had it. This way, integration can be analyzed in more detail with the help of constraintsatisfaction account of coherence between scientific represen-tations. In particular, the account has resources to talk of idealizations and research heuristics employed by researchers to combine separate results and theoretical frameworks. The account is subsequently applied to an example of successful integration in the research on hippocampus and memory, and to a failure of integration in the research on mirror neurons as purportedly explanatory of sexual orientation.

  15. THYROID HORMONE TREATED ASTROCYTES INDUCE MATURATION OF CEREBRAL CORTICAL NEURONS THROUGH MODULATION OF PROTEOGLYCAN LEVELS

    Directory of Open Access Journals (Sweden)

    Romulo Sperduto Dezonne

    2013-08-01

    Full Text Available Proper brain neuronal circuitry formation and synapse development is dependent on specific cues, either genetic or epigenetic, provided by the surrounding neural environment. Within these signals, thyroid hormones (T3 and T4 play crucial role in several steps of brain morphogenesis including proliferation of progenitor cells, neuronal differentiation, maturation, migration, and synapse formation. The lack of thyroid hormones during childhood is associated with several impair neuronal connections, cognitive deficits, and mental disorders. Many of the thyroid hormones effects are mediated by astrocytes, although the mechanisms underlying these events are still unknown. In this work, we investigated the effect of 3, 5, 3’-triiodothyronine-treated (T3-treated astrocytes on cerebral cortex neuronal differentiation. Culture of neural progenitors from embryonic cerebral cortex mice onto T3-treated astrocyte monolayers yielded an increment in neuronal population, followed by enhancement of neuronal maturation, arborization and neurite outgrowth. In addition, real time PCR assays revealed an increase in the levels of the heparan sulfate proteoglycans, Glypican 1 (GPC-1 and Syndecans 3 e 4 (SDC-3 e SDC-4, followed by a decrease in the levels of the chondroitin sulfate proteoglycan, Versican. Disruption of glycosaminoglycan chains by chondroitinase AC or heparanase III completely abolished the effects of T3-treated astrocytes on neuronal morphogenesis. Our work provides evidence that astrocytes are key mediators of T3 actions on cerebral cortex neuronal development and identified potential molecules and pathways involved in neurite extension; which might eventually contribute to a better understanding of axonal regeneration, synapse formation and neuronal circuitry recover.

  16. Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

    Science.gov (United States)

    Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

    2017-11-15

    Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Unbalanced Neuronal Circuits in Addiction

    OpenAIRE

    Volkow, Nora D.; Wang, Gen-Jack; Tomasi, Dardo; Baler, Ruben D.

    2013-01-01

    Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain's neuronal circuits that mediate reward, motivation, , to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it.

  18. Computing with Spiking Neuron Networks

    NARCIS (Netherlands)

    H. Paugam-Moisy; S.M. Bohte (Sander); G. Rozenberg; T.H.W. Baeck (Thomas); J.N. Kok (Joost)

    2012-01-01

    htmlabstractAbstract Spiking Neuron Networks (SNNs) are often referred to as the 3rd gener- ation of neural networks. Highly inspired from natural computing in the brain and recent advances in neurosciences, they derive their strength and interest from an ac- curate modeling of synaptic interactions

  19. What do mirror neurons mirror?

    NARCIS (Netherlands)

    Uithol, S.; Rooij, I.J.E.I. van; Bekkering, H.; Haselager, W.F.G.

    2011-01-01

    Single cell recordings in monkeys provide strong evidence for an important role of the motor system in action understanding. This evidence is backed up by data from studies of the (human) mirror neuron system using neuroimaging or TMS techniques, and behavioral experiments. Although the data

  20. Optimal compensation for neuron loss

    Science.gov (United States)

    Barrett, David GT; Denève, Sophie; Machens, Christian K

    2016-01-01

    The brain has an impressive ability to withstand neural damage. Diseases that kill neurons can go unnoticed for years, and incomplete brain lesions or silencing of neurons often fail to produce any behavioral effect. How does the brain compensate for such damage, and what are the limits of this compensation? We propose that neural circuits instantly compensate for neuron loss, thereby preserving their function as much as possible. We show that this compensation can explain changes in tuning curves induced by neuron silencing across a variety of systems, including the primary visual cortex. We find that compensatory mechanisms can be implemented through the dynamics of networks with a tight balance of excitation and inhibition, without requiring synaptic plasticity. The limits of this compensatory mechanism are reached when excitation and inhibition become unbalanced, thereby demarcating a recovery boundary, where signal representation fails and where diseases may become symptomatic. DOI: http://dx.doi.org/10.7554/eLife.12454.001 PMID:27935480

  1. Hypothalamic neurones governing glucose homeostasis.

    Science.gov (United States)

    Coppari, R

    2015-06-01

    The notion that the brain directly controls the level of glucose in the blood (glycaemia) independent of its known action on food intake and body weight has been known ever since 1849. That year, the French physiologist Dr Claude Bernard reported that physical puncture of the floor of the fourth cerebral ventricle rapidly leads to an increased level of sugar in the blood (and urine) in rabbits. Despite this important discovery, it took approximately 150 years before significant efforts aimed at understanding the underlying mechanism of brain-mediated control of glucose metabolism were made. Technological developments allowing for genetically-mediated manipulation of selected molecular pathways in a neurone-type-specific fashion unravelled the importance of specific molecules in specific neuronal populations. These neuronal pathways govern glucose metabolism in the presence and even in the absence of insulin. Also, a peculiarity of these pathways is that certain biochemically-defined neurones govern glucose metabolism in a tissue-specific fashion. © 2015 British Society for Neuroendocrinology.

  2. Lateral Information Processing by Spiking Neurons: A Theoretical Model of the Neural Correlate of Consciousness

    Directory of Open Access Journals (Sweden)

    Marc Ebner

    2011-01-01

    Full Text Available Cognitive brain functions, for example, sensory perception, motor control and learning, are understood as computation by axonal-dendritic chemical synapses in networks of integrate-and-fire neurons. Cognitive brain functions may occur either consciously or nonconsciously (on “autopilot”. Conscious cognition is marked by gamma synchrony EEG, mediated largely by dendritic-dendritic gap junctions, sideways connections in input/integration layers. Gap-junction-connected neurons define a sub-network within a larger neural network. A theoretical model (the “conscious pilot” suggests that as gap junctions open and close, a gamma-synchronized subnetwork, or zone moves through the brain as an executive agent, converting nonconscious “auto-pilot” cognition to consciousness, and enhancing computation by coherent processing and collective integration. In this study we implemented sideways “gap junctions” in a single-layer artificial neural network to perform figure/ground separation. The set of neurons connected through gap junctions form a reconfigurable resistive grid or sub-network zone. In the model, outgoing spikes are temporally integrated and spatially averaged using the fixed resistive grid set up by neurons of similar function which are connected through gap-junctions. This spatial average, essentially a feedback signal from the neuron's output, determines whether particular gap junctions between neurons will open or close. Neurons connected through open gap junctions synchronize their output spikes. We have tested our gap-junction-defined sub-network in a one-layer neural network on artificial retinal inputs using real-world images. Our system is able to perform figure/ground separation where the laterally connected sub-network of neurons represents a perceived object. Even though we only show results for visual stimuli, our approach should generalize to other modalities. The system demonstrates a moving sub-network zone of

  3. From sensation to cognition.

    Science.gov (United States)

    Mesulam, M M

    1998-06-01

    Sensory information undergoes extensive associative elaboration and attentional modulation as it becomes incorporated into the texture of cognition. This process occurs along a core synaptic hierarchy which includes the primary sensory, upstream unimodal, downstream unimodal, heteromodal, paralimbic and limbic zones of the cerebral cortex. Connections from one zone to another are reciprocal and allow higher synaptic levels to exert a feedback (top-down) influence upon earlier levels of processing. Each cortical area provides a nexus for the convergence of afferents and divergence of efferents. The resultant synaptic organization supports parallel as well as serial processing, and allows each sensory event to initiate multiple cognitive and behavioural outcomes. Upstream sectors of unimodal association areas encode basic features of sensation such as colour, motion, form and pitch. More complex contents of sensory experience such as objects, faces, word-forms, spatial locations and sound sequences become encoded within downstream sectors of unimodal areas by groups of coarsely tuned neurons. The highest synaptic levels of sensory-fugal processing are occupied by heteromodal, paralimbic and limbic cortices, collectively known as transmodal areas. The unique role of these areas is to bind multiple unimodal and other transmodal areas into distributed but integrated multimodal representations. Transmodal areas in the midtemporal cortex, Wernicke's area, the hippocampal-entorhinal complex and the posterior parietal cortex provide critical gateways for transforming perception into recognition, word-forms into meaning, scenes and events into experiences, and spatial locations into targets for exploration. All cognitive processes arise from analogous associative transformations of similar sets of sensory inputs. The differences in the resultant cognitive operation are determined by the anatomical and physiological properties of the transmodal node that acts as the critical

  4. The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

    Science.gov (United States)

    Iacono, D; Markesbery, W R; Gross, M; Pletnikova, O; Rudow, G; Zandi, P; Troncoso, J C

    2009-09-01

    It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

  5. BlastNeuron for Automated Comparison, Retrieval and Clustering of 3D Neuron Morphologies.

    Science.gov (United States)

    Wan, Yinan; Long, Fuhui; Qu, Lei; Xiao, Hang; Hawrylycz, Michael; Myers, Eugene W; Peng, Hanchuan

    2015-10-01

    Characterizing the identity and types of neurons in the brain, as well as their associated function, requires a means of quantifying and comparing 3D neuron morphology. Presently, neuron comparison methods are based on statistics from neuronal morphology such as size and number of branches, which are not fully suitable for detecting local similarities and differences in the detailed structure. We developed BlastNeuron to compare neurons in terms of their global appearance, detailed arborization patterns, and topological similarity. BlastNeuron first compares and clusters 3D neuron reconstructions based on global morphology features and moment invariants, independent of their orientations, sizes, level of reconstruction and other variations. Subsequently, BlastNeuron performs local alignment between any pair of retrieved neurons via a tree-topology driven dynamic programming method. A 3D correspondence map can thus be generated at the resolution of single reconstruction nodes. We applied BlastNeuron to three datasets: (1) 10,000+ neuron reconstructions from a public morphology database, (2) 681 newly and manually reconstructed neurons, and (3) neurons reconstructions produced using several independent reconstruction methods. Our approach was able to accurately and efficiently retrieve morphologically and functionally similar neuron structures from large morphology database, identify the local common structures, and find clusters of neurons that share similarities in both morphology and molecular profiles.

  6. The neuroscience of observing consciousness & mirror neurons in therapeutic hypnosis.

    Science.gov (United States)

    Rossi, Ernest L; Rossi, Kathryn L

    2006-04-01

    Neuroscience documents the activity of "mirror neurons" in the human brain as a mechanism whereby we experience empathy and recognize the intentions of others by observing their behavior and automatically matching their brain activity. This neural basis of empathy finds support in research on dysfunctions in the mirror systems of humans with autism and fMRI research on normal subjects designed to assess intentionality, emotions, and complex cognition. Such empathy research now appears to be consistent with the historical and research literature on hypnotic induction, rapport, and many of the classical phenomena of suggestion. A preliminary outline of how mirror neurons may function as a rapport zone mediating between observing consciousness, the gene expression/protein synthesis cycle, and brain plasticity in therapeutic hypnosis and psychosomatic medicine is proposed. Brain plasticity is generalized in the theory, research, and practice of utilizing mirror neurons as an explanatory framework in developing and training new skill sets for facilitating an activity-dependent approach to creative problem solving, mind-body healing, and rehabilitation with therapeutic hypnosis.

  7. Oscillating from Neurosecretion to Multitasking Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    David R. Grattan

    2016-04-01

    Full Text Available In this issue of Cell Reports, Stagkourakis et al. (2016 report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits.

  8. Music cognition and the cognitive sciences.

    Science.gov (United States)

    Pearce, Marcus; Rohrmeier, Martin

    2012-10-01

    Why should music be of interest to cognitive scientists, and what role does it play in human cognition? We review three factors that make music an important topic for cognitive scientific research. First, music is a universal human trait fulfilling crucial roles in everyday life. Second, music has an important part to play in ontogenetic development and human evolution. Third, appreciating and producing music simultaneously engage many complex perceptual, cognitive, and emotional processes, rendering music an ideal object for studying the mind. We propose an integrated status for music cognition in the Cognitive Sciences and conclude by reviewing challenges and big questions in the field and the way in which these reflect recent developments. Copyright © 2012 Cognitive Science Society, Inc.

  9. Coherence resonance in globally coupled neuronal networks with different neuron numbers

    International Nuclear Information System (INIS)

    Ning Wei-Lian; Zhang Zheng-Zhen; Zeng Shang-You; Luo Xiao-Shu; Hu Jin-Lin; Zeng Shao-Wen; Qiu Yi; Wu Hui-Si

    2012-01-01

    Because a brain consists of tremendous neuronal networks with different neuron numbers ranging from tens to tens of thousands, we study the coherence resonance due to ion channel noises in globally coupled neuronal networks with different neuron numbers. We confirm that for all neuronal networks with different neuron numbers there exist the array enhanced coherence resonance and the optimal synaptic conductance to cause the maximal spiking coherence. Furthermoremore, the enhancement effects of coupling on spiking coherence and on optimal synaptic conductance are almost the same, regardless of the neuron numbers in the neuronal networks. Therefore for all the neuronal networks with different neuron numbers in the brain, relative weak synaptic conductance (0.1 mS/cm 2 ) is sufficient to induce the maximal spiking coherence and the best sub-threshold signal encoding. (interdisciplinary physics and related areas of science and technology)

  10. [Cannabis: A Cognitive Illusion].

    Science.gov (United States)

    Galván, Gonzalo; Guerrero-Martelo, Manuel; Vásquez De la Hoz, Francisco

    The vision of cannabis as a soft drug is due to the low risk perception that young and old people have of the drug. This perception is based on erroneous beliefs that people have about the drug. To compare the beliefs of cannabis use and consequences among adolescents with a lifetime prevalence of cannabis use and those without a lifetime prevalence of cannabis use. Quantitative, descriptive and cross-sectional study with a probability sample of 156 high school students who completed an ad-hoc questionnaire that included sociodemographic data and 22 questions about the beliefs that young people had about cannabis use and its consequences. The lifetime prevalence of cannabis use was 13.5%. The prevalence group consisted mostly of males. Statistically significant differences between different groups and different beliefs were found. The group with no lifetime prevalence of cannabis use perceived higher risk as regards the damage that cannabis can cause to memory, other cognitive functions, neurons, mental health, and general health. The group with a lifetime prevalence of cannabis use perceived a lower risk as regards the use of cannabis, and think that intelligent people smoke cannabis, and that cannabis has positive effects on the brain, increasing creativity. and is used to cure mental diseases. Those who used cannabis once in their life perceive the use of the substance as less harmful or less potential danger to health compared to those who never consumed. In fact those who consumed at some time even have beliefs that suggest positive effects in those people that consume it. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  11. Responses of single neurons and neuronal ensembles in frog first- and second-order olfactory neurons

    Czech Academy of Sciences Publication Activity Database

    Rospars, J. P.; Šanda, Pavel; Lánský, Petr; Duchamp-Viret, P.

    2013-01-01

    Roč. 1536, NOV 6 (2013), s. 144-158 ISSN 0006-8993 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GAP103/11/0282 Institutional support: RVO:67985823 Keywords : olfaction * spiking activity * neuronal model Subject RIV: JD - Computer Applications, Robotics Impact factor: 2.828, year: 2013

  12. Depletion of new neurons by image guided irradiation

    Directory of Open Access Journals (Sweden)

    Yao-Fang eTan

    2011-04-01

    Full Text Available Ionizing radiation continues to be a relevant tool in both imaging and the treatment of cancer. Experimental uses of focal irradiation have recently been expanded to studies of new neurons in the adult brain. Such studies have shown cognitive deficits following radiation treatment and raised caution as to possible unintentional effects that may occur in humans. Conflicting outcomes of the effects of irradiation on adult neurogenesis suggest that the effects are either transient or permanent. In this study, we used an irradiation apparatus employed in the treatment of human tumors to assess radiation effects on rat neurogenesis. For subjects we used adult male rats (Sprague-Dawley under anesthesia. The irradiation beam was directed at the hippocampus, a center for learning and memory and the site of neurogenic activity in adult brain. The irradiation was applied at a dose-rate 0.6 Gy/min for total single-fraction, doses ranging from 0.5-10.0 Gy. The animals were returned to home cages and recovered with no sign of any side effects. The neurogenesis was measured either 1 week or 6 weeks after the irradiation. At 1 week, the number of neuronal progenitors was reduced in a dose-dependent manner with the 50% reduction at 0.78 Gy. The dose-response curve was well fitted by a double exponential suggesting two processes. Examination of the tissue with quantitative immunohistochemistry revealed a dominant low-dose effect on neuronal progenitors resulting in 80% suppression of neurogenesis. This effect was partially reversible, possibly due to compensatory proliferation of the remaining precursors. At higher doses (> 5Gy there was additional, nearly complete block of neurogenesis without compensatory proliferation. We conclude that notwithstanding the usefulness of irradiation for experimental purposes, the exposure of human subjects to doses often used in radiotherapy treatment could be damaging and cause cognitive impairments.

  13. The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

    Directory of Open Access Journals (Sweden)

    Xin Xu

    2017-07-01

    Full Text Available Brain-derived neurotrophic factor (Bdnf has been implicated in several neurological disorders including Rett syndrome (RTT, an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2. The human BDNF gene has a single nucleotide polymorphism (SNP—a methionine (met substitution for valine (val at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT and Mecp2 knockout (KO mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.

  14. Symbiotic Cognitive Computing

    OpenAIRE

    Farrell, Robert G.; Lenchner, Jonathan; Kephjart, Jeffrey O.; Webb, Alan M.; Muller, MIchael J.; Erikson, Thomas D.; Melville, David O.; Bellamy, Rachel K.E.; Gruen, Daniel M.; Connell, Jonathan H.; Soroker, Danny; Aaron, Andy; Trewin, Shari M.; Ashoori, Maryam; Ellis, Jason B.

    2016-01-01

    IBM Research is engaged in a research program in symbiotic cognitive computing to investigate how to embed cognitive computing in physical spaces. This article proposes 5 key principles of symbiotic cognitive computing.  We describe how these principles are applied in a particular symbiotic cognitive computing environment and in an illustrative application.  

  15. Histone deacetylases in memory and cognition.

    Science.gov (United States)

    Penney, Jay; Tsai, Li-Huei

    2014-12-09

    Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease. Copyright © 2014, American Association for the Advancement of Science.

  16. Anticipation: Beyond synthetic biology and cognitive robotics.

    Science.gov (United States)

    Nasuto, Slawomir J; Hayashi, Yoshikatsu

    2016-10-01

    The aim of this paper is to propose that current robotic technologies cannot have intentional states any more than is feasible within the sensorimotor variant of embodied cognition. It argues that anticipation is an emerging concept that can provide a bridge between both the deepest philosophical theories about the nature of life and cognition and the empirical biological and cognitive sciences steeped in reductionist and Newtonian conceptions of causality. The paper advocates that in order to move forward, cognitive robotics needs to embrace new platforms and a conceptual framework that will enable it to pursue, in a meaningful way, questions about autonomy and purposeful behaviour. We suggest that hybrid systems, part robotic and part cultures of neurones, offer experimental platforms where different dimensions of enactivism (sensorimotor, constitutive foundations of biological autonomy, including anticipation), and their relative contributions to cognition, can be investigated in an integrated way. A careful progression, mindful to the deep philosophical concerns but also respecting empirical evidence, will ultimately lead towards unifying theoretical and empirical biological sciences and may offer advancement where reductionist sciences have been so far faltering. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  17. Time-scale invariance as an emergent property in a perceptron with realistic, noisy neurons.

    Science.gov (United States)

    Buhusi, Catalin V; Oprisan, Sorinel A

    2013-05-01

    In most species, interval timing is time-scale invariant: errors in time estimation scale up linearly with the estimated duration. In mammals, time-scale invariance is ubiquitous over behavioral, lesion, and pharmacological manipulations. For example, dopaminergic drugs induce an immediate, whereas cholinergic drugs induce a gradual, scalar change in timing. Behavioral theories posit that time-scale invariance derives from particular computations, rules, or coding schemes. In contrast, we discuss a simple neural circuit, the perceptron, whose output neurons fire in a clockwise fashion based on the pattern of coincidental activation of its input neurons. We show numerically that time-scale invariance emerges spontaneously in a perceptron with realistic neurons, in the presence of noise. Under the assumption that dopaminergic drugs modulate the firing of input neurons, and that cholinergic drugs modulate the memory representation of the criterion time, we show that a perceptron with realistic neurons reproduces the pharmacological clock and memory patterns, and their time-scale invariance, in the presence of noise. These results suggest that rather than being a signature of higher order cognitive processes or specific computations related to timing, time-scale invariance may spontaneously emerge in a massively connected brain from the intrinsic noise of neurons and circuits, thus providing the simplest explanation for the ubiquity of scale invariance of interval timing. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

    Science.gov (United States)

    Moruno Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra M.; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

    2016-01-01

    Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID:27992857

  19. Transgenic miR132 alters neuronal spine density and impairs novel object recognition memory.

    Directory of Open Access Journals (Sweden)

    Katelin F Hansen

    2010-11-01

    Full Text Available Inducible gene expression plays a central role in neuronal plasticity, learning, and memory, and dysfunction of the underlying molecular events can lead to severe neuronal disorders. In addition to coding transcripts (mRNAs, non-coding microRNAs (miRNAs appear to play a role in these processes. For instance, the CREB-regulated miRNA miR132 has been shown to affect neuronal structure in an activity-dependent manner, yet the details of its physiological effects and the behavioral consequences in vivo remain unclear. To examine these questions, we employed a transgenic mouse strain that expresses miR132 in forebrain neurons. Morphometric analysis of hippocampal neurons revealed that transgenic miR132 triggers a marked increase in dendritic spine density. Additionally, miR132 transgenic mice exhibited a decrease in the expression of MeCP2, a protein implicated in Rett Syndrome and other disorders of mental retardation. Consistent with these findings, miR132 transgenic mice displayed significant deficits in novel object recognition. Together, these data support a role for miR132 as a regulator of neuronal structure and function, and raise the possibility that dysregulation of miR132 could contribute to an array of cognitive disorders.

  20. Neural dynamics as sampling: a model for stochastic computation in recurrent networks of spiking neurons.

    Science.gov (United States)

    Buesing, Lars; Bill, Johannes; Nessler, Bernhard; Maass, Wolfgang

    2011-11-01

    The organization of computations in networks of spiking neurons in the brain is still largely unknown, in particular in view of the inherently stochastic features of their firing activity and the experimentally observed trial-to-trial variability of neural systems in the brain. In principle there exists a powerful computational framework for stochastic computations, probabilistic inference by sampling, which can explain a large number of macroscopic experimental data in neuroscience and cognitive science. But it has turned out to be surprisingly difficult to create a link between these abstract models for stochastic computations and more detailed models of the dynamics of networks of spiking neurons. Here we create such a link and show that under some conditions the stochastic firing activity of networks of spiking neurons can be interpreted as probabilistic inference via Markov chain Monte Carlo (MCMC) sampling. Since common methods for MCMC sampling in distributed systems, such as Gibbs sampling, are inconsistent with the dynamics of spiking neurons, we introduce a different approach based on non-reversible Markov chains that is able to reflect inherent temporal processes of spiking neuronal activity through a suitable choice of random variables. We propose a neural network model and show by a rigorous theoretical analysis that its neural activity implements MCMC sampling of a given distribution, both for the case of discrete and continuous time. This provides a step towards closing the gap between abstract functional models of cortical computation and more detailed models of networks of spiking neurons.

  1. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury.

    Directory of Open Access Journals (Sweden)

    Ann C Halbower

    2006-08-01

    Full Text Available Childhood obstructive sleep apnea (OSA is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function.We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6-16 y group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared. Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency. Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001 and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03.Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential.

  2. Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering.

    Science.gov (United States)

    Vukovic, Jana; Borlikova, Gilyana G; Ruitenberg, Marc J; Robinson, Gregory J; Sullivan, Robert K P; Walker, Tara L; Bartlett, Perry F

    2013-04-10

    It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.

  3. Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine.

    Directory of Open Access Journals (Sweden)

    Ping Zhong

    2011-02-01

    Full Text Available Serotonin exerts a powerful influence on neuronal excitability. In this study, we investigated the effects of serotonin on different neuronal populations in prefrontal cortex (PFC, a major area controlling emotion and cognition. Using whole-cell recordings in PFC slices, we found that bath application of 5-HT dose-dependently increased the firing of FS (fast spiking interneurons, and decreased the firing of pyramidal neurons. The enhancing effect of 5-HT in FS interneurons was mediated by 5-HT₂ receptors, while the reducing effect of 5-HT in pyramidal neurons was mediated by 5-HT₁ receptors. Fluoxetine, the selective serotonin reuptake inhibitor, also induced a concentration-dependent increase in the excitability of FS interneurons, but had little effect on pyramidal neurons. In rats with chronic fluoxetine treatment, the excitability of FS interneurons was significantly increased, while pyramidal neurons remained unchanged. Fluoxetine injection largely occluded the enhancing effect of 5-HT in FS interneurons, but did not alter the reducing effect of 5-HT in pyramidal neurons. These data suggest that the excitability of PFC interneurons and pyramidal neurons is regulated by exogenous 5-HT in an opposing manner, and FS interneurons are the major target of Fluoxetine. It provides a framework for understanding the action of 5-HT and antidepressants in altering PFC network activity.

  4. How to make spinal motor neurons.

    Science.gov (United States)

    Davis-Dusenbery, Brandi N; Williams, Luis A; Klim, Joseph R; Eggan, Kevin

    2014-02-01

    All muscle movements, including breathing, walking, and fine motor skills rely on the function of the spinal motor neuron to transmit signals from the brain to individual muscle groups. Loss of spinal motor neuron function underlies several neurological disorders for which treatment has been hampered by the inability to obtain sufficient quantities of primary motor neurons to perform mechanistic studies or drug screens. Progress towards overcoming this challenge has been achieved through the synthesis of developmental biology paradigms and advances in stem cell and reprogramming technology, which allow the production of motor neurons in vitro. In this Primer, we discuss how the logic of spinal motor neuron development has been applied to allow generation of motor neurons either from pluripotent stem cells by directed differentiation and transcriptional programming, or from somatic cells by direct lineage conversion. Finally, we discuss methods to evaluate the molecular and functional properties of motor neurons generated through each of these techniques.

  5. Firing dynamics of an autaptic neuron

    International Nuclear Information System (INIS)

    Wang Heng-Tong; Chen Yong

    2015-01-01

    Autapses are synapses that connect a neuron to itself in the nervous system. Previously, both experimental and theoretical studies have demonstrated that autaptic connections in the nervous system have a significant physiological function. Autapses in nature provide self-delayed feedback, thus introducing an additional timescale to neuronal activities and causing many dynamic behaviors in neurons. Recently, theoretical studies have revealed that an autapse provides a control option for adjusting the response of a neuron: e.g., an autaptic connection can cause the electrical activities of the Hindmarsh–Rose neuron to switch between quiescent, periodic, and chaotic firing patterns; an autapse can enhance or suppress the mode-locking status of a neuron injected with sinusoidal current; and the firing frequency and interspike interval distributions of the response spike train can also be modified by the autapse. In this paper, we review recent studies that showed how an autapse affects the response of a single neuron. (topical review)

  6. Human temporal cortical single neuron activity during working memory maintenance.

    Science.gov (United States)

    Zamora, Leona; Corina, David; Ojemann, George

    2016-06-01

    The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two

  7. Human Temporal Cortical Single Neuron Activity During Working Memory Maintenance

    Science.gov (United States)

    Zamora, Leona; Corina, David; Ojemann, George

    2016-01-01

    The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two

  8. Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

    Science.gov (United States)

    Grbatinić, Ivan; Marić, Dušica L; Milošević, Nebojša T

    2015-04-07

    Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (pneurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short dendrites. These neurons are

  9. Neuronal Cell Death Induced by Mechanical Percussion Trauma in Cultured Neurons is not Preceded by Alterations in Glucose, Lactate and Glutamine Metabolism.

    Science.gov (United States)

    Jayakumar, A R; Bak, L K; Rama Rao, K V; Waagepetersen, H S; Schousboe, A; Norenberg, M D

    2016-02-01

    Traumatic brain injury (TBI) is a devastating neurological disorder that usually presents in acute and chronic forms. Brain edema and associated increased intracranial pressure in the early phase following TBI are major consequences of acute trauma. On the other hand, neuronal injury, leading to neurobehavioral and cognitive impairments, that usually develop months to years after single or repetitive episodes of head trauma, are major consequences of chronic TBI. The molecular mechanisms responsible for TBI-induced injury, however, are unclear. Recent studies have suggested that early mitochondrial dysfunction and subsequent energy failure play a role in the pathogenesis of TBI. We therefore examined whether oxidative metabolism of (13)C-labeled glucose, lactate or glutamine is altered early following in vitro mechanical percussion-induced trauma (5 atm) to neurons (4-24 h), and whether such events contribute to the development of neuronal injury. Cell viability was assayed using the release of the cytoplasmic enzyme lactate dehydrogenase (LDH), together with fluorescence-based cell staining (calcein and ethidium homodimer-1 for live and dead cells, respectively). Trauma had no effect on the LDH release in neurons from 1 to 18 h. However, a significant increase in LDH release was detected at 24 h after trauma. Similar findings were identified when traumatized neurons were stained with fluorescent markers. Additionally (13)C-labeling of glutamate showed a small, but statistically significant decrease at 14 h after trauma. However, trauma had no effect on the cycling ratio of the TCA cycle at any time-period examined. These findings indicate that trauma does not cause a disturbance in oxidative metabolism of any of the substrates used for neurons. Accordingly, such metabolic disturbance does not appear to contribute to the neuronal death in the early stages following trauma.

  10. Mirror neurons and motor intentionality.

    Science.gov (United States)

    Rizzolatti, Giacomo; Sinigaglia, Corrado

    2007-01-01

    Our social life rests to a large extent on our ability to understand the intentions of others. What are the bases of this ability? A very influential view is that we understand the intentions of others because we are able to represent them as having mental states. Without this meta-representational (mind-reading) ability their behavior would be meaningless to us. Over the past few years this view has been challenged by neurophysiological findings and, in particular, by the discovery of mirror neurons. The functional properties of these neurons indicate that intentional understanding is based primarily on a mechanism that directly matches the sensory representation of the observed actions with one's own motor representation of those same actions. These findings reveal how deeply motor and intentional components of action are intertwined, suggesting that both can be fully comprehended only starting from a motor approach to intentionality.

  11. Oscillatory integration windows in neurons

    Science.gov (United States)

    Gupta, Nitin; Singh, Swikriti Saran; Stopfer, Mark

    2016-01-01

    Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. PMID:27976720

  12. Unbalanced neuronal circuits in addiction.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gen-Jack; Tomasi, Dardo; Baler, Ruben D

    2013-08-01

    Through sequential waves of drug-induced neurochemical stimulation, addiction co-opts the brain's neuronal circuits that mediate reward, motivation to behavioral inflexibility and a severe disruption of self-control and compulsive drug intake. Brain imaging technologies have allowed neuroscientists to map out the neural landscape of addiction in the human brain and to understand how drugs modify it. Published by Elsevier Ltd.

  13. Neurochemical phenotypes of cardiorespiratory neurons.

    Science.gov (United States)

    Pilowsky, Paul M

    2008-12-10

    Interactions between the cardiovascular and respiratory systems have been known for many years but the functional significance of the interactions is still widely debated. Here I discuss the possible role of metabotropic receptors in regulating cardiorespiratory neurons in the brainstem and spinal cord. It is clear that, although much has been discovered, cardiorespiratory regulation is certainly one area that still has a long way to go before its secrets are fully divulged and their function in controlling circulatory and respiratory function is revealed.

  14. Trafficking of neuronal calcium channels

    Czech Academy of Sciences Publication Activity Database

    Weiss, Norbert; Zamponi, G. W.

    2017-01-01

    Roč. 1, č. 1 (2017), č. článku NS20160003. ISSN 2059-6553 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : calcium channel * neuron * trafficing Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) http://www.neuronalsignaling.org/content/1/1/NS20160003

  15. A geographical history of social cognitive neuroscience.

    Science.gov (United States)

    Lieberman, Matthew D

    2012-06-01

    The history of social cognitive neuroscience (SCN) began with isolated islands of research in Europe and the United States in the 1990s. In the decade between 1995 and 2004 most of the major areas of current SCN research were identified in a series of high profile first studies. This paper reviews the timeline as well as the geography of important moments in the short history of this field. Of note is the different focus seen in European contributions (theory of mind, mirror neurons, and empathy) and the more self-focused U.S. contributions (self-knowledge, emotion regulation, implicit attitudes). Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity

    International Nuclear Information System (INIS)

    Huang, Y.-N.; Wu, C.-H.; Lin, T.-C.; Wang, J.-Y.

    2009-01-01

    The impairment of cognitive and motor functions in humans and animals caused by methamphetamine (METH) administration underscores the importance of METH toxicity in cortical neurons. The heme oxygenase-1 (HO-1) exerts a cytoprotective effect against various neuronal injures; however, it remains unclear whether HO-1 is involved in METH-induced toxicity. We used primary cortical neuron/glia cocultures to explore the role of HO-1 in METH-induced toxicity. Exposure of cultured cells to various concentrations of METH (0.1, 0.5, 1, 3, 5, and 10 mM) led to cytotoxicity in a concentration-dependent manner. A METH concentration of 5 mM, which caused 50% of neuronal death and glial activation, was chosen for subsequent experiments. RT-PCR and Western blot analysis revealed that METH significantly induced HO-1 mRNA and protein expression, both preceded cell death. Double and triple immunofluorescence staining further identified HO-1-positive cells as activated astrocytes, microglia, and viable neurons, but not dying neurons. Inhibition of the p38 mitogen-activated protein kinase pathway significantly blocked HO-1 induction by METH and aggravated METH neurotoxicity. Inhibition of HO activity using tin protoporphyrine IX significantly reduced HO activity and exacerbated METH neurotoxicity. However, prior induction of HO-1 using cobalt protoporphyrine IX partially protected neurons from METH toxicity. Taken together, our results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.

  17. Selective neuronal degeneration in the retrosplenial cortex impairs the recall of contextual fear memory.

    Science.gov (United States)

    Sigwald, Eric L; Genoud, Manuel E; Giachero, Marcelo; de Olmos, Soledad; Molina, Víctor A; Lorenzo, Alfredo

    2016-05-01

    The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.

  18. Prediction of rat behavior outcomes in memory tasks using functional connections among neurons.

    Directory of Open Access Journals (Sweden)

    Hu Lu

    Full Text Available BACKGROUND: Analyzing the neuronal organizational structures and studying the changes in the behavior of the organism is key to understanding cognitive functions of the brain. Although some studies have indicated that spatiotemporal firing patterns of neuronal populations have a certain relationship with the behavioral responses, the issues of whether there are any relationships between the functional networks comprised of these cortical neurons and behavioral tasks and whether it is possible to take advantage of these networks to predict correct and incorrect outcomes of single trials of animals are still unresolved. METHODOLOGY/PRINCIPAL FINDINGS: This paper presents a new method of analyzing the structures of whole-recorded neuronal functional networks (WNFNs and local neuronal circuit groups (LNCGs. The activity of these neurons was recorded in several rats. The rats performed two different behavioral tasks, the Y-maze task and the U-maze task. Using the results of the assessment of the WNFNs and LNCGs, this paper describes a realization procedure for predicting the behavioral outcomes of single trials. The methodology consists of four main parts: construction of WNFNs from recorded neuronal spike trains, partitioning the WNFNs into the optimal LNCGs using social community analysis, unsupervised clustering of all trials from each dataset into two different clusters, and predicting the behavioral outcomes of single trials. The results show that WNFNs and LNCGs correlate with the behavior of the animal. The U-maze datasets show higher accuracy for unsupervised clustering results than those from the Y-maze task, and these datasets can be used to predict behavioral responses effectively. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest that a methodology proposed in this paper is suitable for analysis of the characteristics of neuronal functional networks and the prediction of rat behavior. These types of structures in cortical

  19. Wave-processing of long-scale information by neuronal chains.

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    José Antonio Villacorta-Atienza

    Full Text Available Investigation of mechanisms of information handling in neural assemblies involved in computational and cognitive tasks is a challenging problem. Synergetic cooperation of neurons in time domain, through synchronization of firing of multiple spatially distant neurons, has been widely spread as the main paradigm. Complementary, the brain may also employ information coding and processing in spatial dimension. Then, the result of computation depends also on the spatial distribution of long-scale information. The latter bi-dimensional alternative is notably less explored in the literature. Here, we propose and theoretically illustrate a concept of spatiotemporal representation and processing of long-scale information in laminar neural structures. We argue that relevant information may be hidden in self-sustained traveling waves of neuronal activity and then their nonlinear interaction yields efficient wave-processing of spatiotemporal information. Using as a testbed a chain of FitzHugh-Nagumo neurons, we show that the wave-processing can be achieved by incorporating into the single-neuron dynamics an additional voltage-gated membrane current. This local mechanism provides a chain of such neurons with new emergent network properties. In particular, nonlinear waves as a carrier of long-scale information exhibit a variety of functionally different regimes of interaction: from complete or asymmetric annihilation to transparent crossing. Thus neuronal chains can work as computational units performing different operations over spatiotemporal information. Exploiting complexity resonance these composite units can discard stimuli of too high or too low frequencies, while selectively compress those in the natural frequency range. We also show how neuronal chains can contextually interpret raw wave information. The same stimulus can be processed differently or identically according to the context set by a periodic wave train injected at the opposite end of the

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

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    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.

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

    Directory of Open Access Journals (Sweden)

    Rui Guo

    2017-06-01

    Full Text Available 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.

  2. Results on a Binding Neuron Model and Their Implications for Modified Hourglass Model for Neuronal Network

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    Viswanathan Arunachalam

    2013-01-01

    Full Text Available The classical models of single neuron like Hodgkin-Huxley point neuron or leaky integrate and fire neuron assume the influence of postsynaptic potentials to last till the neuron fires. Vidybida (2008 in a refreshing departure has proposed models for binding neurons in which the trace of an input is remembered only for a finite fixed period of time after which it is forgotten. The binding neurons conform to the behaviour of real neurons and are applicable in constructing fast recurrent networks for computer modeling. This paper develops explicitly several useful results for a binding neuron like the firing time distribution and other statistical characteristics. We also discuss the applicability of the developed results in constructing a modified hourglass network model in which there are interconnected neurons with excitatory as well as inhibitory inputs. Limited simulation results of the hourglass network are presented.

  3. Single-cell axotomy of cultured hippocampal neurons integrated in neuronal circuits.

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    Gomis-Rüth, Susana; Stiess, Michael; Wierenga, Corette J; Meyn, Liane; Bradke, Frank

    2014-05-01

    An understanding of the molecular mechanisms of axon regeneration after injury is key for the development of potential therapies. Single-cell axotomy of dissociated neurons enables the study of the intrinsic regenerative capacities of injured axons. This protocol describes how to perform single-cell axotomy on dissociated hippocampal neurons containing synapses. Furthermore, to axotomize hippocampal neurons integrated in neuronal circuits, we describe how to set up coculture with a few fluorescently labeled neurons. This approach allows axotomy of single cells in a complex neuronal network and the observation of morphological and molecular changes during axon regeneration. Thus, single-cell axotomy of mature neurons is a valuable tool for gaining insights into cell intrinsic axon regeneration and the plasticity of neuronal polarity of mature neurons. Dissociation of the hippocampus and plating of hippocampal neurons takes ∼2 h. Neurons are then left to grow for 2 weeks, during which time they integrate into neuronal circuits. Subsequent axotomy takes 10 min per neuron and further imaging takes 10 min per neuron.

  4. Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

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    Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

    2016-01-01

    The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

  5. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

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    Levite, Mia

    2014-08-01

    pathological effects: they activate glutamate/AMPA receptors, kill neurons by 'Excitotoxicity', and/or by complement activation modulated by complement regulatory proteins, cause multiple brain damage, aggravate chemoconvulsant-induced seizures, and also induce behavioral/motor impairments. Some patients with 'Autoimmune Epilepsy' that have anti-AMPA-GluR3B antibodies respond well (although sometimes transiently) to immunotherapy, and thanks to that have reduced seizures and overall improved neurological functions. (2) Anti-NMDA-NR1 antibodies are present in patients with autoimmune 'Anti-NMDA-receptor Encephalitis'. In humans, in animal models and in vitro the anti-NMDA-NR1 antibodies can be very pathogenic since they can cause a pronounced decrease of surface NMDA receptors expressed in hippocampal neurons, and also decrease the cluster density and synaptic localization of the NMDA receptors. The anti-NMDA-NR1 antibodies induce these effects by crosslinking and internalization of the NMDA receptors. Such changes can impair glutamate signaling via the NMDA receptors and lead to various neuronal/behavior/cognitive/psychiatric abnormalities. Anti-NMDA-NR1 antibodies are frequently present in high levels in the CSF of the patients with 'Anti-NMDA-receptor encephalitis' due to their intrathecal production. Many patients with 'Anti-NMDA receptor Encephalitis' respond well to several modes of immunotherapy. (3) Anti-NMDA-NR2A/B antibodies are present in a substantial number of patients with Systemic Lupus Erythematosus (SLE) with or without neuropsychiatric problems. The exact percentage of SLE patients having anti-NMDA-NR2A/B antibodies varies in different studies from 14 to 35%, and in one study such antibodies were found in 81% of patients with diffuse 'Neuropshychiatric SLE', and in 44% of patients with focal 'Neuropshychiatric SLE'. Anti-NMDA-NR2A/B antibodies are also present in subpopulations of patients with Epilepsy of several types, Encephalitis of several types (e

  6. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

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    Barik, Jacques; Marti, Fabio; Morel, Carole; Fernandez, Sebastian P; Lanteri, Christophe; Godeheu, Gérard; Tassin, Jean-Pol; Mombereau, Cédric; Faure, Philippe; Tronche, François

    2013-01-18

    Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

  7. Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

    Science.gov (United States)

    Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

    2010-03-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

  8. Are malnutrition and stress risk factors for accelerated cognitive decline? A prisoner of war study.

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    Sulway, M R; Broe, G A; Creasey, H; Dent, O F; Jorm, A F; Kos, S C; Tennant, C C

    1996-03-01

    We set out to test the hypothesis that severe malnutrition and stress experienced by prisoners of war (POWs) are associated with cognitive deficits later in life. We assessed 101 former Australian POWs of the Japanese and 108 veteran control subjects using a battery of neuropsychological tests, a depression scale, a clinical examination for dementia, and CT. We divided the POWs into high weight loss (>35%) and low weight loss groups (malnutrition is a risk factor for accelerated cognitive decline nor the theory that severe stress can lead to hippocampal neuronal loss and cognitive deficits. Cognitive deficits in earlier studies of former POWs may have been associated with concurrent depression.

  9. Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons

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    Ka, Minhan; Chopra, Divyan A.; Dravid, Shashank M.

    2016-01-01

    De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin–Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability. SIGNIFICANCE STATEMENT Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons. PMID:26937011

  10. Neuronal Differentiation Modulated by Polymeric Membrane Properties.

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    Morelli, Sabrina; Piscioneri, Antonella; Drioli, Enrico; De Bartolo, Loredana

    2017-01-01

    In this study, different collagen-blend membranes were successfully constructed by blending collagen with chitosan (CHT) or poly(lactic-co-glycolic acid) (PLGA) to enhance their properties and thus create new biofunctional materials with great potential use for neuronal tissue engineering and regeneration. Collagen blending strongly affected membrane properties in the following ways: (i) it improved the surface hydrophilicity of both pure CHT and PLGA membranes, (ii) it reduced the stiffness of CHT membranes, but (iii) it did not modify the good mechanical properties of PLGA membranes. Then, we investigated the effect of the different collagen concentrations on the neuronal behavior of the membranes developed. Morphological observations, immunocytochemistry, and morphometric measures demonstrated that the membranes developed, especially CHT/Col30, PLGA, and PLGA/Col1, provided suitable microenvironments for neuronal growth owing to their enhanced properties. The most consistent neuronal differentiation was obtained in neurons cultured on PLGA-based membranes, where a well-developed neuronal network was achieved due to their improved mechanical properties. Our findings suggest that tensile strength and elongation at break are key material parameters that have potential influence on both axonal elongation and neuronal structure and organization, which are of fundamental importance for the maintenance of efficient neuronal growth. Hence, our study has provided new insights regarding the effects of membrane mechanical properties on neuronal behavior, and thus it may help to design and improve novel instructive biomaterials for neuronal tissue engineering. © 2017 S. Karger AG, Basel.

  11. Synaptic Circuit Organization of Motor Corticothalamic Neurons

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    Yamawaki, Naoki

    2015-01-01

    Corticothalamic (CT) neurons in layer 6 constitute a large but enigmatic class of cortical projection neurons. How they are integrated into intracortical and thalamo-cortico-thalamic circuits is incompletely understood, especially outside of sensory cortex. Here, we investigated CT circuits in mouse forelimb motor cortex (M1) using multiple circuit-analysis methods. Stimulating and recording from CT, intratelencephalic (IT), and pyramidal tract (PT) projection neurons, we found strong CT↔ CT and CT↔ IT connections; however, CT→IT connections were limited to IT neurons in layer 6, not 5B. There was strikingly little CT↔ PT excitatory connectivity. Disynaptic inhibition systematically accompanied excitation in these pathways, scaling with the amplitude of excitation according to both presynaptic (class-specific) and postsynaptic (cell-by-cell) factors. In particular, CT neurons evoked proportionally more inhibition relative to excitation (I/E ratio) than IT neurons. Furthermore, the amplitude of inhibition was tuned to match the amount of excitation at the level of individual neurons; in the extreme, neurons receiving no excitation received no inhibition either. Extending these studies to dissect the connectivity between cortex and thalamus, we found that M1-CT neurons and thalamocortical neurons in the ventrolateral (VL) nucleus were remarkably unconnected in either direction. Instead, VL axons in the cortex excited both IT and PT neurons, and CT axons in the thalamus excited other thalamic neurons, including those in the posterior nucleus, which additionally received PT excitation. These findings, which contrast in several ways with previous observations in sensory areas, illuminate the basic circuit organization of CT neurons within M1 and between M1 and thalamus. PMID:25653383

  12. Activation of the Akt/mTOR signaling pathway: A potential response to long-term neuronal loss in the hippocampus after sepsis

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    Jia-nan Guo

    2017-01-01

    Full Text Available Survivors of sepsis may suffer chronic cognitive impairment as a long-term sequela. However, the precise mechanisms of cognitive dysfunction after sepsis are not well understood. We employed the cecal ligation-and-puncture-induced septic mouse model. We observed elevated phosphorylation of Akt, mammalian target of rapamycin (mTOR and p70S6K on days 14 and 60, progressive neuronal loss in the cornu ammonis 1 region, and abnormal neuronal morphology in the hippocampus in the sepsis mouse model. These findings indicate that changes in neuronal morphology and number in the hippocampus after sepsis were associated with strong activation of the Akt/mTOR signaling pathway, and may reflect a “self-rescuing” feedback response to neuronal loss after sepsis.

  13. Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration

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    Won, Seok Joon; Jang, Bong Geom; Yoo, Byung Hoon; Sohn, Min; Lee, Min Woo; Choi, Bo Young; Kim, Jin Hee; Song, Hong Ki; Suh, Sang Won

    2012-01-01

    Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD+...

  14. Opposite effects of low and high doses of Abeta42 on electrical network and neuronal excitability in the rat prefrontal cortex.

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    Wang, Yun; Zhang, Guangping; Zhou, Hongwei; Barakat, Amey; Querfurth, Henry

    2009-12-21

    Changes in neuronal synchronization have been found in patients and animal models of Alzheimer's disease (AD). Synchronized behaviors within neuronal networks are important to such complex cognitive processes as working memory. The mechanisms behind these changes are not understood but may involve the action of soluble beta-amyloid (Abeta) on electrical networks. In order to determine if Abeta can induce changes in neuronal synchronization, the activities of pyramidal neurons were recorded in rat prefrontal cortical (PFC) slices under calcium-free conditions using multi-neuron patch clamp technique. Electrical network activities and synchronization among neurons were significantly inhibited by low dose Abeta42 (1 nM) and initially by high dose Abeta42 (500 nM). However, prolonged application of high dose Abeta42 resulted in network activation and tonic firing. Underlying these observations, we discovered that prolonged application of low and high doses of Abeta42 induced opposite changes in action potential (AP)-threshold and after-hyperpolarization (AHP) of neurons. Accordingly, low dose Abeta42 significantly increased the AP-threshold and deepened the AHP, making neurons less excitable. In contrast, high dose Abeta42 significantly reduced the AP-threshold and shallowed the AHP, making neurons more excitable. These results support a model that low dose Abeta42 released into the interstitium has a physiologic feedback role to dampen electrical network activity by reducing neuronal excitability. Higher concentrations of Abeta42 over time promote supra-synchronization between individual neurons by increasing their excitability. The latter may disrupt frontal-based cognitive processing and in some cases lead to epileptiform discharges.

  15. Opposite effects of low and high doses of Abeta42 on electrical network and neuronal excitability in the rat prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available Changes in neuronal synchronization have been found in patients and animal models of Alzheimer's disease (AD. Synchronized behaviors within neuronal networks are important to such complex cognitive processes as working memory. The mechanisms behind these changes are not understood but may involve the action of soluble beta-amyloid (Abeta on electrical networks. In order to determine if Abeta can induce changes in neuronal synchronization, the activities of pyramidal neurons were recorded in rat prefrontal cortical (PFC slices under calcium-free conditions using multi-neuron patch clamp technique. Electrical network activities and synchronization among neurons were significantly inhibited by low dose Abeta42 (1 nM and initially by high dose Abeta42 (500 nM. However, prolonged application of high dose Abeta42 resulted in network activation and tonic firing. Underlying these observations, we discovered that prolonged application of low and high doses of Abeta42 induced opposite changes in action potential (AP-threshold and after-hyperpolarization (AHP of neurons. Accordingly, low dose Abeta42 significantly increased the AP-threshold and deepened the AHP, making neurons less excitable. In contrast, high dose Abeta42 significantly reduced the AP-threshold and shallowed the AHP, making neurons more excitable. These results support a model that low dose Abeta42 released into the interstitium has a physiologic feedback role to dampen electrical network activity by reducing neuronal excitability. Higher concentrations of Abeta42 over time promote supra-synchronization between individual neurons by increasing their excitability. The latter may disrupt frontal-based cognitive processing and in some cases lead to epileptiform discharges.

  16. Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy.

    Science.gov (United States)

    Moruno-Manchon, Jose F; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Townley, Debra M; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S; Sood, Anil K; Tsvetkov, Andrey S

    2018-01-01

    Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Social interaction with a tutor modulates responsiveness of specific auditory neurons in juvenile zebra finches.

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    Yanagihara, Shin; Yazaki-Sugiyama, Yoko

    2018-04-12

    Behavioral states of animals, such as observing the behavior of a conspecific, modify signal perception and/or sensations that influence state-dependent higher cognitive behavior, such as learning. Recent studies have shown that neuronal responsiveness to sensory signals is modified when animals are engaged in social interactions with others or in locomotor activities. However, how these changes produce state-dependent differences in higher cognitive function is still largely unknown. Zebra finches, which have served as the premier songbird model, learn to sing from early auditory experiences with tutors. They also learn from playback of recorded songs however, learning can be greatly improved when song models are provided through social communication with tutors (Eales, 1989; Chen et al., 2016). Recently we found a subset of neurons in the higher-level auditory cortex of juvenile zebra finches that exhibit highly selective auditory responses to the tutor song after song learning, suggesting an auditory memory trace of the tutor song (Yanagihara and Yazaki-Sugiyama, 2016). Here we show that auditory responses of these selective neurons became greater when juveniles were paired with their tutors, while responses of non-selective neurons did not change. These results suggest that social interaction modulates cortical activity and might function in state-dependent song learning. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Audio-vocal interaction in single neurons of the monkey ventrolateral prefrontal cortex.

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    Hage, Steffen R; Nieder, Andreas

    2015-05-06

    Complex audio-vocal integration systems depend on a strong interconnection between the auditory and the vocal motor system. To gain cognitive control over audio-vocal interaction during vocal motor control, the PFC needs to be involved. Neurons in the ventrolateral PFC (VLPFC) have been shown to separately encode the sensory perceptions and motor production of vocalizations. It is unknown, however, whether single neurons in the PFC reflect audio-vocal interactions. We therefore recorded single-unit activity in the VLPFC of rhesus monkeys (Macaca mulatta) while they produced vocalizations on command or passively listened to monkey calls. We found that 12% of randomly selected neurons in VLPFC modulated their discharge rate in response to acoustic stimulation with species-specific calls. Almost three-fourths of these auditory neurons showed an additional modulation of their discharge rates either before and/or during the monkeys' motor production of vocalization. Based on these audio-vocal interactions, the VLPFC might be well positioned to combine higher order auditory processing with cognitive control of the vocal motor output. Such audio-vocal integration processes in the VLPFC might constitute a precursor for the evolution of complex learned audio-vocal integration systems, ultimately giving rise to human speech. Copyright © 2015 the authors 0270-6474/15/357030-11$15.00/0.

  19. Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

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    Takashi eMaejima

    2013-05-01

    Full Text Available Serotonergic neurons project to virtually all regions of the CNS and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing and reproductive success. Therefore serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo.

  20. Tryptophan circuit in fatigue: From blood to brain and cognition.

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    Yamashita, Masatoshi; Yamamoto, Takanobu

    2017-11-15

    Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice

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    Laura B. Ngwenya

    2018-01-01

    Full Text Available Cognitive deficits after traumatic brain injury (TBI are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC. Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation.

  2. Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

    Science.gov (United States)

    Li, Ai-Jun; Wang, Qing; Elsarelli, Megan M; Brown, R Lane; Ritter, Sue

    2015-08-01

    Hindbrain catecholamine neurons are required for elicitation of feeding responses to glucose deficit, but the forebrain circuitry required for these responses is incompletely understood. Here we examined interactions of catecholamine and orexin neurons in eliciting glucoprivic feeding. Orexin neurons, located in the perifornical lateral hypothalamus (PeFLH), are heavily innervated by hindbrain catecholamine neurons, stimulate food intake, and increase arousal and behavioral activation. Orexin neurons may therefore contribute importantly to appetitive responses, such as food seeking, during glucoprivation. Retrograde tracing results showed that nearly all innervation of the PeFLH from the hindbrain originated from catecholamine neurons and some raphe nuclei. Results also suggested that many catecholamine neurons project collaterally to the PeFLH and paraventricular hypothalamic nucleus. Systemic administration of the antiglycolytic agent, 2-deoxy-D-glucose, increased food intake and c-Fos expression in orexin neurons. Both responses were eliminated by a lesion of catecholamine neurons innervating orexin neurons using the retrogradely transported immunotoxin, anti-dopamine-β-hydroxylase saporin, which is specifically internalized by dopamine-β-hydroxylase-expressing catecholamine neurons. Using designer receptors exclusively activated by designer drugs in transgenic rats expressing Cre recombinase under the control of tyrosine hydroxylase promoter, catecholamine neurons in cell groups A1 and C1 of the ventrolateral medulla were activated selectively by peripheral injection of clozapine-N-oxide. Clozapine-N-oxide injection increased food intake and c-Fos expression in PeFLH orexin neurons as well as in paraventricular hypothalamic nucleus neurons. In summary, catecholamine neurons are required for the activation of orexin neurons during glucoprivation. Activation of orexin neurons may contribute to appetitive responses required for glucoprivic feeding.

  3. Selective expression of KCNS3 potassium channel α-subunit in parvalbumin-containing GABA neurons in the human prefrontal cortex.

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    Danko Georgiev

    Full Text Available The cognitive deficits of schizophrenia appear to be associated with altered cortical GABA neurotransmission in the subsets of inhibitory neurons that express either parvalbumin (PV or somatostatin (SST. Identification of molecular mechanisms that operate selectively in these neurons is essential for developing targeted therapeutic strategies that do not influence other cell types. Consequently, we sought to identify, in the human cortex, gene products that are expressed selectively by PV and/or SST neurons, and that might contribute to their distinctive functional properties. Based on previously reported expression patterns in the cortex of mice and humans, we selected four genes: KCNS3, LHX6, KCNAB1, and PPP1R2, encoding K(+ channel Kv9.3 modulatory α-subunit, LIM homeobox protein 6, K(+ channel Kvβ1 subunit, and protein phosphatase 1 regulatory subunit 2, respectively, and examined their colocalization with PV or SST mRNAs in the human prefrontal cortex using dual-label in situ hybridization with (35S- and digoxigenin-labeled antisense riboprobes. KCNS3 mRNA was detected in almost all PV neurons, but not in SST neurons, and PV mRNA was detected in >90% of KCNS3 mRNA-expressing neurons. LHX6 mRNA was detected in almost all PV and >90% of SST neurons, while among all LHX6 mRNA-expressing neurons 50% expressed PV mRNA and >44% expressed SST mRNA. KCNAB1 and PPP1R2 mRNAs were detected in much larger populations of cortical neurons than PV or SST neurons. These findings indicate that KCNS3 is a selective marker of PV neurons, whereas LHX6 is expressed by both PV and SST neurons. KCNS3 and LHX6 might be useful for characterizing cell-type specific molecular alterations of cortical GABA neurotransmission and for the development of novel treatments targeting PV and/or SST neurons in schizophrenia.

  4. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine.

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    Vu, Michael T; Du, Guizhi; Bayliss, Douglas A; Horner, Richard L

    2015-10-07

    Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K(+) (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels