Sample records for abnormal neuronal activity

  1. Abnormal neuronal activity in Tourette syndrome and its modulation using deep brain stimulation

    PubMed Central

    Israelashvili, Michal; Loewenstern, Yocheved

    2015-01-01

    Tourette syndrome (TS) is a common childhood-onset disorder characterized by motor and vocal tics that are typically accompanied by a multitude of comorbid symptoms. Pharmacological treatment options are limited, which has led to the exploration of deep brain stimulation (DBS) as a possible treatment for severe cases. Multiple lines of evidence have linked TS with abnormalities in the motor and limbic cortico-basal ganglia (CBG) pathways. Neurophysiological data have only recently started to slowly accumulate from multiple sources: noninvasive imaging and electrophysiological techniques, invasive electrophysiological recordings in TS patients undergoing DBS implantation surgery, and animal models of the disorder. These converging sources point to system-level physiological changes throughout the CBG pathway, including both general altered baseline neuronal activity patterns and specific tic-related activity. DBS has been applied to different regions along the motor and limbic pathways, primarily to the globus pallidus internus, thalamic nuclei, and nucleus accumbens. In line with the findings that also draw on the more abundant application of DBS to Parkinson's disease, this stimulation is assumed to result in changes in the neuronal firing patterns and the passage of information through the stimulated nuclei. We present an overview of recent experimental findings on abnormal neuronal activity associated with TS and the changes in this activity following DBS. These findings are then discussed in the context of current models of CBG function in the normal state, during TS, and finally in the wider context of DBS in CBG-related disorders. PMID:25925326

  2. Fetal Alcohol Spectrum Disorders and Abnormal Neuronal Plasticity

    PubMed Central

    Medina, Alexandre E.

    2012-01-01

    The ingestion of alcohol during pregnancy can result in a group of neurobehavioral abnormalities collectively known as fetal alcohol spectrum disorders (FASD). During the past decade, studies using animal models indicated that early alcohol exposure can dramatically affect neuronal plasticity, an essential property of the central nervous system responsible for the normal wiring of the brain and involved in processes such as learning and memory. The abnormalities in neuronal plasticity caused by alcohol can explain many of the neurobehavioral deficits observed in FASD. Conversely, improving neuronal plasticity may have important therapeutic benefits. In this review, the author discuss the mechanisms that lead to these abnormalities and comment on recent pharmacological approaches that have been showing promising results in improving neuronal plasticity in FASD. PMID:21383101

  3. The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse.

    PubMed

    Bolivar, Valerie J; Scott Ganus, J; Messer, Anne

    2002-05-24

    The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.

  4. Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human-Induced Pluripotent Cells

    DTIC Science & Technology

    2016-09-01

    AWARD NUMBER: W81XWH-15-1-0433 TITLE: Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced Pluripotent Cells...2015 - 31 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced...functions to normal in neurons derived from human pluripotent cells exposed to Gulf War toxins. 15. SUBJECT TERMS microtubule, neuron, Gulf War Illness

  5. Serotonin Neuron Abnormalities in the BTBR Mouse Model of Autism

    PubMed Central

    Guo, Yue-Ping; Commons, Kathryn G.

    2017-01-01

    The inbred mouse strain BTBR T+ Itpr3tf/J (BTBR) i studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. PMID:27478061

  6. Serotonin neuron abnormalities in the BTBR mouse model of autism.

    PubMed

    Guo, Yue-Ping; Commons, Kathryn G

    2017-01-01

    The inbred mouse strain BTBR T + Itpr3 tf /J (BTBR) is studied as a model of idiopathic autism because they are less social and more resistant to change than other strains. Forebrain serotonin receptors and the response to serotonin drugs are altered in BTBR mice, yet it remains unknown if serotonin neurons themselves are abnormal. In this study, we found that serotonin tissue content and the density of serotonin axons is reduced in the hippocampus of BTBR mice in comparison to C57BL/6J (C57) mice. This was accompanied by possible compensatory changes in serotonin neurons that were most pronounced in regions known to provide innervation to the hippocampus: the caudal dorsal raphe (B6) and the median raphe. These changes included increased numbers of serotonin neurons and hyperactivation of Fos expression. Metrics of serotonin neurons in the rostral 2/3 of the dorsal raphe and serotonin content of the prefrontal cortex were less impacted. Thus, serotonin neurons exhibit region-dependent abnormalities in the BTBR mouse that may contribute to their altered behavioral profile. Autism Res 2017, 10: 66-77. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  7. Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia

    PubMed Central

    Xie, Wenrui; Strong, Judith A.; Ye, Ling; Mao, Ju-Xian; Zhang, Jun-Ming

    2013-01-01

    Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models, and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform NaV1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain following local inflammation of the rat lumbar sensory ganglia. In normal DRG, quantitative PCR showed that cells capable of firing repetitively had significantly higher relative expression of NaV1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of NaV1.6′ immunoreactivity. In vivo knockdown of NaV1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C-cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on NaV1.8, because it is present primarily in unmyelinated C fiber nociceptors, or on NaV1.7, because lack of this channel causes congenital indifference to pain. However, the results suggest that NaV1.6 may be a useful therapeutic target for chronic pain, and that some pain conditions may be primarily mediated by myelinated A-fiber sensory neurons. PMID:23622763

  8. Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs.

    PubMed

    Ando, Hiroyuki; Mochiki, Erito; Ohno, Tetsuro; Yanai, Mitsuhiro; Toyomasu, Yoshitaka; Ogata, Kyoichi; Tabe, Yuichi; Aihara, Ryuusuke; Nakabayashi, Toshihiro; Asao, Takayuki; Kuwano, Hiroyuki

    2014-11-14

    To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity.

  9. Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

    PubMed Central

    Keays, David A.; Tian, Guoling; Poirier, Karine; Huang, Guo-Jen; Siebold, Christian; Cleak, James; Oliver, Peter L.; Fray, Martin; Harvey, Robert J.; Molnár, Zoltán; Piñon, Maria C.; Dear, Neil; Valdar, William; Brown, Steve D.M.; Davies, Kay E.; Rawlins, J. Nicholas P.; Cowan, Nicholas J.; Nolan, Patrick; Chelly, Jamel; Flint, Jonathan

    2007-01-01

    Summary The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders. PMID:17218254

  10. Mechanism of gastrointestinal abnormal motor activity induced by cisplatin in conscious dogs

    PubMed Central

    Ando, Hiroyuki; Mochiki, Erito; Ohno, Tetsuro; Yanai, Mitsuhiro; Toyomasu, Yoshitaka; Ogata, Kyoichi; Tabe, Yuichi; Aihara, Ryuusuke; Nakabayashi, Toshihiro; Asao, Takayuki; Kuwano, Hiroyuki

    2014-01-01

    AIM: To investigate whether 5-hydroxytryptamine (serotonin; 5-HT) is involved in mediating abnormal motor activity in dogs after cisplatin administration. METHODS: After the dogs had been given a 2-wk recovery period, all of them were administered cisplatin, and the motor activity was recorded using strain gauge force transducers. Blood and intestinal fluid samples were collected to measure 5-HT for 24 h. To determine whether 5-HT in plasma or that in intestinal fluids is more closely related to abnormal motor activity we injected 5-HT into the bloodstream and the intestinal tract of the dogs. RESULTS: Cisplatin given intravenously produced abnormal motor activity that lasted up to 5 h. From 3 to 4 h after cisplatin administration, normal intact dogs exhibited retropropagation of motor activity accompanied by emesis. The concentration of 5-HT in plasma reached the peak at 4 h, and that in intestinal fluids reached the peak at 3 h. In normal intact dogs with resection of the vagus nerve that were administered kytril, cisplatin given intravenously did not produce abnormal motor activity. Intestinal serotonin administration did not produce abnormal motor activity, but intravenous serotonin administration did. CONCLUSION: After the intravenous administration of cisplatin, abnormal motor activity was produced in the involved vagus nerve and in the involved serotonergic neurons via another pathway. This study was the first to determine the relationship between 5-HT and emesis-induced motor activity. PMID:25400453

  11. Morphological patterns in children with ganglion related enteric neuronal abnormalities.

    PubMed

    Henna, Nausheen; Nagi, Abdul H; Sheikh, Muhammad A; Shaukat, Mahmood

    2011-01-01

    Hirschsprung's Disease (HD) is a developmental disorder of enteric nervous system characterised by the absence of ganglion cells in submucosal (Meissner's) and myenteric (Aurbach's) plexuses of distal bowel. The purpose of the present study was to observe and report the morphological patterns of ganglion related enteric neuronal abnormalities in children presented with clinical features of (HD) in a Pakistani population. A total of 92 patients with clinical presentation of HD were enrolled between March 2009 and October 2009. Among them, 8 were excluded according to the exclusion criteria. After detailed history and physical examination, paraffin embedded H and E stained sections were prepared from the serial open biopsies from colorectum. The data was analysed using SPSS-17. Frequencies and percentages are given for qualitative variables. Non-parametric Binomial Chi-Square test was applied to observe within group associations and p<0.05 was considered statistically significant. Among 84 patients, 13 (15.5%) proved to be normally ganglionic whereas 71 (84.5%) showed ganglion related enteric neuronal abnormalities namely isolated hypoganglionosis 9 (12.7%), immaturity of ganglion cells 9 (12.7%), isolated hyperganglionosis (IND Type B) 2 (2.8%) and Hirschsprung's disease 51 (71.8%). Among HD group, 34 (66.7%) belonged to isolated form and 17 (33.3%) showed combined ganglion related abnormalities. Hirschsprung's disease is common in Pakistani population, followed by hypoganglionosis, immaturity of ganglion cells and IND type B. The presence of hypertrophic nerve fibres was significant in HD, hyperganglionosis and hypoganglionosis, whereas, no hypertrophic nerve fibres were appreciated in immaturity of ganglion cell group.

  12. Pericellular innervation of neurons expressing abnormally hyperphosphorylated tau in the hippocampal formation of Alzheimer's disease patients.

    PubMed

    Blazquez-Llorca, Lidia; Garcia-Marin, Virginia; Defelipe, Javier

    2010-01-01

    Neurofibrillary tangles (NFT) represent one of the main neuropathological features in the cerebral cortex associated with Alzheimer's disease (AD). This neurofibrillary lesion involves the accumulation of abnormally hyperphosphorylated or abnormally phosphorylated microtubule-associated protein tau into paired helical filaments (PHF-tau) within neurons. We have used immunocytochemical techniques and confocal microscopy reconstructions to examine the distribution of PHF-tau-immunoreactive (ir) cells, and their perisomatic GABAergic and glutamatergic innervations in the hippocampal formation and adjacent cortex of AD patients. Furthermore, correlative light and electron microscopy was employed to examine these neurons and the perisomatic synapses. We observed two patterns of staining in PHF-tau-ir neurons, pattern I (without NFT) and pattern II (with NFT), the distribution of which varies according to the cortical layer and area. Furthermore, the distribution of both GABAergic and glutamatergic terminals around the soma and proximal processes of PHF-tau-ir neurons does not seem to be altered as it is indistinguishable from both control cases and from adjacent neurons that did not contain PHF-tau. At the electron microscope level, a normal looking neuropil with typical symmetric and asymmetric synapses was observed around PHF-tau-ir neurons. These observations suggest that the synaptic connectivity around the perisomatic region of these PHF-tau-ir neurons was apparently unaltered.

  13. Tinnitus Perception and Distress Is Related to Abnormal Spontaneous Brain Activity as Measured by Magnetoencephalography

    PubMed Central

    Weisz, Nathan; Moratti, Stephan; Meinzer, Marcus; Dohrmann, Katalin; Elbert, Thomas

    2005-01-01

    Background The neurophysiological mechanisms underlying tinnitus perception are not well understood. Surprisingly, there have been no group studies comparing abnormalities in ongoing, spontaneous neuronal activity in individuals with and without tinnitus perception. Methods and Findings Here, we show that the spontaneous neuronal activity of a group of individuals with tinnitus (n = 17) is characterised by a marked reduction in alpha (8–12 Hz) power together with an enhancement in delta (1.5–4 Hz) as compared to a normal hearing control group (n = 16). This pattern was especially pronounced for temporal regions. Moreover, correlations with tinnitus-related distress revealed strong associations with this abnormal spontaneous activity pattern, particularly in right temporal and left frontal areas. Overall, effects were stronger for the alpha than for the delta frequency band. A data stream of 5 min, recorded with a whole-head neuromagnetometer under a resting condition, was sufficient to extract the marked differences. Conclusions Despite some limitations, there are arguments that the regional pattern of abnormal spontaneous activity we found could reflect a tinnitus-related cortical network. This finding, which suggests that a neurofeedback approach could reduce the adverse effects of this disturbing condition, could have important implications for the treatment of tinnitus. PMID:15971936

  14. Abnormally increased and incoherent resting-state activity is shared between patients with schizophrenia and their unaffected siblings.

    PubMed

    Liu, Chang; Xue, Zhimin; Palaniyappan, Lena; Zhou, Li; Liu, Haihong; Qi, Chang; Wu, Guowei; Mwansisya, Tumbwene E; Tao, Haojuan; Chen, Xudong; Huang, Xiaojun; Liu, Zhening; Pu, Weidan

    2016-03-01

    Several resting-state neuroimaging studies in schizophrenia indicate an excessive brain activity while others report an incoherent brain activity at rest. No direct evidence for the simultaneous presence of both excessive and incoherent brain activity has been established to date. Moreover, it is unclear whether unaffected siblings of schizophrenia patients who share half of the affected patient's genotype also exhibit the excessive and incoherent brain activity that may render them vulnerable to the development of schizophrenia. 27 pairs of schizophrenia patients and their unaffected siblings, as well as 27 healthy controls, were scanned using gradient-echo echo-planar imaging at rest. By using amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (Reho), we investigated the intensity and synchronization of local spontaneous neuronal activity in three groups. We observed that increased amplitude and reduced synchronization (coherence) of spontaneous neuronal activity were shared by patients and their unaffected siblings. The key brain regions with this abnormal neural pattern in both patients and siblings included the middle temporal, orbito-frontal, inferior occipital and fronto-insular gyrus. This abnormal neural pattern of excessive and incoherent neuronal activity shared by schizophrenia patients and their healthy siblings may improve our understanding of neuropathology and genetic predisposition in schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse.

    PubMed

    Kimura, Eiki; Kubo, Ken-Ichiro; Endo, Toshihiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2017-01-01

    The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

  16. Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?

    PubMed

    Parker, Lindsay M; Le, Sheng; Wearne, Travis A; Hardwick, Kate; Kumar, Natasha N; Robinson, Katherine J; McMullan, Simon; Goodchild, Ann K

    2017-06-15

    Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed. © 2017 Wiley Periodicals, Inc.

  17. Enhanced exosome secretion in Down syndrome brain - a protective mechanism to alleviate neuronal endosomal abnormalities.

    PubMed

    Gauthier, Sébastien A; Pérez-González, Rocío; Sharma, Ajay; Huang, Fang-Ke; Alldred, Melissa J; Pawlik, Monika; Kaur, Gurjinder; Ginsberg, Stephen D; Neubert, Thomas A; Levy, Efrat

    2017-08-29

    A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer's disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology.

  18. Attenuation of dichlorvos-induced microglial activation and neuronal apoptosis by 4-hydroxy TEMPO.

    PubMed

    Sunkaria, Aditya; Sharma, Deep Raj; Wani, Willayat Yousuf; Gill, Kiran Dip

    2014-02-01

    The neurotoxic consequences of acute high-level as well as chronic low-level organophosphates exposure are associated with a range of abnormalities in nerve functions. Previously, we have shown that after 24 h of dichlorvos exposure, microglia become activated and secrete pro-inflammatory molecules like nitric oxide, tumour necrosis factor-α and interleukin-1β. Here, we extended our findings and focused on the neuronal damage caused by dichlorvos via microglial activation. For this, neurons and microglia were isolated separately from 1-day-old Wistar rat pups. Microglia were treated with dichlorvos for 24 h and supernatant was collected (dichlorvos-induced conditioned medium, DCM). However, when 4-hydroxy TEMPO (4-HT) pretreatment was given, we observed significant attenuation of dichlorvos-induced microglial activation; we also collected the supernatant of this culture (4-HT + DCM, TDCM). Next, we checked the effects of DCM on neurons and found heavy loss in viability as evident from NF-H immunostaining and MTT results, whereas dichlorvos alone-treated neurons showed comparatively less damage. However, we observed significant increase in neuronal viability when cells were treated with TDCM. Semi-quantitative PCR and western blot results revealed significant increase in p53, Bax and cytochrome c levels along with caspase 3 activation after 24 h of DCM treatment. However, TDCM-treated neurons showed significant decrease in the expression of these pro-apoptotic molecules. Taken together, these findings suggest that 4-HT can significantly attenuate dichlorvos-induced microglial activation and prevent apoptotic neuronal cell death.

  19. GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal.

    PubMed

    Bagley, Elena E; Gerke, Michelle B; Vaughan, Christopher W; Hack, Stephen P; Christie, MacDonald J

    2005-02-03

    Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.

  20. Intrinsically active and pacemaker neurons in pluripotent stem cell-derived neuronal populations.

    PubMed

    Illes, Sebastian; Jakab, Martin; Beyer, Felix; Gelfert, Renate; Couillard-Despres, Sébastien; Schnitzler, Alfons; Ritter, Markus; Aigner, Ludwig

    2014-03-11

    Neurons generated from pluripotent stem cells (PSCs) self-organize into functional neuronal assemblies in vitro, generating synchronous network activities. Intriguingly, PSC-derived neuronal assemblies develop spontaneous activities that are independent of external stimulation, suggesting the presence of thus far undetected intrinsically active neurons (IANs). Here, by using mouse embryonic stem cells, we provide evidence for the existence of IANs in PSC-neuronal networks based on extracellular multielectrode array and intracellular patch-clamp recordings. IANs remain active after pharmacological inhibition of fast synaptic communication and possess intrinsic mechanisms required for autonomous neuronal activity. PSC-derived IANs are functionally integrated in PSC-neuronal populations, contribute to synchronous network bursting, and exhibit pacemaker properties. The intrinsic activity and pacemaker properties of the neuronal subpopulation identified herein may be particularly relevant for interventions involving transplantation of neural tissues. IANs may be a key element in the regulation of the functional activity of grafted as well as preexisting host neuronal networks.

  1. Intrinsically Active and Pacemaker Neurons in Pluripotent Stem Cell-Derived Neuronal Populations

    PubMed Central

    Illes, Sebastian; Jakab, Martin; Beyer, Felix; Gelfert, Renate; Couillard-Despres, Sébastien; Schnitzler, Alfons; Ritter, Markus; Aigner, Ludwig

    2014-01-01

    Summary Neurons generated from pluripotent stem cells (PSCs) self-organize into functional neuronal assemblies in vitro, generating synchronous network activities. Intriguingly, PSC-derived neuronal assemblies develop spontaneous activities that are independent of external stimulation, suggesting the presence of thus far undetected intrinsically active neurons (IANs). Here, by using mouse embryonic stem cells, we provide evidence for the existence of IANs in PSC-neuronal networks based on extracellular multielectrode array and intracellular patch-clamp recordings. IANs remain active after pharmacological inhibition of fast synaptic communication and possess intrinsic mechanisms required for autonomous neuronal activity. PSC-derived IANs are functionally integrated in PSC-neuronal populations, contribute to synchronous network bursting, and exhibit pacemaker properties. The intrinsic activity and pacemaker properties of the neuronal subpopulation identified herein may be particularly relevant for interventions involving transplantation of neural tissues. IANs may be a key element in the regulation of the functional activity of grafted as well as preexisting host neuronal networks. PMID:24672755

  2. Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.

    PubMed

    Li, Yaqin; Cao, Jiqing; Chen, Menglong; Li, Jing; Sun, Yiming; Zhang, Yu; Zhu, Yuling; Wang, Liang; Zhang, Cheng

    2017-04-11

    Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Mirror neuron function, psychosis, and empathy in schizophrenia

    PubMed Central

    McCormick, Laurie M.; Brumm, Michael C.; Beadle, Janelle N.; Paradiso, Sergio; Yamada, Thoru; Andreasen, Nancy

    2013-01-01

    Processing of social and emotional information has been shown to be disturbed in schizophrenia. The biological underpinnings of these abnormalities may be explained by an abnormally functioning mirror neuron system. Yet the relationship between mirror neuron system activity in schizophrenia, as measured using an electroencephalography (EEG) paradigm, and socio-emotional functioning has not been assessed. The present research measured empathy and mirror neuron activity using an established EEG paradigm assessing the integrity of the Mu rhythm (8–13 Hz) suppression over the sensorimotor cortex during observed and actual hand movement in 16 schizophrenia-spectrum disorder (SSD) participants (n=8 actively psychotic and n=8 in residual illness phase) and 16 age- and gender-matched healthy comparison participants. Actively psychotic SSD participants showed significantly greater mu suppression over the sensorimotor cortex of the left hemisphere than residual phase SSD and healthy comparison individuals. The latter two groups showed similar levels of mu suppression. Greater left-sided mu suppression was positively correlated with psychotic symptoms (i.e., greater mu suppression/mirror neuron activity was highest among subjects with the greater severity of psychotic symptoms). SSD subjects tended to have significantly higher levels of Personal Distress (as measured by the Interpersonal Reactivity Index) than healthy participants. The present study suggests that abnormal mirror neuron activity may exist among patients with schizophrenia during the active (psychotic) phase of the illness, and correlates with severity of psychosis. PMID:22510432

  4. Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease.

    PubMed

    Sajan, Mini P; Hansen, Barbara C; Higgs, Margaret G; Kahn, C Ron; Braun, Ursula; Leitges, Michael; Park, Collin R; Diamond, David M; Farese, Robert V

    2018-01-01

    Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ 1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ 1-40/42 , β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), β-secretase, and Aβ 1-40/42 , and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ 1-40/42 . Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-ι/λ activation by insulin, metformin, or expression of constitutive PKC-ι provoked increases in β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt inhibitor. PKC-λ/ι provokes increases in brain β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau. Excessive signaling via PKC-λ/ι may link hyperinsulinemia and other PKC-λ/ι activators to pathological and functional abnormalities in Alzheimer's disease. Published by Elsevier Inc.

  5. Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

    PubMed Central

    Lim, M. A.; Selak, M. A.; Xiang, Z.; Krainc, D.; Neve, R. L.; Kraemer, B. C.; Watts, J. L.

    2012-01-01

    A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease. PMID:22262909

  6. In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

    PubMed

    Thomas, Elizabeth A; Coppola, Giovanni; Tang, Bin; Kuhn, Alexandre; Kim, SoongHo; Geschwind, Daniel H; Brown, Timothy B; Luthi-Carter, Ruth; Ehrlich, Michelle E

    2011-03-15

    Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

  7. Small reduction of neurokinin-1 receptor-expressing neurons in the pre-Bötzinger complex area induces abnormal breathing periods in awake goats.

    PubMed

    Wenninger, J M; Pan, L G; Klum, L; Leekley, T; Bastastic, J; Hodges, M R; Feroah, T; Davis, S; Forster, H V

    2004-11-01

    In awake rats, >80% bilateral reduction of neurokinin-1 receptor (NK1R)-expressing neurons in the pre-Bötzinger complex (pre-BötzC) resulted in hypoventilation and an "ataxic" breathing pattern (Gray PA, Rekling JC, Bocchiaro CM, Feldman JL, Science 286: 1566-1568, 1999). Accordingly, the present study was designed to gain further insight into the role of the pre-BötzC area NK1R-expressing neurons in the control of breathing during physiological conditions. Microtubules were chronically implanted bilaterally into the medulla of adult goats. After recovery from surgery, the neurotoxin saporin conjugated to substance P, specific for NK1R-expressing neurons, was bilaterally injected (50 pM in 10 microl) into the pre-BötzC area during the awake state (n = 8). In unoperated goats, 34 +/- 0.01% of the pre-BötzC area neurons are immunoreactive for the NK1R, but, in goats after bilateral injection of SP-SAP into the pre-BötzC area, NK1R immunoreactivity was reduced to 22.5 +/- 2.5% (29% decrease, P < 0.01). Ten to fourteen days after the injection, the frequency of abnormal breathing periods was sixfold greater than before injection (107.8 +/- 21.8/h, P < 0.001). Fifty-six percent of these periods were breaths of varying duration and volume with an altered respiratory muscle activation pattern, whereas the remaining were rapid, complete breaths with coordinated inspiratory-expiratory cycles. The rate of occurrence and characteristics of abnormal breathing periods were not altered during a CO2 inhalation-induced hyperpnea. Pathological breathing patterns were eliminated during non-rapid eye movement sleep in seven of eight goats, but they frequently occurred on arousal from non-rapid eye movement sleep. We conclude that a moderate reduction in pre-BötzC NK1R-expressing neurons results in state-dependent transient changes in respiratory rhythm and/or eupneic respiratory muscle activation patterns.

  8. Hindbrain Catecholamine Neurons Activate Orexin Neurons During Systemic Glucoprivation in Male Rats.

    PubMed

    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.

  9. AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons.

    PubMed

    Essner, Rachel A; Smith, Alison G; Jamnik, Adam A; Ryba, Anna R; Trutner, Zoe D; Carter, Matthew E

    2017-09-06

    To maintain energy homeostasis, orexigenic (appetite-inducing) and anorexigenic (appetite suppressing) brain systems functionally interact to regulate food intake. Within the hypothalamus, neurons that express agouti-related protein (AgRP) sense orexigenic factors and orchestrate an increase in food-seeking behavior. In contrast, calcitonin gene-related peptide (CGRP)-expressing neurons in the parabrachial nucleus (PBN) suppress feeding. PBN CGRP neurons become active in response to anorexigenic hormones released following a meal, including amylin, secreted by the pancreas, and cholecystokinin (CCK), secreted by the small intestine. Additionally, exogenous compounds, such as lithium chloride (LiCl), a salt that creates gastric discomfort, and lipopolysaccharide (LPS), a bacterial cell wall component that induces inflammation, exert appetite-suppressing effects and activate PBN CGRP neurons. The effects of increasing the homeostatic drive to eat on feeding behavior during appetite suppressing conditions are unknown. Here, we show in mice that food deprivation or optogenetic activation of AgRP neurons induces feeding to overcome the appetite suppressing effects of amylin, CCK, and LiCl, but not LPS. AgRP neuron photostimulation can also increase feeding during chemogenetic-mediated stimulation of PBN CGRP neurons. AgRP neuron stimulation reduces Fos expression in PBN CGRP neurons across all conditions. Finally, stimulation of projections from AgRP neurons to the PBN increases feeding following administration of amylin, CCK, and LiCl, but not LPS. These results demonstrate that AgRP neurons are sufficient to increase feeding during noninflammatory-based appetite suppression and to decrease activity in anorexigenic PBN CGRP neurons, thereby increasing food intake during homeostatic need. SIGNIFICANCE STATEMENT The motivation to eat depends on the relative balance of activity in distinct brain regions that induce or suppress appetite. An abnormal amount of activity in

  10. Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting.

    PubMed

    Dung, Vuu My; Suong, Dang Ngoc Anh; Okamaoto, Yuji; Hiramatsu, Yu; Thao, Dang Thi Phuong; Yoshida, Hideki; Takashima, Hiroshi; Yamaguchi, Masamitsu

    2018-05-15

    Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    PubMed Central

    Nakhaei-Rad, Saeideh; Montenegro-Venegas, Carolina; Pina-Fernández, Eneko; Marini, Claudia; Santos, Monica; Ahmadian, Mohammad R.; Stork, Oliver; Zenker, Martin

    2017-01-01

    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-induced signaling and regulation

  12. Dynamic transition of neuronal firing induced by abnormal astrocytic glutamate oscillation

    NASA Astrophysics Data System (ADS)

    Li, Jiajia; Tang, Jun; Ma, Jun; Du, Mengmeng; Wang, Rong; Wu, Ying

    2016-08-01

    The gliotransmitter glutamate released from astrocytes can modulate neuronal firing by activating neuronal N-methyl-D-aspartic acid (NMDA) receptors. This enables astrocytic glutamate(AG) to be involved in neuronal physiological and pathological functions. Based on empirical results and classical neuron-glial “tripartite synapse” model, we propose a practical model to describe extracellular AG oscillation, in which the fluctuation of AG depends on the threshold of calcium concentration, and the effect of AG degradation is considered as well. We predict the seizure-like discharges under the dysfunction of AG degradation duration. Consistent with our prediction, the suppression of AG uptake by astrocytic transporters, which operates by modulating the AG degradation process, can account for the emergence of epilepsy.

  13. Population activity structure of excitatory and inhibitory neurons

    PubMed Central

    Doiron, Brent

    2017-01-01

    Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure. PMID:28817581

  14. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro.

    PubMed

    Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H

    2015-05-19

    Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

  15. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

    PubMed Central

    Bardy, Cedric; van den Hurk, Mark; Eames, Tameji; Marchand, Cynthia; Hernandez, Ruben V.; Kellogg, Mariko; Gorris, Mark; Galet, Ben; Palomares, Vanessa; Brown, Joshua; Bang, Anne G.; Mertens, Jerome; Böhnke, Lena; Boyer, Leah; Simon, Suzanne; Gage, Fred H.

    2015-01-01

    Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro. PMID:25870293

  16. Sleep-Active Neurons: Conserved Motors of Sleep

    PubMed Central

    Bringmann, Henrik

    2018-01-01

    Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

  17. Activation of VTA GABA neurons disrupts reward consumption

    PubMed Central

    van Zessen, Ruud; Phillips, Jana L.; Budygin, Evgeny A.; Stuber, Garret D.

    2012-01-01

    The activity of Ventral Tegmental Area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors, however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior, but not conditioned anticipatory behavior in response to reward-predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release, but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons, as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors. PMID:22445345

  18. Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities.

    PubMed

    McNally, James M; McCarley, Robert W

    2016-05-01

    We review our current understanding of abnormal γ band oscillations in schizophrenia, their association with symptoms and the underlying cortical circuit abnormality, with a particular focus on the role of fast-spiking parvalbumin gamma-aminobutyric acid (GABA) neurons in the disease state. Clinical electrophysiological studies of schizophrenia patients and pharmacological models of the disorder show an increase in spontaneous γ band activity (not stimulus-evoked) measures. These findings provide a crucial link between preclinical and clinical work examining the role of γ band activity in schizophrenia. MRI-based experiments measuring cortical GABA provides evidence supporting impaired GABAergic neurotransmission in schizophrenia patients, which is correlated with γ band activity level. Several studies suggest that stimulation of the cortical circuitry, directly or via subcortical structures, has the potential to modulate cortical γ activity, and improve cognitive function. Abnormal γ band activity is observed in patients with schizophrenia and disease models in animals, and is suggested to underlie the psychosis and cognitive/perceptual deficits. Convergent evidence from both clinical and preclinical studies suggest the central factor in γ band abnormalities is impaired GABAergic neurotransmission, particularly in a subclass of neurons which express parvalbumin. Rescue of γ band abnormalities presents an intriguing option for therapeutic intervention.

  19. Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities

    PubMed Central

    McNally, James M.; McCarley, Robert W.

    2016-01-01

    Purpose of review We review our current understanding of abnormal γ band oscillations in schizophrenia, their association with symptoms and the underlying cortical circuit abnormality, with a particular focus on the role of fast-spiking parvalbumin gamma-aminobutyric acid (GABA) neurons in the disease state. Recent findings Clinical electrophysiological studies of schizophrenia patients and pharmacological models of the disorder show an increase in spontaneous γ band activity (not stimulus-evoked) measures. These findings provide a crucial link between preclinical and clinical work examining the role of γ band activity in schizophrenia. MRI-based experiments measuring cortical GABA provides evidence supporting impaired GABAergic neurotransmission in schizophrenia patients, which is correlated with γ band activity level. Several studies suggest that stimulation of the cortical circuitry, directly or via subcortical structures, has the potential to modulate cortical γ activity, and improve cognitive function. Summary Abnormal γ band activity is observed in patients with schizophrenia and disease models in animals, and is suggested to underlie the psychosis and cognitive/perceptual deficits. Convergent evidence from both clinical and preclinical studies suggest the central factor in γ band abnormalities is impaired GABAergic neurotransmission, particularly in a subclass of neurons which express parvalbumin. Rescue of γ band abnormalities presents an intriguing option for therapeutic intervention. PMID:26900672

  20. Neuronal avalanches of a self-organized neural network with active-neuron-dominant structure.

    PubMed

    Li, Xiumin; Small, Michael

    2012-06-01

    Neuronal avalanche is a spontaneous neuronal activity which obeys a power-law distribution of population event sizes with an exponent of -3/2. It has been observed in the superficial layers of cortex both in vivo and in vitro. In this paper, we analyze the information transmission of a novel self-organized neural network with active-neuron-dominant structure. Neuronal avalanches can be observed in this network with appropriate input intensity. We find that the process of network learning via spike-timing dependent plasticity dramatically increases the complexity of network structure, which is finally self-organized to be active-neuron-dominant connectivity. Both the entropy of activity patterns and the complexity of their resulting post-synaptic inputs are maximized when the network dynamics are propagated as neuronal avalanches. This emergent topology is beneficial for information transmission with high efficiency and also could be responsible for the large information capacity of this network compared with alternative archetypal networks with different neural connectivity.

  1. Shaping Neuronal Network Activity by Presynaptic Mechanisms

    PubMed Central

    Ashery, Uri

    2015-01-01

    Neuronal microcircuits generate oscillatory activity, which has been linked to basic functions such as sleep, learning and sensorimotor gating. Although synaptic release processes are well known for their ability to shape the interaction between neurons in microcircuits, most computational models do not simulate the synaptic transmission process directly and hence cannot explain how changes in synaptic parameters alter neuronal network activity. In this paper, we present a novel neuronal network model that incorporates presynaptic release mechanisms, such as vesicle pool dynamics and calcium-dependent release probability, to model the spontaneous activity of neuronal networks. The model, which is based on modified leaky integrate-and-fire neurons, generates spontaneous network activity patterns, which are similar to experimental data and robust under changes in the model's primary gain parameters such as excitatory postsynaptic potential and connectivity ratio. Furthermore, it reliably recreates experimental findings and provides mechanistic explanations for data obtained from microelectrode array recordings, such as network burst termination and the effects of pharmacological and genetic manipulations. The model demonstrates how elevated asynchronous release, but not spontaneous release, synchronizes neuronal network activity and reveals that asynchronous release enhances utilization of the recycling vesicle pool to induce the network effect. The model further predicts a positive correlation between vesicle priming at the single-neuron level and burst frequency at the network level; this prediction is supported by experimental findings. Thus, the model is utilized to reveal how synaptic release processes at the neuronal level govern activity patterns and synchronization at the network level. PMID:26372048

  2. Abnormal activity in reward brain circuits in human narcolepsy with cataplexy.

    PubMed

    Ponz, Aurélie; Khatami, Ramin; Poryazova, Rositsa; Werth, Esther; Boesiger, Peter; Bassetti, Claudio L; Schwartz, Sophie

    2010-02-01

    Hypothalamic hypocretins (or orexins) regulate energy metabolism and arousal maintenance. Recent animal research suggests that hypocretins may also influence reward-related behaviors. In humans, the loss of hypocretin-containing neurons results in a major sleep-wake disorder called narcolepsy-cataplexy, which is associated with emotional disturbances. Here, we aim to test whether narcoleptic patients show an abnormal pattern of brain activity during reward processing. We used functional magnetic resonance imaging in 12 unmedicated patients with narcolepsy-cataplexy to measure the neural responses to expectancy and experience of monetary gains and losses. We statistically compared the patients' data with those obtained in a group of 12 healthy matched controls. Our results reveal that activity in the dopaminergic ventral midbrain (ventral tegmental area) was not modulated in narcolepsy-cataplexy patients during high reward expectancy (unlike controls), and that ventral striatum activity was reduced during winning. By contrast, the patients showed abnormal activity increases in the amygdala and in dorsal striatum for positive outcomes. In addition, we found that activity in the nucleus accumbens and the ventral-medial prefrontal cortex correlated with disease duration, suggesting that an alternate neural circuit could be privileged over the years to control affective responses to emotional challenges and compensate for the lack of influence from ventral midbrain regions. Our study offers a detailed picture of the distributed brain network involved during distinct stages of reward processing and shows for the first time, to our knowledge, how this network is affected in hypocretin-deficient narcoleptic patients.

  3. Resveratrol stimulates AMP kinase activity in neurons.

    PubMed

    Dasgupta, Biplab; Milbrandt, Jeffrey

    2007-04-24

    Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.

  4. Cell death in neural precursor cells and neurons before neurite formation prevents the emergence of abnormal neural structures in the Drosophila optic lobe.

    PubMed

    Hara, Yusuke; Sudo, Tatsuya; Togane, Yu; Akagawa, Hiromi; Tsujimura, Hidenobu

    2018-04-01

    Programmed cell death is a conserved strategy for neural development both in vertebrates and invertebrates and is recognized at various developmental stages in the brain from neurogenesis to adulthood. To understand the development of the central nervous system, it is essential to reveal not only molecular mechanisms but also the role of neural cell death (Pinto-Teixeira et al., 2016). To understand the role of cell death in neural development, we investigated the effect of inhibition of cell death on optic lobe development. Our data demonstrate that, in the optic lobe of Drosophila, cell death occurs in neural precursor cells and neurons before neurite formation and functions to prevent various developmental abnormalities. When neuronal cell death was inhibited by an effector caspase inhibitor, p35, multiple abnormal neuropil structures arose during optic lobe development-e.g., enlarged or fused neuropils, misrouted neurons and abnormal neurite lumps. Inhibition of cell death also induced morphogenetic defects in the lamina and medulla development-e.g., failures in the separation of the lamina and medulla cortices and the medulla rotation. These defects were reproduced in the mutant of an initiator caspase, dronc. If cell death was a mechanism for removing the abnormal neuropil structures, we would also expect to observe them in mutants defective for corpse clearance. However, they were not observed in these mutants. When dead cell-membranes were visualized with Apoliner, they were observed only in cortices and not in neuropils. These results suggest that the cell death occurs before mature neurite formation. Moreover, we found that inhibition of cell death induced ectopic neuroepithelial cells, neuroblasts and ganglion mother cells in late pupal stages, at sites where the outer and inner proliferation centers were located at earlier developmental stages. Caspase-3 activation was observed in the neuroepithelial cells and neuroblasts in the proliferation centers

  5. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

    PubMed

    Tabet, Ricardos; Moutin, Enora; Becker, Jérôme A J; Heintz, Dimitri; Fouillen, Laetitia; Flatter, Eric; Krężel, Wojciech; Alunni, Violaine; Koebel, Pascale; Dembélé, Doulaye; Tassone, Flora; Bardoni, Barbara; Mandel, Jean-Louis; Vitale, Nicolas; Muller, Dominique; Le Merrer, Julie; Moine, Hervé

    2016-06-28

    Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.

  6. Control of Abnormal Synchronization in Neurological Disorders

    PubMed Central

    Popovych, Oleksandr V.; Tass, Peter A.

    2014-01-01

    In the nervous system, synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson’s disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR) neuromodulation, we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, non-linear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP), CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from an abnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved. PMID:25566174

  7. Rhythmic activities of hypothalamic magnocellular neurons: autocontrol mechanisms.

    PubMed

    Richard, P; Moos, F; Dayanithi, G; Gouzènes, L; Sabatier, N

    1997-12-01

    Electrophysiological recordings in lactating rats show that oxytocin (OT) and vasopressin (AVP) neurons exhibit specific patterns of activities in relation to peripheral stimuli: periodic bursting firing for OT neurons during suckling, phasic firing for AVP neurons during hyperosmolarity (systemic injection of hypertonic saline). These activities are autocontrolled by OT and AVP released somato-dentritically within the hypothalamic magnocellular nuclei. In vivo, OT enhances the amplitude and frequency of bursts, an effect accompanied with an increase in basal firing rate. However, the characteristics of firing change as facilitation proceeds: the spike patterns become very irregular with clusters of spikes spaced by long silences; the firing rate is highly variable and clearly oscillates before facilitated bursts. This unstable behaviour dramatically decreases during intense tonic activation which temporarily interrupts bursting, and could therefore be a prerequisite for bursting. In vivo, the effects of AVP depend on the initial firing pattern of AVP neurons: AVP excites weakly active neurons (increasing duration of active periods and decreasing silences), inhibits highly active neurons, and does not affect neurons with intermediate phasic activity. AVP brings the entire population of AVP neurons to discharge with a medium phasic activity characterised by periods of firing and silence lasting 20-40 s, a pattern shown to optimise the release of AVP from the neurohypophysis. Each of the peptides (OT or AVP) induces an increase in intracellular Ca2+ concentration, specifically in the neurons containing either OT or AVP respectively. OT evokes the release of Ca2+ from IP3-sensitive intracellular stores. AVP induces an influx of Ca2+ through voltage-dependent Ca2+ channels of T-, L- and N-types. We postulate that the facilitatory autocontrol of OT and AVP neurons could be mediated by Ca2+ known to play a key role in the control of the patterns of phasic neurons.

  8. Negative BOLD with Large Increases in Neuronal Activity

    PubMed Central

    Khubchandani, Manjula; Motelow, Joshua E.; Sanganahalli, Basavaraju G.; Hyder, Fahmeed

    2008-01-01

    Blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used in neuroscience to study brain activity. However, BOLD fMRI does not measure neuronal activity directly but depends on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO2) consumption. Using fMRI, CBV, CBF, neuronal recordings, and CMRO2 modeling, we investigated how the signals are related during seizures in rats. We found that increases in hemodynamic, neuronal, and metabolic activity were associated with positive BOLD signals in the cortex, but with negative BOLD signals in hippocampus. Our data show that negative BOLD signals do not necessarily imply decreased neuronal activity or CBF, but can result from increased neuronal activity, depending on the interplay between hemodynamics and metabolism. Caution should be used in interpreting fMRI signals because the relationship between neuronal activity and BOLD signals may depend on brain region and state and can be different during normal and pathological conditions. PMID:18063563

  9. Impaired cortical activation in autistic children: is the mirror neuron system involved?

    PubMed

    Martineau, Joëlle; Cochin, Stéphanie; Magne, Rémy; Barthelemy, Catherine

    2008-04-01

    The inability to imitate becomes obvious early in autistic children and seems to contribute to learning delay and to disorders of communication and contact. Posture, motility and imitation disorders in autistic syndrome might be the consequence of an abnormality of sensori-motor integration, related to the visual perception of movement, and could reflect impairment of the mirror neuron system (MNS). We compared EEG activity during the observation of videos showing actions or still scenes in 14 right-handed autistic children and 14 right-handed, age- and gender-matched control children (3 girls and 11 boys, aged 5 years 3 months-7 years 11 months). We showed desynchronisation of the EEG in the motor cerebral cortex and the frontal and temporal areas during observation of human actions in the group of healthy children. No such desynchronisation was found in autistic children. Moreover, inversion of the pattern of hemispheric activation was found in autistic children, with increased cortical activity in the right hemisphere in the posterior region, including the centro-parietal and temporo-occipital sites. These results are in agreement with the hypothesis of impairment of the mirror neuron system in autistic disorder.

  10. Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition.

    PubMed

    Takayanagi, Yuki; Yoshida, Masahide; Takashima, Akihide; Takanami, Keiko; Yoshida, Shoma; Nishimori, Katsuhiko; Nishijima, Ichiko; Sakamoto, Hirotaka; Yamagata, Takanori; Onaka, Tatsushi

    2017-02-01

    Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights

  11. GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

    PubMed

    Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

    2016-04-06

    Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. GABAergic neuron-specific loss of Ube3a causes Angelman syndrome-like EEG abnormalities and enhances seizure susceptibility

    PubMed Central

    Judson, Matthew C.; Wallace, Michael L.; Sidorov, Michael S.; Burette, Alain C.; Gu, Bin; van Woerden, Geeske M.; King, Ian F.; Han, Ji Eun; Zylka, Mark J.; Elgersma, Ype; Weinberg, Richard J.; Philpot, Benjamin D.

    2016-01-01

    SUMMARY Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs) – all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS. PMID:27021170

  13. Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.

    PubMed

    McConnell, George C; So, Rosa Q; Grill, Warren M

    2016-06-01

    Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia. Copyright © 2016 the American Physiological Society.

  14. Abnormal tau phosphorylation in the thorny excrescences of CA3 hippocampal neurons in patients with Alzheimer's disease.

    PubMed

    Blazquez-Llorca, Lidia; Garcia-Marin, Virginia; Merino-Serrais, Paula; Ávila, Jesús; DeFelipe, Javier

    2011-01-01

    A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.

  15. The emergence of spontaneous activity in neuronal cultures

    NASA Astrophysics Data System (ADS)

    Orlandi, J. G.; Alvarez-Lacalle, E.; Teller, S.; Soriano, J.; Casademunt, J.

    2013-01-01

    In vitro neuronal networks of dissociated hippocampal or cortical tissues are one of the most attractive model systems for the physics and neuroscience communities. Cultured neurons grow and mature, develop axons and dendrites, and quickly connect to their neighbors to establish a spontaneously active network within a week. The resulting neuronal network is characterized by a combination of excitatory and inhibitory neurons coupled through synaptic connections that interact in a highly nonlinear manner. The nonlinear behavior emerges from the dynamics of both the neurons' spiking activity and synaptic transmission, together with biological noise. These ingredients give rise to a rich repertoire of phenomena that are still poorly understood, including the emergence and maintenance of periodic spontaneous activity, avalanches, propagation of fronts and synchronization. In this work we present an overview on the rich activity of cultured neuronal networks, and detail the minimal theoretical considerations needed to describe experimental observations.

  16. Invisible Brain: Knowledge in Research Works and Neuron Activity.

    PubMed

    Segev, Aviv; Curtis, Dorothy; Jung, Sukhwan; Chae, Suhyun

    2016-01-01

    If the market has an invisible hand, does knowledge creation and representation have an "invisible brain"? While knowledge is viewed as a product of neuron activity in the brain, can we identify knowledge that is outside the brain but reflects the activity of neurons in the brain? This work suggests that the patterns of neuron activity in the brain can be seen in the representation of knowledge-related activity. Here we show that the neuron activity mechanism seems to represent much of the knowledge learned in the past decades based on published articles, in what can be viewed as an "invisible brain" or collective hidden neural networks. Similar results appear when analyzing knowledge activity in patents. Our work also tries to characterize knowledge increase as neuron network activity growth. The results propose that knowledge-related activity can be seen outside of the neuron activity mechanism. Consequently, knowledge might exist as an independent mechanism.

  17. Invisible Brain: Knowledge in Research Works and Neuron Activity

    PubMed Central

    Segev, Aviv; Curtis, Dorothy; Jung, Sukhwan; Chae, Suhyun

    2016-01-01

    If the market has an invisible hand, does knowledge creation and representation have an “invisible brain”? While knowledge is viewed as a product of neuron activity in the brain, can we identify knowledge that is outside the brain but reflects the activity of neurons in the brain? This work suggests that the patterns of neuron activity in the brain can be seen in the representation of knowledge-related activity. Here we show that the neuron activity mechanism seems to represent much of the knowledge learned in the past decades based on published articles, in what can be viewed as an “invisible brain” or collective hidden neural networks. Similar results appear when analyzing knowledge activity in patents. Our work also tries to characterize knowledge increase as neuron network activity growth. The results propose that knowledge-related activity can be seen outside of the neuron activity mechanism. Consequently, knowledge might exist as an independent mechanism. PMID:27439199

  18. Abnormal mTOR Activation in Autism.

    PubMed

    Winden, Kellen D; Ebrahimi-Fakhari, Darius; Sahin, Mustafa

    2018-01-25

    The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic molecular processes and cell growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these associations are of great interest because of the clinical availability of mTOR inhibitors. Clinical trials evaluating the efficacy of mTOR Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  19. Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189

    PubMed Central

    McAfee, Samuel S.; Guley, Natalie M.; Del Mar, Nobel; Bu, Wei; Heldt, Scott A.; Honig, Marcia G.; Moore, Bob M.

    2017-01-01

    Abstract Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189. PMID:28828401

  20. Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189.

    PubMed

    Liu, Yu; McAfee, Samuel S; Guley, Natalie M; Del Mar, Nobel; Bu, Wei; Heldt, Scott A; Honig, Marcia G; Moore, Bob M; Reiner, Anton; Heck, Detlef H

    2017-01-01

    Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

  1. Dopamine suppresses neuronal activity of Helisoma B5 neurons via a D2-like receptor, activating PLC and K channels.

    PubMed

    Zhong, L R; Artinian, L; Rehder, V

    2013-01-03

    Dopamine (DA) plays fundamental roles as a neurotransmitter and neuromodulator in the central nervous system. How DA modulates the electrical excitability of individual neurons to elicit various behaviors is of great interest in many systems. The buccal ganglion of the freshwater pond snail Helisoma trivolvis contains the neuronal circuitry for feeding and DA is known to modulate the feeding motor program in Helisoma. The buccal neuron B5 participates in the control of gut contractile activity and is surrounded by dopaminergic processes, which are expected to release DA. In order to study whether DA modulates the electrical activity of individual B5 neurons, we performed experiments on physically isolated B5 neurons in culture and on B5 neurons within the buccal ganglion in situ. We report that DA application elicited a strong hyperpolarization in both conditions and turned the electrical activity from a spontaneously firing state to an electrically silent state. Using the cell culture system, we demonstrated that the strong hyperpolarization was inhibited by the D2 receptor antagonist sulpiride and the phospholipase C (PLC) inhibitor U73122, indicating that DA affected the membrane potential of B5 neurons through the activation of a D2-like receptor and PLC. Further studies revealed that the DA-induced hyperpolarization was inhibited by the K channel blockers 4-aminopyridine and tetraethylammonium, suggesting that K channels might serve as the ultimate target of DA signaling. Through its modulatory effect on the electrical activity of B5 neurons, the release of DA in vivo may contribute to a neuronal output that results in a variable feeding motor program. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Activity-Dependent Neurorehabilitation Beyond Physical Trainings: "Mental Exercise" Through Mirror Neuron Activation.

    PubMed

    Yuan, Ti-Fei; Chen, Wei; Shan, Chunlei; Rocha, Nuno; Arias-Carrión, Oscar; Paes, Flávia; de Sá, Alberto Souza; Machado, Sergio

    2015-01-01

    The activity dependent brain repair mechanism has been widely adopted in many types of neurorehabilitation. The activity leads to target specific and non-specific beneficial effects in different brain regions, such as the releasing of neurotrophic factors, modulation of the cytokines and generation of new neurons in adult hood. However physical exercise program clinically are limited to some of the patients with preserved motor functions; while many patients suffered from paralysis cannot make such efforts. Here the authors proposed the employment of mirror neurons system in promoting brain rehabilitation by "observation based stimulation". Mirror neuron system has been considered as an important basis for action understanding and learning by mimicking others. During the action observation, mirror neuron system mediated the direct activation of the same group of motor neurons that are responsible for the observed action. The effect is clear, direct, specific and evolutionarily conserved. Moreover, recent evidences hinted for the beneficial effects on stroke patients after mirror neuron system activation therapy. Finally some music-relevant therapies were proposed to be related with mirror neuron system.

  3. CRISPR Epigenome Editing of AKAP150 in DRG Neurons Abolishes Degenerative IVD-Induced Neuronal Activation.

    PubMed

    Stover, Joshua D; Farhang, Niloofar; Berrett, Kristofer C; Gertz, Jason; Lawrence, Brandon; Bowles, Robby D

    2017-09-06

    Back pain is a major contributor to disability and has significant socioeconomic impacts worldwide. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to back pain, but a better understanding of the interactions between the degenerative IVD and nociceptive neurons innervating the disc and treatment strategies that directly target these interactions is needed to improve our understanding and treatment of back pain. We investigated degenerative IVD-induced changes to dorsal root ganglion (DRG) neuron activity and utilized CRISPR epigenome editing as a neuromodulation strategy. By exposing DRG neurons to degenerative IVD-conditioned media under both normal and pathological IVD pH levels, we demonstrate that degenerative IVDs trigger interleukin (IL)-6-induced increases in neuron activity to thermal stimuli, which is directly mediated by AKAP and enhanced by acidic pH. Utilizing this novel information on AKAP-mediated increases in nociceptive neuron activity, we developed lentiviral CRISPR epigenome editing vectors that modulate endogenous expression of AKAP150 by targeted promoter histone methylation. When delivered to DRG neurons, these epigenome-modifying vectors abolished degenerative IVD-induced DRG-elevated neuron activity while preserving non-pathologic neuron activity. This work elucidates the potential for CRISPR epigenome editing as a targeted gene-based pain neuromodulation strategy. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  4. Anti-Hu antibodies activate enteric and sensory neurons

    PubMed Central

    Li, Qin; Michel, Klaus; Annahazi, Anita; Demir, Ihsan E.; Ceyhan, Güralp O.; Zeller, Florian; Komorowski, Lars; Stöcker, Winfried; Beyak, Michael J.; Grundy, David; Farrugia, Gianrico; De Giorgio, Roberto; Schemann, Michael

    2016-01-01

    IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spike discharge in enteric and visceral sensory neurons. Both labelling and activation of enteric neurons was prevented by preincubation with the HuD antigen. Activation of enteric neurons was inhibited by the nicotinic receptor antagonists hexamethonium and dihydro-β-erythroidine and reduced by the P2X antagonist pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid (PPADS) but not by the 5-HT3 antagonist tropisetron or the N-type Ca-channel blocker ω-Conotoxin GVIA. Ca++ imaging experiments confirmed activation of enteric neurons but not enteric glia. These findings demonstrate a direct excitatory action of ANNA-1, in particular anti-HuD, on visceral sensory and enteric neurons, which involves nicotinic and P2X receptors. The results provide evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction. PMID:27905561

  5. Methamphetamine Regulation of Firing Activity of Dopamine Neurons

    PubMed Central

    Lin, Min; Sambo, Danielle

    2016-01-01

    Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METH has also been shown to alter the excitability of dopamine neurons. The mechanism of METH regulation of the intrinsic firing behaviors of dopamine neurons is less understood. Here we identified an unexpected and unique property of METH on the regulation of firing activity of mouse dopamine neurons. METH produced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed that METH increased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca2+ homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca2+-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggest METH exposure decreased the activity of BK channels by decreasing BK-α subunit levels at the plasma membrane. SIGNIFICANCE STATEMENT Methamphetamine (METH) competes with dopamine uptake, increases dopamine efflux via the dopamine transporter, and affects the excitability of

  6. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

    PubMed Central

    Suh, Sang Won; Gum, Elizabeth T.; Hamby, Aaron M.; Chan, Pak H.; Swanson, Raymond A.

    2007-01-01

    Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase. PMID:17404617

  7. Rostral dorsolateral pontine neurons with sympathetic nerve-related activity.

    PubMed

    Barman, S M; Gebber, G L; Kitchens, H

    1999-02-01

    Spike-triggered averaging, arterial pulse-triggered analysis, and coherence analysis were used to classify rostral dorsolateral pontine (RDLP) neurons into groups whose naturally occurring discharges were correlated to only the 10-Hz rhythm (n = 29), to only the cardiac-related rhythm (n = 15), and to both rhythms (n = 15) in inferior cardiac sympathetic nerve discharge (SND) of urethan-anesthetized cats. Most of the neurons with activity correlated to only the cardiac-related rhythm were located medial to the other two groups of neurons. The firing rates of most RDLP neurons with activity correlated to only the 10-Hz rhythm (9 of 12) or both rhythms (7 of 8) were decreased during baroreceptor reflex-induced inhibition of SND produced by aortic obstruction; thus, they are presumed to be sympathoexcitatory. The firing rates of four of seven RDLP neurons with activity correlated to only the cardiac-related rhythm increased during baroreceptor reflex activation; thus, they may be sympathoinhibitory. We conclude that the RDLP contains a functionally heterogeneous population of neurons with sympathetic nerve-related activity. These neurons could not be antidromically activated by stimulation of the thoracic spinal cord.

  8. Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders.

    PubMed

    Dapretto, Mirella; Davies, Mari S; Pfeifer, Jennifer H; Scott, Ashley A; Sigman, Marian; Bookheimer, Susan Y; Iacoboni, Marco

    2006-01-01

    To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional 'mirror neuron system' may underlie the social deficits observed in autism.

  9. Activity of nigral dopaminergic neurons after lesion of the neostriatum in rats.

    PubMed

    Doudet, D; Gross, C; Seal, J; Bioulac, B

    1984-06-04

    As shown by post-mortem analysis the major neuropathological trait of Huntington's chorea is a degeneration of the intrinsic neurons of the neostriatum (caudate nucleus and putamen). Such a situation can be reproduced by a destruction of the neostriatum by kainic acid. When injected into the caudate nucleus this excitatory amino acid destroys the intrinsic neurons of the neostriatum and spares fairly well the passing fibers. In the present work, we have chosen to examine the influence of neostriatal destruction on the activity of identified dopaminergic cells in the pars compacta of the substantia nigra. As a key element in the nigro-neostriato-nigral loop, this structure is a relevant site for observing the functional effects of neostriatal lesion. Our research hypothesis was based on the generally accepted view that the suppression of the important neostriato-nigral pathway and in particular the inhibitory GABAergic contingent, could generate a hyperactivity of nigral dopaminergic cells. One may therefore consider that the dopaminergic hyperactivity produces abnormal messages which can influence via several pathways the motoneurons, and which participates in the genesis of the hyperkinetic movements characteristic of chorea. After destruction of the neostriatum, we have shown that the pattern of discharge of most identified nigral dopaminergic neurons becomes greatly disorganized. This drastic change in the pattern of activity cannot be interpreted as the simple 'lift of a brake' on these cells by the suppression of the inhibitory GABAergic striato-nigral tract.

  10. Prediction of primary somatosensory neuron activity during active tactile exploration

    PubMed Central

    Campagner, Dario; Evans, Mathew Hywel; Bale, Michael Ross; Erskine, Andrew; Petersen, Rasmus Strange

    2016-01-01

    Primary sensory neurons form the interface between world and brain. Their function is well-understood during passive stimulation but, under natural behaving conditions, sense organs are under active, motor control. In an attempt to predict primary neuron firing under natural conditions of sensorimotor integration, we recorded from primary mechanosensory neurons of awake, head-fixed mice as they explored a pole with their whiskers, and simultaneously measured both whisker motion and forces with high-speed videography. Using Generalised Linear Models, we found that primary neuron responses were poorly predicted by whisker angle, but well-predicted by rotational forces acting on the whisker: both during touch and free-air whisker motion. These results are in apparent contrast to previous studies of passive stimulation, but could be reconciled by differences in the kinematics-force relationship between active and passive conditions. Thus, simple statistical models can predict rich neural activity elicited by natural, exploratory behaviour involving active movement of sense organs. DOI: http://dx.doi.org/10.7554/eLife.10696.001 PMID:26880559

  11. Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

    PubMed

    Roland, Alison V; Moenter, Suzanne M

    2011-02-01

    Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

  12. Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons

    PubMed Central

    Yao, Pamela J.; Manor, Uri; Petralia, Ronald S.; Brose, Rebecca D.; Wu, Ryan T. Y.; Ott, Carolyn; Wang, Ya-Xian; Charnoff, Ari; Lippincott-Schwartz, Jennifer; Mattson, Mark P.

    2017-01-01

    Mitochondria are essential organelles whose biogenesis, structure, and function are regulated by many signaling pathways. We present evidence that, in hippocampal neurons, activation of the Sonic hedgehog (Shh) signaling pathway affects multiple aspects of mitochondria. Mitochondrial mass was increased significantly in neurons treated with Shh. Using biochemical and fluorescence imaging analyses, we show that Shh signaling activity reduces mitochondrial fission and promotes mitochondrial elongation, at least in part, via suppression of the mitochondrial fission protein dynamin-like GTPase Drp1. Mitochondria from Shh-treated neurons were more electron-dense, as revealed by electron microscopy, and had higher membrane potential and respiratory activity. We further show that Shh protects neurons against a variety of stresses, including the mitochondrial poison rotenone, amyloid β-peptide, hydrogen peroxide, and high levels of glutamate. Collectively our data suggest a link between Shh pathway activity and the physiological properties of mitochondria in hippocampal neurons. PMID:27932496

  13. Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain.

    PubMed

    Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook; Zheng, Qin; Agarwal, Amit; Gong, Catherine; Saijilafu; Young, LeAnne; He, Shaoqiu; LaVinka, Pamela Colleen; Zhou, Fengquan; Bergles, Dwight; Hanani, Menachem; Guan, Yun; Spray, David C; Dong, Xinzhong

    2016-09-07

    Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by "hijacking" neighboring neurons through gap junctions. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    PubMed

    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.

  15. Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons?

    PubMed

    Kim, Ji-Il; Cho, Hye-Yeon; Han, Jin-Hee; Kaang, Bong-Kiun

    2016-04-01

    During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression.

  16. Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons?

    PubMed Central

    Kim, Ji-il; Cho, Hye-Yeon; Han, Jin-Hee

    2016-01-01

    During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. PMID:27122991

  17. Cellular Links between Neuronal Activity and Energy Homeostasis.

    PubMed

    Shetty, Pavan K; Galeffi, Francesca; Turner, Dennis A

    2012-01-01

    Neuronal activity, astrocytic responses to this activity, and energy homeostasis are linked together during baseline, conscious conditions, and short-term rapid activation (as occurs with sensory or motor function). Nervous system energy homeostasis also varies during long-term physiological conditions (i.e., development and aging) and with adaptation to pathological conditions, such as ischemia or low glucose. Neuronal activation requires increased metabolism (i.e., ATP generation) which leads initially to substrate depletion, induction of a variety of signals for enhanced astrocytic function, and increased local blood flow and substrate delivery. Energy generation (particularly in mitochondria) and use during ATP hydrolysis also lead to considerable heat generation. The local increases in blood flow noted following neuronal activation can both enhance local substrate delivery but also provides a heat sink to help cool the brain and removal of waste by-products. In this review we highlight the interactions between short-term neuronal activity and energy metabolism with an emphasis on signals and factors regulating astrocyte function and substrate supply.

  18. Epac activation sensitizes rat sensory neurons through activation of Ras.

    PubMed

    Shariati, Behzad; Thompson, Eric L; Nicol, Grant D; Vasko, Michael R

    2016-01-01

    Guanine nucleotide exchange factors directly activated by cAMP (Epacs) have emerged as important signaling molecules mediating persistent hypersensitivity in animal models of inflammation, by augmenting the excitability of sensory neurons. Although Epacs activate numerous downstream signaling cascades, the intracellular signaling which mediates Epac-induced sensitization of capsaicin-sensitive sensory neurons remains unknown. Here, we demonstrate that selective activation of Epacs with 8-CPT-2'-O-Me-cAMP-AM (8CPT-AM) increases the number of action potentials (APs) generated by a ramp of depolarizing current and augments the evoked release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons. Internal perfusion of capsaicin-sensitive sensory neurons with GDP-βS, substituted for GTP, blocks the ability of 8CPT-AM to increase AP firing, demonstrating that Epac-induced sensitization is G-protein dependent. Treatment with 8CPT-AM activates the small G-proteins Rap1 and Ras in cultures of sensory neurons. Inhibition of Rap1, by internal perfusion of a Rap1-neutralizing antibody or through a reduction in the expression of the protein using shRNA does not alter the Epac-induced enhancement of AP generation or CGRP release, despite the fact that in most other cell types, Epacs act as Rap-GEFs. In contrast, inhibition of Ras through expression of a dominant negative Ras (DN-Ras) or through internal perfusion of a Ras-neutralizing antibody blocks the increase in AP firing and attenuates the increase in the evoked release of CGRP induced by Epac activation. Thus, in this subpopulation of nociceptive sensory neurons, it is the novel interplay between Epacs and Ras, rather than the canonical Epacs and Rap1 pathway, that is critical for mediating Epac-induced sensitization. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Epac activation sensitizes rat sensory neurons via activation of Ras

    PubMed Central

    Shariati, Behzad; Thompson, Eric L.; Nicol, Grant D.; Vasko, Michael R.

    2015-01-01

    Guanine nucleotide exchange factors directly activated by cAMP (Epacs) have emerged as important signaling molecules mediating persistent hypersensitivity in animal models of inflammation, by augmenting the excitability of sensory neurons. Although Epacs activate numerous downstream signaling cascades, the intracellular signaling which mediates Epac-induced sensitization of capsaicin-sensitive sensory neurons remains unknown. Here, we demonstrate that selective activation of Epacs with 8-CPT-2′-O-Me-cAMP-AM (8CPT-AM) increases the number of action potentials (APs) generated by a ramp of depolarizing current and augments the evoked release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons. Internal perfusion of capsaicin-sensitive sensory neurons with GDP-βS, substituted for GTP, blocks the ability of 8CPT-AM to increase AP firing, demonstrating that Epac-induced sensitization is G-protein dependent. Treatment with 8CPT-AM activates the small G-proteins Rap1 and Ras in cultures of sensory neurons. Inhibition of Rap1, by internal perfusion of a Rap1-neutralizing antibody or through a reduction in the expression of the protein using shRNA does not alter the Epac-induced enhancement of AP generation or CGRP release, despite the fact that in most other cell types, Epacs act as Rap-GEFs. In contrast, inhibition of Ras through expression of a dominant negative Ras (DN-Ras) or through internal perfusion of a Ras-neutralizing antibody blocks the increase in AP firing and attenuates the increase in the evoked release of CGRP induced by Epac activation. Thus, in this subpopulation of nociceptive sensory neurons, it is the novel interplay between Epacs and Ras, rather than the canonical Epacs and Rap1 pathway, that is critical for mediating Epac-induced sensitization. PMID:26596174

  20. Abnormal Glycogen Storage by Retinal Neurons in Diabetes.

    PubMed

    Gardiner, Tom A; Canning, Paul; Tipping, Nuala; Archer, Desmond B; Stitt, Alan W

    2015-12-01

    It is widely held that neurons of the central nervous system do not store glycogen and that accumulation of the polysaccharide may cause neurodegeneration. Since primary neural injury occurs in diabetic retinopathy, we examined neuronal glycogen status in the retina of streptozotocin-induced diabetic and control rats. Glycogen was localized in eyes of streptozotocin-induced diabetic and control rats using light microscopic histochemistry and electron microscopy, and correlated with immunohistochemical staining for glycogen phosphorylase and phosphorylated glycogen synthase (pGS). Electron microscopy of 2-month-old diabetic rats (n = 6) showed massive accumulations of glycogen in the perinuclear cytoplasm of many amacrine neurons. In 4-month-old diabetic rats (n = 11), quantification of glycogen-engorged amacrine cells showed a mean of 26 cells/mm of central retina (SD ± 5), compared to 0.5 (SD ± 0.2) in controls (n = 8). Immunohistochemical staining for glycogen phosphorylase revealed strong expression in amacrine and ganglion cells of control retina, and increased staining in cell processes of the inner plexiform layer in diabetic retina. In control retina, the inactive pGS was consistently sequestered within the cell nuclei of all retinal neurons and the retinal pigment epithelium (RPE), but in diabetics nuclear pGS was reduced or lost in all classes of retinal cell except the ganglion cells and cone photoreceptors. The present study identifies a large population of retinal neurons that normally utilize glycogen metabolism but show pathologic storage of the polysaccharide during uncontrolled diabetes.

  1. PERSPECTIVE: Electrical activity enhances neuronal survival and regeneration

    NASA Astrophysics Data System (ADS)

    Corredor, Raul G.; Goldberg, Jeffrey L.

    2009-10-01

    The failure of regeneration in the central nervous system (CNS) remains an enormous scientific and clinical challenge. After injury or in degenerative diseases, neurons in the adult mammalian CNS fail to regrow their axons and reconnect with their normal targets, and furthermore the neurons frequently die and are not normally replaced. While significant progress has been made in understanding the molecular basis for this lack of regenerative ability, a second approach has gained momentum: replacing lost neurons or lost connections with artificial electrical circuits that interface with the nervous system. In the visual system, gene therapy-based 'optogenetics' prostheses represent a competing technology. Now, the two approaches are converging, as recent data suggest that electrical activity itself, via the molecular signaling pathways such activity stimulates, is sufficient to induce neuronal survival and regeneration, particularly in retinal ganglion cells. Here, we review these data, discuss the effects of electrical activity on neurons' molecular signaling pathways and propose specific mechanisms by which exogenous electrical activity may be acting to enhance survival and regeneration.

  2. Computational implications of activity-dependent neuronal processes

    NASA Astrophysics Data System (ADS)

    Goldman, Mark Steven

    Synapses, the connections between neurons, often fail to transmit a large percentage of the action potentials that they receive. I describe several models of synaptic transmission at a single stochastic synapse with an activity-dependent probability of transmission and demonstrate how synaptic transmission failures may increase the efficiency with which a synapse transmits information. Spike trains in the visual cortex of freely viewing monkeys have positive auto correlations that are indicative of a redundant representation of the information they contain. I show how a synapse with activity-dependent transmission failures modeled after those occurring in visual cortical synapses can remove this redundancy by transmitting a decorrelated subset of the spike trains it receives. I suggest that redundancy reduction at individual synapses saves synaptic resources while increasing the sensitivity of the postsynaptic neuron to information arriving along many inputs. For a neuron receiving input from many decorrelating synapses, my analysis leads to a prediction of the number of visual inputs to a neuron and the cross-correlations between these inputs and suggests that the time scale of synaptic dynamics observed in sensory areas corresponds to a fundamental time scale for processing sensory information. Systems with activity-dependent changes in their parameters, or plasticity, often display a wide variability in their individual components that belies the stability of their function, Motivated by experiments demonstrating that identified neurons with stereotyped function can have a large variability in the densities of their ion channels, or ionic conductances, I build a conductance-based model of a single neuron. The neuron's firing activity is relatively insensitive to changes in certain combinations of conductances, but markedly sensitive to changes in other combinations. Using a combined modeling and experimental approach, I show that neuromodulators and regulatory

  3. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

    PubMed

    Venkatesh, Humsa S; Johung, Tessa B; Caretti, Viola; Noll, Alyssa; Tang, Yujie; Nagaraja, Surya; Gibson, Erin M; Mount, Christopher W; Polepalli, Jai; Mitra, Siddhartha S; Woo, Pamelyn J; Malenka, Robert C; Vogel, Hannes; Bredel, Markus; Mallick, Parag; Monje, Michelle

    2015-05-07

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity.

    PubMed

    Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Masseck, Olivia A; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

    2017-04-25

    Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.

  5. Serotonin neurons in the dorsal raphe mediate the anticataplectic action of orexin neurons by reducing amygdala activity

    PubMed Central

    Hasegawa, Emi; Maejima, Takashi; Yoshida, Takayuki; Herlitze, Stefan; Yoshioka, Mitsuhiro; Sakurai, Takeshi; Mieda, Michihiro

    2017-01-01

    Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing. PMID:28396432

  6. Knockout Mice for Dyslexia Susceptibility Gene Homologs KIAA0319 and KIAA0319L have Unaffected Neuronal Migration but Display Abnormal Auditory Processing

    PubMed Central

    Guidi, Luiz G; Mattley, Jane; Martinez-Garay, Isabel; Monaco, Anthony P; Linden, Jennifer F; Velayos-Baeza, Antonio

    2017-01-01

    Abstract Developmental dyslexia is a neurodevelopmental disorder that affects reading ability caused by genetic and non-genetic factors. Amongst the susceptibility genes identified to date, KIAA0319 is a prime candidate. RNA-interference experiments in rats suggested its involvement in cortical migration but we could not confirm these findings in Kiaa0319-mutant mice. Given its homologous gene Kiaa0319L (AU040320) has also been proposed to play a role in neuronal migration, we interrogated whether absence of AU040320 alone or together with KIAA0319 affects migration in the developing brain. Analyses of AU040320 and double Kiaa0319;AU040320 knockouts (dKO) revealed no evidence for impaired cortical lamination, neuronal migration, neurogenesis or other anatomical abnormalities. However, dKO mice displayed an auditory deficit in a behavioral gap-in-noise detection task. In addition, recordings of click-evoked auditory brainstem responses revealed suprathreshold deficits in wave III amplitude in AU040320-KO mice, and more general deficits in dKOs. These findings suggest that absence of AU040320 disrupts firing and/or synchrony of activity in the auditory brainstem, while loss of both proteins might affect both peripheral and central auditory function. Overall, these results stand against the proposed role of KIAA0319 and AU040320 in neuronal migration and outline their relationship with deficits in the auditory system. PMID:29045729

  7. PDF neuron firing phase-shifts key circadian activity neurons in Drosophila.

    PubMed

    Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

    2014-06-17

    Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY.

  8. Assessing the sensitivity of diffusion MRI to detect neuronal activity directly.

    PubMed

    Bai, Ruiliang; Stewart, Craig V; Plenz, Dietmar; Basser, Peter J

    2016-03-22

    Functional MRI (fMRI) is widely used to study brain function in the neurosciences. Unfortunately, conventional fMRI only indirectly assesses neuronal activity via hemodynamic coupling. Diffusion fMRI was proposed as a more direct and accurate fMRI method to detect neuronal activity, yet confirmative findings have proven difficult to obtain. Given that the underlying relation between tissue water diffusion changes and neuronal activity remains unclear, the rationale for using diffusion MRI to monitor neuronal activity has yet to be clearly established. Here, we studied the correlation between water diffusion and neuronal activity in vitro by simultaneous calcium fluorescence imaging and diffusion MR acquisition. We used organotypic cortical cultures from rat brains as a biological model system, in which spontaneous neuronal activity robustly emerges free of hemodynamic and other artifacts. Simultaneous fluorescent calcium images of neuronal activity are then directly correlated with diffusion MR signals now free of confounds typically encountered in vivo. Although a simultaneous increase of diffusion-weighted MR signals was observed together with the prolonged depolarization of neurons induced by pharmacological manipulations (in which cell swelling was demonstrated to play an important role), no evidence was found that diffusion MR signals directly correlate with normal spontaneous neuronal activity. These results suggest that, whereas current diffusion MR methods could monitor pathological conditions such as hyperexcitability, e.g., those seen in epilepsy, they do not appear to be sensitive or specific enough to detect or follow normal neuronal activity.

  9. Assessing the sensitivity of diffusion MRI to detect neuronal activity directly

    PubMed Central

    Bai, Ruiliang; Stewart, Craig V.; Plenz, Dietmar; Basser, Peter J.

    2016-01-01

    Functional MRI (fMRI) is widely used to study brain function in the neurosciences. Unfortunately, conventional fMRI only indirectly assesses neuronal activity via hemodynamic coupling. Diffusion fMRI was proposed as a more direct and accurate fMRI method to detect neuronal activity, yet confirmative findings have proven difficult to obtain. Given that the underlying relation between tissue water diffusion changes and neuronal activity remains unclear, the rationale for using diffusion MRI to monitor neuronal activity has yet to be clearly established. Here, we studied the correlation between water diffusion and neuronal activity in vitro by simultaneous calcium fluorescence imaging and diffusion MR acquisition. We used organotypic cortical cultures from rat brains as a biological model system, in which spontaneous neuronal activity robustly emerges free of hemodynamic and other artifacts. Simultaneous fluorescent calcium images of neuronal activity are then directly correlated with diffusion MR signals now free of confounds typically encountered in vivo. Although a simultaneous increase of diffusion-weighted MR signals was observed together with the prolonged depolarization of neurons induced by pharmacological manipulations (in which cell swelling was demonstrated to play an important role), no evidence was found that diffusion MR signals directly correlate with normal spontaneous neuronal activity. These results suggest that, whereas current diffusion MR methods could monitor pathological conditions such as hyperexcitability, e.g., those seen in epilepsy, they do not appear to be sensitive or specific enough to detect or follow normal neuronal activity. PMID:26941239

  10. New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks

    PubMed Central

    Clark, Peter J.; Bhattacharya, Tushar K.; Miller, Daniel S.; Kohman, Rachel A.; DeYoung, Erin K.; Rhodes, Justin S.

    2012-01-01

    Running increases the formation of new neurons in the adult rodent hippocampus. However, the function of new neurons generated from running is currently unknown. One hypothesis is that new neurons from running contribute to enhanced cognitive function by increasing plasticity in the adult hippocampus. An alternative hypothesis is that new neurons generated from running incorporate into experience-specific hippocampal networks that only become active during running. The purpose of this experiment was to determine if new neurons generated from running are selectively activated by running, or can become recruited into granule cell activity occurring during performance on other behavioral tasks that engage the hippocampus. Therefore, the activation of new 5–6 week neurons was detected using BrdU, NeuN, and Zif268 triple-label immunohistochemistry in cohorts of female running and sedentary adult C57BL/6J mice following participation in one of three different tasks: the Morris water maze, novel environment exploration, or wheel running. Results showed that running and sedentary mice displayed a nearly equivalent proportion of new neurons that expressed Zif268 following each task. Since running approximately doubled the number of new neurons, the results demonstrated that running mice had a greater number of new neurons recruited into the Zif268 induction in the granule cell layer following each task than sedentary mice. The results suggest that new neurons incorporated into hippocampal circuitry from running are not just activated by wheel running itself, but rather become broadly recruited into granule cell layer activity during distinct behavioral experiences. PMID:22467337

  11. Mechanisms of specificity in neuronal activity-regulated gene transcription

    PubMed Central

    Lyons, Michelle R.; West, Anne E.

    2011-01-01

    The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain. PMID:21620929

  12. Drugs of abuse that cause developing neurons to commit suicide.

    PubMed

    Farber, Nuri B; Olney, John W

    2003-12-30

    When neuronal activity is abnormally suppressed during the developmental period of synaptogenesis, the timing and sequence of synaptic connections is disrupted, and this causes nerve cells to receive an internal signal to commit suicide, a form of cell death known as "apoptosis". By altering glutamate and GABA transmission alcohol suppresses neuronal activity, causing millions of nerve cells to commit suicide in the developing brain. This proapoptotic effect of alcohol provides a likely explanation for the diminished brain size and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome. These findings have public health significance, not only in relation to fetal alcohol syndrome, but also in relation to several other drugs of abuse and various drugs used in obstetric and pediatric medicine, because these additional drugs (e.g. phencyclidine, ketamine, benzodiazepines, barbiturates) also suppress neuronal activity and drive developing neurons to commit suicide.

  13. A robust activity marking system for exploring active neuronal ensembles

    PubMed Central

    Sørensen, Andreas T; Cooper, Yonatan A; Baratta, Michael V; Weng, Feng-Ju; Zhang, Yuxiang; Ramamoorthi, Kartik; Fropf, Robin; LaVerriere, Emily; Xue, Jian; Young, Andrew; Schneider, Colleen; Gøtzsche, Casper René; Hemberg, Martin; Yin, Jerry CP; Maier, Steven F; Lin, Yingxi

    2016-01-01

    Understanding how the brain captures transient experience and converts it into long lasting changes in neural circuits requires the identification and investigation of the specific ensembles of neurons that are responsible for the encoding of each experience. We have developed a Robust Activity Marking (RAM) system that allows for the identification and interrogation of ensembles of neurons. The RAM system provides unprecedented high sensitivity and selectivity through the use of an optimized synthetic activity-regulated promoter that is strongly induced by neuronal activity and a modified Tet-Off system that achieves improved temporal control. Due to its compact design, RAM can be packaged into a single adeno-associated virus (AAV), providing great versatility and ease of use, including application to mice, rats, flies, and potentially many other species. Cre-dependent RAM, CRAM, allows for the study of active ensembles of a specific cell type and anatomical connectivity, further expanding the RAM system’s versatility. DOI: http://dx.doi.org/10.7554/eLife.13918.001 PMID:27661450

  14. Prolactin regulation of oxytocin neurone activity in pregnancy and lactation.

    PubMed

    Augustine, Rachael A; Ladyman, Sharon R; Bouwer, Gregory T; Alyousif, Yousif; Sapsford, Tony J; Scott, Victoria; Kokay, Ilona C; Grattan, David R; Brown, Colin H

    2017-06-01

    During lactation, prolactin promotes milk synthesis and oxytocin stimulates milk ejection. In virgin rats, prolactin inhibits the activity of oxytocin-secreting neurones. We found that prolactin inhibition of oxytocin neurone activity is lost in lactation, and that some oxytocin neurones were excited by prolactin in lactating rats. The change in prolactin regulation of oxytocin neurone activity was not associated with a change in activation of intracellular signalling pathways known to couple to prolactin receptors. The change in prolactin regulation of oxytocin neurone activity in lactation might allow coordinated activation of both populations of neurones when required for successful lactation. Secretion of prolactin for milk synthesis and oxytocin for milk secretion is required for successful lactation. In virgin rats, prolactin inhibits oxytocin neurones but this effect would be counterproductive during lactation when secretion of both hormones is required for synthesis and delivery of milk to the newborn. Hence, we determined the effects of intracerebroventricular (i.c.v.) prolactin on oxytocin neurones in urethane-anaesthetised virgin, pregnant and lactating rats. Prolactin (2 μg) consistently inhibited oxytocin neurones in virgin and pregnant rats (by 1.9 ± 0.4 and 1.8 ± 0.5 spikes s -1 , respectively), but not in lactating rats; indeed, prolactin excited six of 27 oxytocin neurones by >1 spike s -1 in lactating rats but excited none in virgin or pregnant rats (χ 2 2  = 7.2, P = 0.03). Vasopressin neurones were unaffected by prolactin (2 μg) in virgin rats but were inhibited by 1.1 ± 0.2 spikes s -1 in lactating rats. Immunohistochemistry showed that i.c.v. prolactin increased oxytocin expression in virgin and lactating rats and increased signal transducer and activator of transcription 5 phosphorylation to a similar extent in oxytocin neurones of virgin and lactating rats. Western blotting showed that i.c.v. prolactin did not affect

  15. Dynamical analysis of Parkinsonian state emulated by hybrid Izhikevich neuron models

    NASA Astrophysics Data System (ADS)

    Liu, Chen; Wang, Jiang; Yu, Haitao; Deng, Bin; Wei, Xile; Li, Huiyan; Loparo, Kenneth A.; Fietkiewicz, Chris

    2015-11-01

    Computational models play a significant role in exploring novel theories to complement the findings of physiological experiments. Various computational models have been developed to reveal the mechanisms underlying brain functions. Particularly, in the development of therapies to modulate behavioral and pathological abnormalities, computational models provide the basic foundations to exhibit transitions between physiological and pathological conditions. Considering the significant roles of the intrinsic properties of the globus pallidus and the coupling connections between neurons in determining the firing patterns and the dynamical activities of the basal ganglia neuronal network, we propose a hypothesis that pathological behaviors under the Parkinsonian state may originate from combined effects of intrinsic properties of globus pallidus neurons and synaptic conductances in the whole neuronal network. In order to establish a computational efficient network model, hybrid Izhikevich neuron model is used due to its capacity of capturing the dynamical characteristics of the biological neuronal activities. Detailed analysis of the individual Izhikevich neuron model can assist in understanding the roles of model parameters, which then facilitates the establishment of the basal ganglia-thalamic network model, and contributes to a further exploration of the underlying mechanisms of the Parkinsonian state. Simulation results show that the hybrid Izhikevich neuron model is capable of capturing many of the dynamical properties of the basal ganglia-thalamic neuronal network, such as variations of the firing rates and emergence of synchronous oscillations under the Parkinsonian condition, despite the simplicity of the two-dimensional neuronal model. It may suggest that the computational efficient hybrid Izhikevich neuron model can be used to explore basal ganglia normal and abnormal functions. Especially it provides an efficient way of emulating the large-scale neuron network

  16. A simple method for characterizing passive and active neuronal properties: application to striatal neurons.

    PubMed

    Lepora, Nathan F; Blomeley, Craig P; Hoyland, Darren; Bracci, Enrico; Overton, Paul G; Gurney, Kevin

    2011-11-01

    The study of active and passive neuronal dynamics usually relies on a sophisticated array of electrophysiological, staining and pharmacological techniques. We describe here a simple complementary method that recovers many findings of these more complex methods but relies only on a basic patch-clamp recording approach. Somatic short and long current pulses were applied in vitro to striatal medium spiny (MS) and fast spiking (FS) neurons from juvenile rats. The passive dynamics were quantified by fitting two-compartment models to the short current pulse data. Lumped conductances for the active dynamics were then found by compensating this fitted passive dynamics within the current-voltage relationship from the long current pulse data. These estimated passive and active properties were consistent with previous more complex estimations of the neuron properties, supporting the approach. Relationships within the MS and FS neuron types were also evident, including a graduation of MS neuron properties consistent with recent findings about D1 and D2 dopamine receptor expression. Application of the method to simulated neuron data supported the hypothesis that it gives reasonable estimates of membrane properties and gross morphology. Therefore detailed information about the biophysics can be gained from this simple approach, which is useful for both classification of neuron type and biophysical modelling. Furthermore, because these methods rely upon no manipulations to the cell other than patch clamping, they are ideally suited to in vivo electrophysiology. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  17. Tansig activation function (of MLP network) for cardiac abnormality detection

    NASA Astrophysics Data System (ADS)

    Adnan, Ja'afar; Daud, Nik Ghazali Nik; Ishak, Mohd Taufiq; Rizman, Zairi Ismael; Rahman, Muhammad Izzuddin Abd

    2018-02-01

    Heart abnormality often occurs regardless of gender, age and races. This problem sometimes does not show any symptoms and it can cause a sudden death to the patient. In general, heart abnormality is the irregular electrical activity of the heart. This paper attempts to develop a program that can detect heart abnormality activity through implementation of Multilayer Perceptron (MLP) network. A certain amount of data of the heartbeat signals from the electrocardiogram (ECG) will be used in this project to train the MLP network by using several training algorithms with Tansig activation function.

  18. PDF neuron firing phase-shifts key circadian activity neurons in Drosophila

    PubMed Central

    Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

    2014-01-01

    Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY. DOI: http://dx.doi.org/10.7554/eLife.02780.001 PMID:24939987

  19. Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

    PubMed Central

    Isaksen, Toke Jost; Vedovato, Natascia; Vitenzon, Ariel; Gadsby, David C.; Khodakhah, Kamran

    2017-01-01

    Mutations in the neuron-specific α3 isoform of the Na+/K+-ATPase are found in patients suffering from Rapid onset Dystonia Parkinsonism and Alternating Hemiplegia of Childhood, two closely related movement disorders. We show that mice harboring a heterozygous hot spot disease mutation, D801Y (α3+/D801Y), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α3+/D801Y mice revealed irregular firing of Purkinje cells and their synaptic targets, the deep cerebellar nuclei neurons, which was further exacerbated during dystonia and evolved into abnormal high-frequency burst-like firing. Biophysically, we show that the D-to-Y mutation abolished pump-mediated Na+/K+ exchange, but allowed the pumps to bind Na+ and become phosphorylated. These findings implicate aberrant cerebellar activity in α3 isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3 isoform Na+/K+-ATPase. PMID:28472154

  20. Active transport of vesicles in neurons is modulated by mechanical tension.

    PubMed

    Ahmed, Wylie W; Saif, Taher A

    2014-03-27

    Effective intracellular transport of proteins and organelles is critical in cells, and is especially important for ensuring proper neuron functionality. In neurons, most proteins are synthesized in the cell body and must be transported through thin structures over long distances where normal diffusion is insufficient. Neurons transport subcellular cargo along axons and neurites through a stochastic interplay of active and passive transport. Mechanical tension is critical in maintaining proper function in neurons, but its role in transport is not well understood. To this end, we investigate the active and passive transport of vesicles in Aplysia neurons while changing neurite tension via applied strain, and quantify the resulting dynamics. We found that tension in neurons modulates active transport of vesicles by increasing the probability of active motion, effective diffusivity, and induces a retrograde bias. We show that mechanical tension modulates active transport processes in neurons and that external forces can couple to internal (subcellular) forces and change the overall transport dynamics.

  1. Active transport of vesicles in neurons is modulated by mechanical tension

    PubMed Central

    Ahmed, Wylie W.; Saif, Taher A.

    2014-01-01

    Effective intracellular transport of proteins and organelles is critical in cells, and is especially important for ensuring proper neuron functionality. In neurons, most proteins are synthesized in the cell body and must be transported through thin structures over long distances where normal diffusion is insufficient. Neurons transport subcellular cargo along axons and neurites through a stochastic interplay of active and passive transport. Mechanical tension is critical in maintaining proper function in neurons, but its role in transport is not well understood. To this end, we investigate the active and passive transport of vesicles in Aplysia neurons while changing neurite tension via applied strain, and quantify the resulting dynamics. We found that tension in neurons modulates active transport of vesicles by increasing the probability of active motion, effective diffusivity, and induces a retrograde bias. We show that mechanical tension modulates active transport processes in neurons and that external forces can couple to internal (subcellular) forces and change the overall transport dynamics. PMID:24670781

  2. Network feedback regulates motor output across a range of modulatory neuron activity

    PubMed Central

    Spencer, Robert M.

    2016-01-01

    Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity that is further shaped by network feedback, yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron modulatory commissural neuron 1 (MCN1) activates and modulates two networks that generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5–35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed, and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However, for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output and feedback can be effective in shaping network output regardless of the extent of network modulation. PMID:27030739

  3. Network feedback regulates motor output across a range of modulatory neuron activity.

    PubMed

    Spencer, Robert M; Blitz, Dawn M

    2016-06-01

    Modulatory projection neurons alter network neuron synaptic and intrinsic properties to elicit multiple different outputs. Sensory and other inputs elicit a range of modulatory neuron activity that is further shaped by network feedback, yet little is known regarding how the impact of network feedback on modulatory neurons regulates network output across a physiological range of modulatory neuron activity. Identified network neurons, a fully described connectome, and a well-characterized, identified modulatory projection neuron enabled us to address this issue in the crab (Cancer borealis) stomatogastric nervous system. The modulatory neuron modulatory commissural neuron 1 (MCN1) activates and modulates two networks that generate rhythms via different cellular mechanisms and at distinct frequencies. MCN1 is activated at rates of 5-35 Hz in vivo and in vitro. Additionally, network feedback elicits MCN1 activity time-locked to motor activity. We asked how network activation, rhythm speed, and neuron activity levels are regulated by the presence or absence of network feedback across a physiological range of MCN1 activity rates. There were both similarities and differences in responses of the two networks to MCN1 activity. Many parameters in both networks were sensitive to network feedback effects on MCN1 activity. However, for most parameters, MCN1 activity rate did not determine the extent to which network output was altered by the addition of network feedback. These data demonstrate that the influence of network feedback on modulatory neuron activity is an important determinant of network output and feedback can be effective in shaping network output regardless of the extent of network modulation. Copyright © 2016 the American Physiological Society.

  4. Activity patterns of serotonin neurons underlying cognitive flexibility

    PubMed Central

    Matias, Sara; Lottem, Eran; Dugué, Guillaume P; Mainen, Zachary F

    2017-01-01

    Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine–serotonin opponency with potential clinical implications. DOI: http://dx.doi.org/10.7554/eLife.20552.001 PMID:28322190

  5. Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

    PubMed Central

    Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

    2016-01-01

    For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

  6. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

    PubMed Central

    Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

    2015-01-01

    Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated

  7. Mnemonic neuronal activity in somatosensory cortex.

    PubMed Central

    Zhou, Y D; Fuster, J M

    1996-01-01

    Single-unit activity was recorded from the hand areas of the somatosensory cortex of monkeys trained to perform a haptic delayed matching to sample task with objects of identical dimensions but different surface features. During the memory retention period of the task (delay), many units showed sustained firing frequency change, either excitation or inhibition. In some cases, firing during that period was significantly higher after one sample object than after another. These observations indicate the participation of somatosensory neurons not only in the perception but in the short-term memory of tactile stimuli. Neurons most directly implicated in tactile memory are (i) those with object-selective delay activity, (ii) those with nondifferential delay activity but without activity related to preparation for movement, and (iii) those with delay activity in the haptic-haptic delayed matching task but no such activity in a control visuo-haptic delayed matching task. The results indicate that cells in early stages of cortical somatosensory processing participate in haptic short-term memory. PMID:8927629

  8. Inhibition of swallowing reflex following phosphorylation of extracellular signal-regulated kinase in nucleus tractus solitarii neurons in rats with masseter muscle nociception.

    PubMed

    Tsujimura, Takanori; Kitagawa, Junichi; Ueda, Koichiro; Iwata, Koichi

    2009-02-06

    Pain is associated with swallowing abnormalities in dysphagic patients. Understanding neuronal mechanisms underlying the swallowing abnormalities associated with orofacial abnormal pain is crucial for developing new methods to treat dysphagic patients. However, how the orofacial abnormal pain is involved in the swallowing abnormalities is not known. In order to evaluate neuronal mechanisms of modulation of the swallows by masticatory muscle pain, here we first induced swallows by topical administration of distilled water to the pharyngolaryngeal region. The swallowing reflex was significantly inhibited after capsaicin (10, 30mM) injection into the masseter muscle compared to vehicle injection. Moreover the number of phosphorylated extracellular signal-regulated kinase-like immunoreactive (pERK-LI) neurons in the nucleus tractus solitarii (NTS) was significantly increased in the rats with capsaicin injection into the masseter muscle compared to that with vehicle injection. Rostro-caudal distribution of pERK-LI neurons in the NTS was peaked at the obex level. The capsaicin-induced inhibitory effect on swallowing reflex was reversed after intrathecal administration of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, PD98059. The present findings suggest that phosphorylation of ERK in NTS neurons may be involved in capsaicin-induced inhibition of swallowing reflex.

  9. Neuronal activity in the globus pallidus internus in patients with tics.

    PubMed

    Zhuang, P; Hallett, M; Zhang, X; Li, J; Zhang, Y; Li, Y

    2009-10-01

    To explore the role of neuronal activity in the globus pallidus internus (GPi) in the generation of tic movements. 8 patients with Tourette's syndrome with medically intractable tics who underwent a unilateral pallidotomy for severe tics were studied. They ranged in age from 17 to 24 years; disease duration was 7-19 years. Microelectrode recording was performed in the GPi. The electromyogram (EMG) was simultaneously recorded in muscle groups appropriate for the patient's tics. The relationship between neuronal firing pattern and the EMG was studied. 232 neurons were recorded during tics from eight trajectories. Of these neurons, in addition to decreased neuronal firing rate and irregular firing pattern, 105 (45%) were tic related showing either a burst of activity or a pause in ongoing tonic activity. They could be synchronous (n = 75), earlier than EMG onset (n = 27) or following EMG onset (n = 3). The GPi neuronal bursts preceded EMG onset with decreased (n = 6) or increased activity (n = 21). The initial change in neural activity occurred about 50 ms to 2 s before the EMG onset. Although the data are descriptive and preliminary, the tic related neuronal activity observed in GPi appears to indicate that the basal ganglia motor circuit is involved in tic movements. The early neuronal activity seen in GPi may reflect premonitory sensations that precede a tic.

  10. Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron.

    PubMed

    Wang, Jing; Liu, Huaide; Jin, Weihua; Zhang, Hong; Zhang, Quanbin

    2016-01-01

    Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (P<0.01 or P<0.001) which provides further evidence that DF1 and DF2 also exerts a direct protection against the neuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

    PubMed

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

  12. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

    PubMed Central

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P.

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes. PMID:29474476

  13. Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons.

    PubMed

    Darvesh, Sultan; Arora, Rakesh C; Martin, Earl; Magee, David; Hopkins, David A; Armour, J Andrew

    2004-08-01

    Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.

  14. Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

    PubMed Central

    Patel, Anant B.; Lai, James C. K.; Chowdhury, Golam M. I.; Hyder, Fahmeed; Rothman, Douglas L.; Shulman, Robert G.; Behar, Kevin L.

    2014-01-01

    Previous 13C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-d-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG6P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions. PMID:24706914

  15. Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle.

    PubMed

    Patel, Anant B; Lai, James C K; Chowdhury, Golam M I; Hyder, Fahmeed; Rothman, Douglas L; Shulman, Robert G; Behar, Kevin L

    2014-04-08

    Previous (13)C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-D-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG6P), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions.

  16. Essential roles of mitochondrial depolarization in neuron loss through microglial activation and attraction toward neurons.

    PubMed

    Nam, Min-Kyung; Shin, Hyun-Ah; Han, Ji-Hye; Park, Dae-Wook; Rhim, Hyangshuk

    2013-04-10

    As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron-microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. On the Dynamics of the Spontaneous Activity in Neuronal Networks

    PubMed Central

    Bonifazi, Paolo; Ruaro, Maria Elisabetta; Torre, Vincent

    2007-01-01

    Most neuronal networks, even in the absence of external stimuli, produce spontaneous bursts of spikes separated by periods of reduced activity. The origin and functional role of these neuronal events are still unclear. The present work shows that the spontaneous activity of two very different networks, intact leech ganglia and dissociated cultures of rat hippocampal neurons, share several features. Indeed, in both networks: i) the inter-spike intervals distribution of the spontaneous firing of single neurons is either regular or periodic or bursting, with the fraction of bursting neurons depending on the network activity; ii) bursts of spontaneous spikes have the same broad distributions of size and duration; iii) the degree of correlated activity increases with the bin width, and the power spectrum of the network firing rate has a 1/f behavior at low frequencies, indicating the existence of long-range temporal correlations; iv) the activity of excitatory synaptic pathways mediated by NMDA receptors is necessary for the onset of the long-range correlations and for the presence of large bursts; v) blockage of inhibitory synaptic pathways mediated by GABAA receptors causes instead an increase in the correlation among neurons and leads to a burst distribution composed only of very small and very large bursts. These results suggest that the spontaneous electrical activity in neuronal networks with different architectures and functions can have very similar properties and common dynamics. PMID:17502919

  18. The Mast Cell Degranulator Compound 48/80 Directly Activates Neurons

    PubMed Central

    Schemann, Michael; Kugler, Eva Maria; Buhner, Sabine; Eastwood, Christopher; Donovan, Jemma; Jiang, Wen; Grundy, David

    2012-01-01

    Background Compound 48/80 is widely used in animal and tissue models as a “selective” mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents. Methodology/Principal Findings We used in vivo recordings from extrinsic intestinal afferents together with Ca++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H1 and H2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca++ transients in mast cell-free enteric neuron cultures. Conclusions/Significance The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn. PMID:23272218

  19. Early physiological abnormalities after simian immunodeficiency virus infection.

    PubMed

    Horn, T F; Huitron-Resendiz, S; Weed, M R; Henriksen, S J; Fox, H S

    1998-12-08

    Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction.

  20. Ectopic Expression of Nolz-1 in Neural Progenitors Promotes Cell Cycle Exit/Premature Neuronal Differentiation Accompanying with Abnormal Apoptosis in the Developing Mouse Telencephalon

    PubMed Central

    Chang, Sunny Li-Yun; Chen, Shih-Yun; Huang, Huai-Huei; Ko, Hsin-An; Liu, Pei-Tsen; Liu, Ya-Chi; Chen, Ping-Hau; Liu, Fu-Chin

    2013-01-01

    Nolz-1, as a murine member of the NET zinc-finger protein family, is expressed in post-mitotic differentiating neurons of striatum during development. To explore the function of Nolz-1 in regulating the neurogenesis of forebrain, we studied the effects of ectopic expression of Nolz-1 in neural progenitors. We generated the Cre-loxP dependent conditional transgenic mice in which Nolz-1 was ectopically expressed in proliferative neural progenitors. Ectopic expression of Nolz-1 in neural progenitors by intercrossing the Nolz-1 conditional transgenic mice with the nestin-Cre mice resulted in hypoplasia of telencephalon in double transgenic mice. Decreased proliferation of neural progenitor cells were found in the telencephalon, as evidenced by the reduction of BrdU−, Ki67− and phospho-histone 3-positive cells in E11.5–12.5 germinal zone of telencephalon. Transgenic Nolz-1 also promoted cell cycle exit and as a consequence might facilitate premature differentiation of progenitors, because TuJ1-positive neurons were ectopically found in the ventricular zone and there was a general increase of TuJ1 immunoreactivity in the telencephalon. Moreover, clusters of strong TuJ1-expressing neurons were present in E12.5 germinal zone. Some of these strong TuJ1-positive clusters, however, contained apoptotic condensed DNA, suggesting that inappropriate premature differentiation may lead to abnormal apoptosis in some progenitor cells. Consistent with the transgenic mouse analysis in vivo, similar effects of Nozl-1 over-expression in induction of apoptosis, inhibition of cell proliferation and promotion of neuronal differentiation were also observed in three different N18, ST14A and N2A neural cell lines in vitro. Taken together, our study indicates that ectopic expression of Nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation and induces abnormal apoptosis in the developing telencephalon. PMID:24073229

  1. Ectopic expression of nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation accompanying with abnormal apoptosis in the developing mouse telencephalon.

    PubMed

    Chang, Sunny Li-Yun; Chen, Shih-Yun; Huang, Huai-Huei; Ko, Hsin-An; Liu, Pei-Tsen; Liu, Ya-Chi; Chen, Ping-Hau; Liu, Fu-Chin

    2013-01-01

    Nolz-1, as a murine member of the NET zinc-finger protein family, is expressed in post-mitotic differentiating neurons of striatum during development. To explore the function of Nolz-1 in regulating the neurogenesis of forebrain, we studied the effects of ectopic expression of Nolz-1 in neural progenitors. We generated the Cre-loxP dependent conditional transgenic mice in which Nolz-1 was ectopically expressed in proliferative neural progenitors. Ectopic expression of Nolz-1 in neural progenitors by intercrossing the Nolz-1 conditional transgenic mice with the nestin-Cre mice resulted in hypoplasia of telencephalon in double transgenic mice. Decreased proliferation of neural progenitor cells were found in the telencephalon, as evidenced by the reduction of BrdU-, Ki67- and phospho-histone 3-positive cells in E11.5-12.5 germinal zone of telencephalon. Transgenic Nolz-1 also promoted cell cycle exit and as a consequence might facilitate premature differentiation of progenitors, because TuJ1-positive neurons were ectopically found in the ventricular zone and there was a general increase of TuJ1 immunoreactivity in the telencephalon. Moreover, clusters of strong TuJ1-expressing neurons were present in E12.5 germinal zone. Some of these strong TuJ1-positive clusters, however, contained apoptotic condensed DNA, suggesting that inappropriate premature differentiation may lead to abnormal apoptosis in some progenitor cells. Consistent with the transgenic mouse analysis in vivo, similar effects of Nozl-1 over-expression in induction of apoptosis, inhibition of cell proliferation and promotion of neuronal differentiation were also observed in three different N18, ST14A and N2A neural cell lines in vitro. Taken together, our study indicates that ectopic expression of Nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation and induces abnormal apoptosis in the developing telencephalon.

  2. Manipulating neural activity in physiologically classified neurons: triumphs and challenges

    PubMed Central

    Gore, Felicity; Schwartz, Edmund C.; Salzman, C. Daniel

    2015-01-01

    Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour. PMID:26240431

  3. BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway.

    PubMed

    Klenke, Ulrike; Constantin, Stephanie; Wray, Susan

    2016-05-01

    Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons.

  4. BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway

    PubMed Central

    Klenke, Ulrike; Constantin, Stephanie

    2016-01-01

    Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons. PMID:26934298

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

    PubMed Central

    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 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. PMID:26630957

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

    PubMed

    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.

  7. Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities

    PubMed Central

    Passeri, Eleonora; Wilson, Ashley M.; Primerano, Amedeo; Kondo, Mari A.; Sengupta, Srona; Srivastava, Rupali; Koga, Minori; Obie, Cassandra; Zandi, Peter P.; Goes, Fernando S.; Valle, David; Rapoport, Judith L.; Sawa, Akira; Kano, Shin-ichi; Ishizuka, Koko

    2016-01-01

    The novel technology of induced neuronal cells (iN cells) is promising for translational neuroscience, as it allows the conversion of human fibroblasts into cells with postmitotic neuronal traits. However, a major technical barrier is the low conversion rate. To overcome this problem, we optimized the conversion media. Using our improved formulation, we studied how major mental illness-associated chromosomal abnormalities may impact the characteristics of iN cells. We demonstrated that our new iN cell culture protocol enabled us to obtain more precise measurement of neuronal cellular phenotypes than previous iN cell methods. Thus, this iN cell culture provides a platform to efficiently obtain possible cellular phenotypes caused by genetic differences, which can be more thoroughly studied in research using other human cell models such as induced pluripotent stem cells. PMID:26260244

  8. Activity of Raphé Serotonergic Neurons Controls Emotional Behaviors.

    PubMed

    Teissier, Anne; Chemiakine, Alexei; Inbar, Benjamin; Bagchi, Sneha; Ray, Russell S; Palmiter, Richard D; Dymecki, Susan M; Moore, Holly; Ansorge, Mark S

    2015-12-01

    Despite the well-established role of serotonin signaling in mood regulation, causal relationships between serotonergic neuronal activity and behavior remain poorly understood. Using a pharmacogenetic approach, we find that selectively increasing serotonergic neuronal activity in wild-type mice is anxiogenic and reduces floating in the forced-swim test, whereas inhibition has no effect on the same measures. In a developmental mouse model of altered emotional behavior, increased anxiety and depression-like behaviors correlate with reduced dorsal raphé and increased median raphé serotonergic activity. These mice display blunted responses to serotonergic stimulation and behavioral rescues through serotonergic inhibition. Furthermore, we identify opposing consequences of dorsal versus median raphé serotonergic neuron inhibition on floating behavior, together suggesting that median raphé hyperactivity increases anxiety, whereas a low dorsal/median raphé serotonergic activity ratio increases depression-like behavior. Thus, we find a critical role of serotonergic neuronal activity in emotional regulation and uncover opposing roles of median and dorsal raphé function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing

    PubMed Central

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H. Sophie; Wahis, Jérôme; Gouveia, Miriam da Silva; Tang, Yan; Ciobanu, Alexandru Cristian; del Rio, Rodrigo Triana; Roth, Lena C.; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L.; Mitre, Mariela; Froemke, Robert C.; Chao, Moses V.; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H.; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2017-01-01

    SUMMARY Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. PMID:26948889

  10. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    PubMed

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana Del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Measure of synchrony in the activity of intrinsic cardiac neurons

    PubMed Central

    Longpré, Jean-Philippe; Salavatian, Siamak; Beaumont, Eric; Armour, J. Andrew; Ardell, Jeffrey L.; Jacquemet, Vincent

    2014-01-01

    Recent multielectrode array recordings in ganglionated plexi of canine atria have opened the way to the study of population dynamics of intrinsic cardiac neurons. These data provide critical insights into the role of local processing that these ganglia play in the regulation of cardiac function. Low firing rates, marked non-stationarity, interplay with the cardiovascular and pulmonary systems and artifacts generated by myocardial activity create new constraints not present in brain recordings for which almost all neuronal analysis techniques have been developed. We adapted and extended the jitter-based synchrony index (SI) to (1) provide a robust and computationally-efficient tool for assessing the level and statistical significance of SI between cardiac neurons, (2) estimate the bias on SI resulting from neuronal activity possibly hidden in myocardial artifacts, (3) quantify the synchrony or anti-synchrony between neuronal activity and the phase in the cardiac and respiratory cycles. The method was validated on firing time series from a total of 98 individual neurons identified in 8 dog experiments. SI ranged from −0.14 to 0.66, with 23 pairs of neurons with SI>0.1. The estimated bias due to artifacts was typically < 1%. Strongly cardiovascular- and pulmonary-related neurons (SI>0.5) were found. Results support the use of jitter-based synchrony index in the context of intrinsic cardiac neurons. PMID:24621585

  12. Abnormal Reward System Activation in Mania

    PubMed Central

    Abler, Birgit; Greenhouse, Ian; Ongur, Dost; Walter, Henrik; Heckers, Stephan

    2008-01-01

    Transmission of reward signals is a function of dopamine, a neurotransmitter known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), we investigated how expectation and receipt of monetary rewards modulate brain activation in patients with bipolar mania and schizophrenia. We studied 12 acutely manic patients with a history of bipolar disorder, 12 patients with a current episode of schizoaffective disorder or schizophrenia and 12 healthy subjects. All patients were treated with dopamine antagonists at the time of the study. Subjects performed a delayed incentive paradigm with monetary reward in the scanner that allowed for investigating effects of expectation, receipt, and omission of rewards. Patients with schizophrenia and healthy control subjects showed the expected activation of dopaminergic brain areas, that is, ventral tegmentum activation upon expectation of monetary rewards and nucleus accumbens activation during receipt vs omission of rewards. In manic patients, however, we did not find a similar pattern of brain activation and the differential signal in the nucleus accumbens upon receipt vs omission of rewards was significantly lower compared to the healthy control subjects. Our findings provide evidence for abnormal function of the dopamine system during receipt or omission of expected rewards in bipolar disorder. These deficits in prediction error processing in acute mania may help to explain symptoms of disinhibition and abnormal goal pursuit regulation. PMID:17987058

  13. Nitrergic ventro-medial medullary neurons activated during cholinergically induced active (REM) sleep in the cat

    PubMed Central

    Pose, Inés; Sampogna, Sharon; Chase, Michael H.; Morales, Francisco R.

    2010-01-01

    The rostral ventro-medial medullary reticular formation is a complex structure that is involved with a variety of motor functions. It contains glycinergic neurons that are activated during active (REM) sleep (AS); these neurons appear to be responsible for the postsynaptic inhibition of motoneurons that occurs during this state. We have reported that neurons in this same region contain nitric oxide (NO) synthase and that they innervate brainstem motor pools. In the present study we examined the c-fos expression of these neurons after carbachol-induced active sleep (C-AS). Three control and four experimental cats were employed to identify c-fos expressing nitrergic neurons using immunocytochemical techniques to detect the Fos protein together with neuronal nitric oxide synthase (nNOS) or NADPH-diaphorase activity. The classical neurotransmitter content of the nitrergic cells in this region was examined through the combination of immunocytochemical techniques for the detection of glutamate, glycine, choline acetyltransferase (ChAT), tyrosine hydroxilase (TH) or GABA together with nNOS. During C-AS, there was a 1074% increase in the number of nitrergic neurons that expressed c-fos. These neurons did not contain glycine, ChAT, TH or GABA, but a subpopulation (15%) of them displayed glutamate-like immunoreactivity. Therefore, some of these neurons contain both an excitatory neurotransmitter (glutamate) and an excitatory neuromodulator (NO); the neurotransmitter content of the rest of them remains to be determined. Because some of the nitrergic neurons innervate brainstem motoneurons it is possible that they participate in the generation of tonic and excitatory phasic motor events that occur during AS. We also suggest that these nitrergic neurons may be involved in autonomic regulation during this state. In addition, because NO has trophic effects on target neurons, the present findings represent the first, albeit indirect, evidence for a possible trophic function of

  14. Simultaneous profiling of activity patterns in multiple neuronal subclasses.

    PubMed

    Parrish, R Ryley; Grady, John; Codadu, Neela K; Trevelyan, Andrew J; Racca, Claudia

    2018-06-01

    Neuronal networks typically comprise heterogeneous populations of neurons. A core objective when seeking to understand such networks, therefore, is to identify what roles these different neuronal classes play. Acquiring single cell electrophysiology data for multiple cell classes can prove to be a large and daunting task. Alternatively, Ca 2+ network imaging provides activity profiles of large numbers of neurons simultaneously, but without distinguishing between cell classes. We therefore developed a strategy for combining cellular electrophysiology, Ca 2+ network imaging, and immunohistochemistry to provide activity profiles for multiple cell classes at once. This involves cross-referencing easily identifiable landmarks between imaging of the live and fixed tissue, and then using custom MATLAB functions to realign the two imaging data sets, to correct for distortions of the tissue introduced by the fixation or immunohistochemical processing. We illustrate the methodology for analyses of activity profiles during epileptiform events recorded in mouse brain slices. We further demonstrate the activity profile of a population of parvalbumin-positive interneurons prior, during, and following a seizure-like event. Current approaches to Ca 2+ network imaging analyses are severely limited in their ability to subclassify neurons, and often rely on transgenic approaches to identify cell classes. In contrast, our methodology is a generic, affordable, and flexible technique to characterize neuronal behaviour with respect to classification based on morphological and neurochemical identity. We present a new approach for analysing Ca 2+ network imaging datasets, and use this to explore the parvalbumin-positive interneuron activity during epileptiform events. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

    PubMed

    Frank, Julie G; Mendelowitz, David

    2012-01-01

    GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for

  16. Regular theta-firing neurons in the nucleus incertus during sustained hippocampal activation.

    PubMed

    Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Martínez-Ricós, Joana; Ruiz-Torner, Amparo; Luque-Garcia, Aina; Luque-Martinez, Aina; Blasco-Serra, Arantxa; Guerrero-Martínez, Juan; Bataller-Mompeán, Manuel; Teruel-Martí, Vicent

    2015-04-01

    This paper describes the existence of theta-coupled neuronal activity in the nucleus incertus (NI). Theta rhythm is relevant for cognitive processes such as spatial navigation and memory processing, and can be recorded in a number of structures related to the hippocampal activation including the NI. Strong evidence supports the role of this tegmental nucleus in neural circuits integrating behavioural activation with the hippocampal theta rhythm. Theta oscillations have been recorded in the local field potential of the NI, highly coupled to the hippocampal waves, although no rhythmical activity has been reported in neurons of this nucleus. The present work analyses the neuronal activity in the NI in conditions leading to sustained hippocampal theta in the urethane-anaesthetised rat, in order to test whether such activation elicits a differential firing pattern. Wavelet analysis has been used to better define the neuronal activity already described in the nucleus, i.e., non-rhythmical neurons firing at theta frequency (type I neurons) and fast-firing rhythmical neurons (type II). However, the most remarkable finding was that sustained stimulation activated regular-theta neurons (type III), which were almost silent in baseline conditions and have not previously been reported. Thus, we describe the electrophysiological properties of type III neurons, focusing on their coupling to the hippocampal theta. Their spike rate, regularity and phase locking to the oscillations increased at the beginning of the stimulation, suggesting a role in the activation or reset of the oscillation. Further research is needed to address the specific contribution of these neurons to the entire circuit. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  17. Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior.

    PubMed

    Reis, Wagner L; Yi, Chun-Xia; Gao, Yuanqing; Tschöp, Mathias H; Stern, Javier E

    2015-04-01

    Hypothalamic inflammation, involving microglia activation in the arcuate nucleus (ARC), is proposed as a novel underlying mechanism in obesity, insulin and leptin resistance. However, whether activated microglia affects ARC neuronal activity, and consequently basal and hormonal-induced food intake, is unknown. We show that lipopolysaccharide, an agonist of the toll-like receptor-4 (TLR4), which we found to be expressed in ARC microglia, inhibited the firing activity of the majority of orexigenic agouti gene-related protein/neuropeptide Y neurons, whereas it increased the activity of the majority of anorexigenic proopiomelanocortin neurons. Lipopolysaccharide effects in agouti gene-related protein/neuropeptide Y (but not in proopiomelanocortin) neurons were occluded by inhibiting microglia function or by blocking TLR4 receptors. Finally, we report that inhibition of hypothalamic microglia altered basal food intake, also preventing central orexigenic responses to ghrelin. Our studies support a major role for a TLR4-mediated microglia signaling pathway in the control of ARC neuronal activity and feeding behavior.

  18. Enhancement of oscillatory activity in the endopiriform nucleus of rats raised under abnormal oral conditions.

    PubMed

    Yoshimura, Hiroshi; Hasumoto-Honjo, Miho; Sugai, Tokio; Segami, Natsuki; Kato, Nobuo

    2014-02-21

    Endopiriform nucleus (EPN) is located deep to the piriform cortex, and has neural connections with not only neighboring sensory areas but also subcortical areas where emotional and nociceptive information is processed. Well-balanced oral condition might play an important role in stability of brain activities. When the oral condition is impaired, several areas in the brain might be affected. In the present study, we investigated whether abnormal conditions of oral region influence neural activities in the EPN. Orthodontic appliance that generates continuous force and chronic pain-related stress was fixed to maxillary incisors of rats, and raised. Field potential recordings were made from the EPN of brain slices. We previously reported that the EPN has an ability to generate membrane potential oscillation. In the present study, we have applied the same methods to assess activities of neuron clusters in the EPN. In the case of normal rats, stable field potential oscillations were induced in the EPN by application of low-frequency electrical stimulation under the medium with caffeine. In the case of rats with the orthodontic appliance, stable field potential oscillations were also induced, but both duration of oscillatory activities and wavelet number were increased. The enhanced oscillations were depressed by blockade of NMDA receptors. Thus, impairment of oral health under application of continuous orthodontic force and chronic pain-related stress enhanced neural activities in the EPN, in which up-regulation of NMDA receptors may be concerned. These findings suggest that the EPN might be involved in information processing with regard to abnormal conditions of oral region. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Neuronal activity-dependent membrane traffic at the neuromuscular junction

    PubMed Central

    Miana-Mena, Francisco Javier; Roux, Sylvie; Benichou, Jean-Claude; Osta, Rosario; Brûlet, Philippe

    2002-01-01

    During development and also in adulthood, synaptic connections are modulated by neuronal activity. To follow such modifications in vivo, new genetic tools are designed. The nontoxic C-terminal fragment of tetanus toxin (TTC) fused to a reporter gene such as LacZ retains the retrograde and transsynaptic transport abilities of the holotoxin itself. In this work, the hybrid protein is injected intramuscularly to analyze in vivo the mechanisms of intracellular and transneuronal traffics at the neuromuscular junction (NMJ). Traffic on both sides of the synapse are strongly dependent on presynaptic neural cell activity. In muscle, a directional membrane traffic concentrates β-galactosidase-TTC hybrid protein into the NMJ postsynaptic side. In neurons, the probe is sorted across the cell to dendrites and subsequently to an interconnected neuron. Such fusion protein, sensitive to presynaptic neuronal activity, would be extremely useful to analyze morphological changes and plasticity at the NMJ. PMID:11880654

  20. Active Dendrites Enhance Neuronal Dynamic Range

    PubMed Central

    Gollo, Leonardo L.; Kinouchi, Osame; Copelli, Mauro

    2009-01-01

    Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the past decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of an active dendritic tree is a highly non-linear function of its afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease in dynamic range. PMID:19521531

  1. Spontaneous neuronal activity as a self-organized critical phenomenon

    NASA Astrophysics Data System (ADS)

    de Arcangelis, L.; Herrmann, H. J.

    2013-01-01

    Neuronal avalanches are a novel mode of activity in neuronal networks, experimentally found in vitro and in vivo, and exhibit a robust critical behaviour. Avalanche activity can be modelled within the self-organized criticality framework, including threshold firing, refractory period and activity-dependent synaptic plasticity. The size and duration distributions confirm that the system acts in a critical state, whose scaling behaviour is very robust. Next, we discuss the temporal organization of neuronal avalanches. This is given by the alternation between states of high and low activity, named up and down states, leading to a balance between excitation and inhibition controlled by a single parameter. During these periods both the single neuron state and the network excitability level, keeping memory of past activity, are tuned by homeostatic mechanisms. Finally, we verify if a system with no characteristic response can ever learn in a controlled and reproducible way. Learning in the model occurs via plastic adaptation of synaptic strengths by a non-uniform negative feedback mechanism. Learning is a truly collective process and the learning dynamics exhibits universal features. Even complex rules can be learned provided that the plastic adaptation is sufficiently slow.

  2. Dehydration-induced modulation of κ-opioid inhibition of vasopressin neurone activity

    PubMed Central

    Scott, Victoria; Bishop, Valerie R; Leng, Gareth; Brown, Colin H

    2009-01-01

    Dehydration increases vasopressin (antidiuretic hormone) secretion from the posterior pituitary gland to reduce water loss in the urine. Vasopressin secretion is determined by action potential firing in vasopressin neurones, which can exhibit continuous, phasic (alternating periods of activity and silence), or irregular activity. Autocrine κ-opioid inhibition contributes to the generation of activity patterning of vasopressin neurones under basal conditions and so we used in vivo extracellular single unit recording to test the hypothesis that changes in autocrine κ-opioid inhibition drive changes in activity patterning of vasopressin neurones during dehydration. Dehydration increased the firing rate of rat vasopressin neurones displaying continuous activity (from 7.1 ± 0.5 to 9.0 ± 0.6 spikes s−1) and phasic activity (from 4.2 ± 0.7 to 7.8 ± 0.9 spikes s−1), but not those displaying irregular activity. The dehydration-induced increase in phasic activity was via an increase in intraburst firing rate. The selective κ-opioid receptor antagonist nor-binaltorphimine increased the firing rate of phasic neurones in non-dehydrated rats (from 3.4 ± 0.8 to 5.3 ± 0.6 spikes s−1) and dehydrated rats (from 6.4 ± 0.5 to 9.1 ± 1.2 spikes s−1), indicating that κ-opioid feedback inhibition of phasic bursts is maintained during dehydration. In a separate series of experiments, prodynorphin mRNA expression was increased in vasopressin neurones of hyperosmotic rats, compared to hypo-osmotic rats. Hence, it appears that dynorphin expression in vasopressin neurones undergoes dynamic changes in proportion to the required secretion of vasopressin so that, even under stimulated conditions, autocrine feedback inhibition of vasopressin neurones prevents over-excitation. PMID:19822541

  3. Oligodendrocyte-Neuron Interactions: Impact on Myelination and Brain Function.

    PubMed

    Shimizu, Takeshi; Osanai, Yasuyuki; Ikenaka, Kazuhiro

    2018-01-01

    In the past, glial cells were considered to be 'glue' cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function.

  4. Motor Neurons Tune Premotor Activity in a Vertebrate Central Pattern Generator

    PubMed Central

    2017-01-01

    Central patterns generators (CPGs) are neural circuits that drive rhythmic motor output without sensory feedback. Vertebrate CPGs are generally believed to operate in a top-down manner in which premotor interneurons activate motor neurons that in turn drive muscles. In contrast, the frog (Xenopus laevis) vocal CPG contains a functionally unexplored neuronal projection from the motor nucleus to the premotor nucleus, indicating a recurrent pathway that may contribute to rhythm generation. In this study, we characterized the function of this bottom-up connection. The X. laevis vocal CPG produces a 50–60 Hz “fast trill” song used by males during courtship. We recorded “fictive vocalizations” in the in vitro CPG from the laryngeal nerve while simultaneously recording premotor activity at the population and single-cell level. We show that transecting the motor-to-premotor projection eliminated the characteristic firing rate of premotor neurons. Silencing motor neurons with the intracellular sodium channel blocker QX-314 also disrupted premotor rhythms, as did blockade of nicotinic synapses in the motor nucleus (the putative location of motor neuron-to-interneuron connections). Electrically stimulating the laryngeal nerve elicited primarily IPSPs in premotor neurons that could be blocked by a nicotinic receptor antagonist. Our results indicate that an inhibitory signal, activated by motor neurons, is required for proper CPG function. To our knowledge, these findings represent the first example of a CPG in which precise premotor rhythms are tuned by motor neuron activity. SIGNIFICANCE STATEMENT Central pattern generators (CPGs) are neural circuits that produce rhythmic behaviors. In vertebrates, motor neurons are not commonly known to contribute to CPG function, with the exception of a few spinal circuits where the functional significance of motor neuron feedback is still poorly understood. The frog hindbrain vocal circuit contains a previously unexplored

  5. GHRELIN ACTIVATES HYPOPHYSIOTROPIC CORTICOTROPIN-RELEASING FACTOR NEURONS INDEPENDENTLY OF THE ARCUATE NUCLEUS

    PubMed Central

    Cabral, Agustina; Portiansky, Enrique; Sánchez-Jaramillo, Edith; Zigman, Jeffrey M.; Perello, Mario

    2016-01-01

    Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin’s orexigenic action vs. its role as a stress signal are anatomically dissociated. PMID:26874559

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

    PubMed

    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.

  7. Motor Control Abnormalities in Parkinson’s Disease

    PubMed Central

    Mazzoni, Pietro; Shabbott, Britne; Cortés, Juan Camilo

    2012-01-01

    The primary manifestations of Parkinson’s disease are abnormalities of movement, including movement slowness, difficulties with gait and balance, and tremor. We know a considerable amount about the abnormalities of neuronal and muscle activity that correlate with these symptoms. Motor symptoms can also be described in terms of motor control, a level of description that explains how movement variables, such as a limb’s position and speed, are controlled and coordinated. Understanding motor symptoms as motor control abnormalities means to identify how the disease disrupts normal control processes. In the case of Parkinson’s disease, movement slowness, for example, would be explained by a disruption of the control processes that determine normal movement speed. Two long-term benefits of understanding the motor control basis of motor symptoms include the future design of neural prostheses to replace the function of damaged basal ganglia circuits, and the rational design of rehabilitation strategies. This type of understanding, however, remains limited, partly because of limitations in our knowledge of normal motor control. In this article, we review the concept of motor control and describe a few motor symptoms that illustrate the challenges in understanding such symptoms as motor control abnormalities. PMID:22675667

  8. Sustained neuronal activity generated by glial plasticity

    PubMed Central

    Pirttimaki, Tiina M.; Hall, Stephen D.; Parri, H. Rheinallt

    2011-01-01

    Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of N-methyl D-aspartate receptor (NMDA-R) mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs, and their physiological roles are largely unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of Lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by an hour. This long term enhancement (LTE) of astrocytic glutamate release is induced by group I metabotropic glutamate receptors (mGluRs), and is dependent on astrocytic intracellular calcium ([Ca2+]i). Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca2+ channel dependent bursts of action potentials, and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, non-synaptic plasticity in the central nervous system (CNS) that feeds forward to generate local neuronal firing long after stimulus termination. PMID:21613477

  9. GABAergic inhibition through synergistic astrocytic neuronal interaction transiently decreases vasopressin neuronal activity during hypoosmotic challenge.

    PubMed

    Wang, Yu-Feng; Sun, Min-Yu; Hou, Qiuling; Hamilton, Kathryn A

    2013-04-01

    The neuropeptide vasopressin is crucial to mammalian osmotic regulation. Local hypoosmotic challenge transiently decreases and then increases vasopressin secretion. To investigate mechanisms underlying this transient response, we examined the effects of hypoosmotic challenge on the electrical activity of rat hypothalamic supraoptic nucleus (SON) vasopressin neurons using patch-clamp recordings. We found that 5 min exposure of hypothalamic slices to hypoosmotic solution transiently increased inhibitory postsynaptic current (IPSC) frequency and reduced the firing rate of vasopressin neurons. Recovery occurred by 10 min of exposure, even though the osmolality remained low. The γ-aminobutyric acid (GABA)A receptor blocker, gabazine, blocked the IPSCs and the hypoosmotic suppression of firing. The gliotoxin l-aminoadipic acid blocked the increase in IPSC frequency at 5 min and the recovery of firing at 10 min, indicating astrocytic involvement in hypoosmotic modulation of vasopressin neuronal activity. Moreover, β-alanine, an osmolyte of astrocytes and GABA transporter (GAT) inhibitor, blocked the increase in IPSC frequency at 5 min of hypoosmotic challenge. Confocal microscopy of immunostained SON sections revealed that astrocytes and magnocellular neurons both showed positive staining of vesicular GATs (VGAT). Hypoosmotic stimulation in vivo reduced the number of VGAT-expressing neurons, and increased co-localisation and molecular association of VGAT with glial fibrillary acidic protein that increased significantly by 10 min. By 30 min, neuronal VGAT labelling was partially restored, and astrocytic VGAT was relocated to the ventral portion while it decreased in the somatic zone of the SON. Thus, synergistic astrocytic and neuronal GABAergic inhibition could ensure that vasopressin neuron firing is only transiently suppressed under hypoosmotic conditions. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  10. Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats.

    PubMed

    Kharas, Natasha; Whitt, Holly; Reyes-Vasquez, Cruz; Dafny, Nachum

    2017-01-01

    Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1-6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Effects of Microwave Radiation on Neuronal Activity

    DTIC Science & Technology

    1991-10-01

    salivary glands and human cultured cells to extremely low- frequency (ELF) EMF alters patterns of polypeptide synthesis (18,19). The effects displayed...at 16 Hz. Continuous exposure to radio- frequency radiation for 4 consecutive days led to the development of a cell number density gradient. The...RADIATION ON NEURONAL ACTIVITY SUMMARY The effects of radiofrequency radiation on rat hippocampal fetal neurons were examined. Carrier frequencies of 300 to

  12. Early physiological abnormalities after simian immunodeficiency virus infection

    PubMed Central

    Horn, Thomas F. W.; Huitron-Resendiz, Salvador; Weed, Michael R.; Henriksen, Steven J.; Fox, Howard S.

    1998-01-01

    Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction. PMID:9844017

  13. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro.

    PubMed

    Janefjord, Emelie; Mååg, Jesper L V; Harvey, Benjamin S; Smid, Scott D

    2014-01-01

    Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.

  14. Multiplicative and additive modulation of neuronal tuning with population activity affects encoded information

    PubMed Central

    Arandia-Romero, Iñigo; Tanabe, Seiji; Drugowitsch, Jan; Kohn, Adam; Moreno-Bote, Rubén

    2016-01-01

    Numerous studies have shown that neuronal responses are modulated by stimulus properties, and also by the state of the local network. However, little is known about how activity fluctuations of neuronal populations modulate the sensory tuning of cells and affect their encoded information. We found that fluctuations in ongoing and stimulus-evoked population activity in primate visual cortex modulate the tuning of neurons in a multiplicative and additive manner. While distributed on a continuum, neurons with stronger multiplicative effects tended to have less additive modulation, and vice versa. The information encoded by multiplicatively-modulated neurons increased with greater population activity, while that of additively-modulated neurons decreased. These effects offset each other, so that population activity had little effect on total information. Our results thus suggest that intrinsic activity fluctuations may act as a `traffic light' that determines which subset of neurons are most informative. PMID:26924437

  15. Human single neuron activity precedes emergence of conscious perception.

    PubMed

    Gelbard-Sagiv, Hagar; Mudrik, Liad; Hill, Michael R; Koch, Christof; Fried, Itzhak

    2018-05-25

    Identifying the neuronal basis of spontaneous changes in conscious experience in the absence of changes in the external environment is a major challenge. Binocular rivalry, in which two stationary monocular images lead to continuously changing perception, provides a unique opportunity to address this issue. We studied the activity of human single neurons in the medial temporal and frontal lobes while patients were engaged in binocular rivalry. Here we report that internal changes in the content of perception are signaled by very early (~-2000 ms) nonselective medial frontal activity, followed by selective activity of medial temporal lobe neurons that precedes the perceptual change by ~1000 ms. Such early activations are not found for externally driven perceptual changes. These results suggest that a medial fronto-temporal network may be involved in the preconscious internal generation of perceptual transitions.

  16. Neuronal Activity and the Expression of Clathrin Assembly Protein AP180

    PubMed Central

    Wu, Fangbai; Mattson, Mark P.; Yao, Pamela J.

    2010-01-01

    The clathrin assembly protein AP180 is known to promote the assembly of clathrin-coated vesicles in the neuron. However, it is unknown whether the expression of AP180 is influenced by neuronal activity. In this study, we report that chronic depolarization results in a reduction of AP180 from hippocampal neurons, while acute depolarization causes a dispersed synaptic distribution of AP180. Activity-induced effects are observed only for AP180, but not for the structurally-related clathrin assembly proteins CALM, epsin1, or HIP1. These findings suggest that AP180 levels and synaptic distribution are highly sensitive to neuronal activity. PMID:20937255

  17. AMP-activated protein kinase (AMPK)-induced preconditioning in primary cortical neurons involves activation of MCL-1.

    PubMed

    Anilkumar, Ujval; Weisová, Petronela; Düssmann, Heiko; Concannon, Caoimhín G; König, Hans-Georg; Prehn, Jochen H M

    2013-03-01

    Neuronal preconditioning is a phenomenon where a previous exposure to a sub-lethal stress stimulus increases the resistance of neurons towards a second, normally lethal stress stimulus. Activation of the energy stress sensor, AMP-activated protein kinase (AMPK) has been shown to contribute to the protective effects of ischaemic and mitochondrial uncoupling-induced preconditioning in neurons, however, the molecular basis of AMPK-mediated preconditioning has been less well characterized. We investigated the effect of AMPK preconditioning using 5-aminoimidazole-4-carboxamide riboside (AICAR) in a model of NMDA-mediated excitotoxic injury in primary mouse cortical neurons. Activation of AMPK with low concentrations of AICAR (0.1 mM for 2 h) induced a transient increase in AMPK phosphorylation, protecting neurons against NMDA-induced excitotoxicity. Analysing potential targets of AMPK activation, demonstrated a marked increase in mRNA expression and protein levels of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) in AICAR-preconditioned neurons. Interestingly, over-expression of MCL-1 protected neurons against NMDA-induced excitotoxicity while MCL-1 gene silencing abolished the effect of AICAR preconditioning. Monitored intracellular Ca²⁺ levels during NMDA excitation revealed that MCL-1 over-expressing neurons exhibited improved bioenergetics and markedly reduced Ca²⁺ elevations, suggesting a potential mechanism through which MCL-1 confers neuroprotection. This study identifies MCL-1 as a key effector of AMPK-induced preconditioning in neurons. © 2012 International Society for Neurochemistry.

  18. Antiapoptotic property of human alpha-synuclein in neuronal cell lines is associated with the inhibition of caspase-3 but not caspase-9 activity.

    PubMed

    Li, Wenxue; Lee, Michael K

    2005-06-01

    Abnormalities of alpha-synuclein (alpha-Syn) are mechanistically linked to Parkinson's disease (PD) and other alpha-synucleinopathies. To gain additional insights into the relationships between alpha-Syn expression and cell death, we examined the effects of expressing human alpha-Syn (Hualpha-Syn) variants on the cellular vulnerability to apoptotic stimuli. We show that the expression of wild-type (WT) and A30P mutant, but not A53T mutant, Hualpha-Syn leads to the protection of neuronal cell lines from apoptosis but not necrosis. Significantly, Hualpha-Syn did not protect non-neuronal cell lines from apoptosis. We also show that A53T mutant is a loss of function in regards to the antiapoptotic property since the expression of WT Hualpha-Syn with an excess of A53T mutant Hualpha-Syn leads to protection of the cells from apoptosis. The antiapoptotic property is specific to human alpha-Syn as neither beta-Syn nor mouse alpha-Syn protected cells from apoptosis, and the carboxy-terminal 20 amino acids are required for the antiapoptotic property. Analyses of capase-3 and caspase-9 activation reveal that the antiapoptotic property of Hualpha-Syn in neuronal cell lines is associated with the attenuation of caspase-3 activity without affecting the caspase-9 activity or the levels of cleaved, active caspase-3. We conclude that Hualpha-Syn modulates the activity of cleaved caspase-3 product in neuronal cell lines.

  19. Inhibition of propofol on single neuron and neuronal ensemble activity in prefrontal cortex of rats during working memory task.

    PubMed

    Xu, Xinyu; Tian, Yu; Wang, Guolin; Tian, Xin

    2014-08-15

    Working memory (WM) refers to the temporary storage and manipulation of information necessary for performance of complex cognitive tasks. There is a growing interest in whether and how propofol anesthesia inhibits WM function. The aim of this study is to investigate the possible inhibition mechanism of propofol anesthesia from the view of single neuron and neuronal ensemble activities. Adult SD rats were randomly divided into two groups: propofol group (0.9 mg kg(-1)min(-1), 2h via a tail vein catheter) and control group. All the rats were tested for working memory performances in a Y-maze-rewarded alternation task (a task of delayed non-matched-to-sample) at 24, 48, 72 h after propofol anesthesia, and the behavior results of WM tasks were recorded at the same time. Spatio-temporal trains of action potentials were obtained from the original signals. Single neuron activity was characterized by peri-event time histograms analysis and neuron ensemble activities were characterized by Granger causality to describe the interactions within the neuron ensemble. The results show that: comparing with the control group, the percentage of neurons excited and related to WM was significantly decreased (p<0.01 in 24h, p<0.05 in 48 h); the interactions within neuron ensemble were significantly weakened (p<0.01 in 24h, p<0.05 in 48 h), whereas no significant difference in 72 h (p>0.05), which were consistent with the behavior results. These findings could lead to improved understanding of the mechanism of anesthesia inhibition on WM functions from the view of single neuron activity and neuron ensemble interactions. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism

    PubMed Central

    Lundgaard, Iben; Li, Baoman; Xie, Lulu; Kang, Hongyi; Sanggaard, Simon; Haswell, John Douglas R; Sun, Wei; Goldman, Siri; Blekot, Solomiya; Nielsen, Michael; Takano, Takahiro; Deane, Rashid; Nedergaard, Maiken

    2015-01-01

    Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using 2-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyze the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identifies the neuron as the principal locus of glucose uptake as visualized by functional brain imaging. PMID:25904018

  1. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism.

    PubMed

    Lundgaard, Iben; Li, Baoman; Xie, Lulu; Kang, Hongyi; Sanggaard, Simon; Haswell, John D R; Sun, Wei; Goldman, Siri; Blekot, Solomiya; Nielsen, Michael; Takano, Takahiro; Deane, Rashid; Nedergaard, Maiken

    2015-04-23

    Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using two-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anaesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyses the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identify the neuron as the principal locus of glucose uptake as visualized by functional brain imaging.

  2. Relationship between inter-stimulus-intervals and intervals of autonomous activities in a neuronal network.

    PubMed

    Ito, Hidekatsu; Minoshima, Wataru; Kudoh, Suguru N

    2015-08-01

    To investigate relationships between neuronal network activity and electrical stimulus, we analyzed autonomous activity before and after electrical stimulus. Recordings of autonomous activity were performed using dissociated culture of rat hippocampal neurons on a multi-electrodes array (MEA) dish. Single stimulus and pared stimuli were applied to a cultured neuronal network. Single stimulus was applied every 1 min, and paired stimuli was performed by two sequential stimuli every 1 min. As a result, the patterns of synchronized activities of a neuronal network were changed after stimulus. Especially, long range synchronous activities were induced by paired stimuli. When 1 s inter-stimulus-intervals (ISI) and 1.5 s ISI paired stimuli are applied to a neuronal network, relatively long range synchronous activities expressed in case of 1.5 s ISI. Temporal synchronous activity of neuronal network is changed according to inter-stimulus-intervals (ISI) of electrical stimulus. In other words, dissociated neuronal network can maintain given information in temporal pattern and a certain type of an information maintenance mechanism was considered to be implemented in a semi-artificial dissociated neuronal network. The result is useful toward manipulation technology of neuronal activity in a brain system.

  3. BAD and KATP channels regulate neuron excitability and epileptiform activity

    PubMed Central

    Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L

    2018-01-01

    Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity. PMID:29368690

  4. Activation of Pedunculopontine Glutamate Neurons Is Reinforcing

    PubMed Central

    Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook

    2017-01-01

    neuron activity and behavioral reinforcement. PMID:28053028

  5. Are dragon-king neuronal avalanches dungeons for self-organized brain activity?

    NASA Astrophysics Data System (ADS)

    de Arcangelis, L.

    2012-05-01

    Recent experiments have detected a novel form of spontaneous neuronal activity both in vitro and in vivo: neuronal avalanches. The statistical properties of this activity are typical of critical phenomena, with power laws characterizing the distributions of avalanche size and duration. A critical behaviour for the spontaneous brain activity has important consequences on stimulated activity and learning. Very interestingly, these statistical properties can be altered in significant ways in epilepsy and by pharmacological manipulations. In particular, there can be an increase in the number of large events anticipated by the power law, referred to herein as dragon-king avalanches. This behaviour, as verified by numerical models, can originate from a number of different mechanisms. For instance, it is observed experimentally that the emergence of a critical behaviour depends on the subtle balance between excitatory and inhibitory mechanisms acting in the system. Perturbing this balance, by increasing either synaptic excitation or the incidence of depolarized neuronal up-states causes frequent dragon-king avalanches. Conversely, an unbalanced GABAergic inhibition or long periods of low activity in the network give rise to sub-critical behaviour. Moreover, the existence of power laws, common to other stochastic processes, like earthquakes or solar flares, suggests that correlations are relevant in these phenomena. The dragon-king avalanches may then also be the expression of pathological correlations leading to frequent avalanches encompassing all neurons. We will review the statistics of neuronal avalanches in experimental systems. We then present numerical simulations of a neuronal network model introducing within the self-organized criticality framework ingredients from the physiology of real neurons, as the refractory period, synaptic plasticity and inhibitory synapses. The avalanche critical behaviour and the role of dragon-king avalanches will be discussed in

  6. Thrombin-induced apoptosis in neurons through activation of c-Jun-N-terminal kinase.

    PubMed

    Bao, Lei; Zu, Jie; He, Qianqian; Zhao, Hui; Zhou, Su; Ye, Xinchun; Yang, Xinxin; Zan, Kun; Zhang, Zuohui; Shi, Hongjuan; Cui, Guiyun

    2017-01-01

    Studies have shown that thrombin activation played a central role in cell injuries associated with intracerebral hemorrhage (ICH). Here, our study investigated the cytotoxicity of thrombin on neurons, and determined the involvement of JNK pathways in thrombin-induced neuronal apoptosis. Primary cultured neurons were treated with different doses of thrombin. Some neurons were given either SP600125 or vehicle. LDH release assay and flow cytometry were used to measure neuronal apoptosis caused by thrombin. The activation of JNK and capases-3 were measured by Western blot. Our results showed large doses of thrombin that increased the LDH release, the level of cleaved caspase-3 and apoptosis rate of neurons. JNK was activated by thrombin in a time-dependent manner. Administration of SP600125 protects neurons from thrombin-induced apoptosis. These data indicate that the activation of JNK is crucial for thrombin-induced neuronal apoptosis, and inhibition of JNK may be a potential therapeutic target for ICH.

  7. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.

    PubMed

    Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin

    2010-09-01

    Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

  8. Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

    PubMed Central

    Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori

    2015-01-01

    Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation. PMID:25713104

  9. In situ immunodetection of neuronal caspase-3 activation in Alzheimer disease.

    PubMed

    Selznick, L A; Holtzman, D M; Han, B H; Gökden, M; Srinivasan, A N; Johnson, E M; Roth, K A

    1999-09-01

    The mechanism by which cells die in Alzheimer disease (AD) is unknown. Several investigators speculate that much of the cell loss may be due to apoptosis, a highly regulated form of programmed cell death. Caspase-3 is a critical effector of neuronal apoptosis and may be inappropriately activated in AD. To address this possibility, we examined cortical and hippocampal brain sections from AD patients, as well as 2 animal models of AD, for in situ evidence of caspase-3 activation. We report here that senile plaques and neurofibrillary tangles in the AD brain are not associated with caspase-3 activation. Furthermore, amyloid beta (A beta) deposition in the APPsw transgenic mouse model of AD does not result in caspase-3 activation despite the ability of A beta to induce caspase-3 activation and neuronal apoptosis in vitro. AD brain sections do, however, exhibit caspase-3 activation in hippocampal neurons undergoing granulovacuolar degeneration. Our data suggests that caspase-3 does not have a significant role in the widespread neuronal cell death that occurs in AD, but may contribute to the specific loss of hippocampal neurons involved in learning and memory.

  10. Linking neuronal brain activity to the glucose metabolism.

    PubMed

    Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

    2013-08-29

    Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

  11. Linking neuronal brain activity to the glucose metabolism

    PubMed Central

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. Methods First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Results Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. Conclusions The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID:23988084

  12. Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala.

    PubMed

    Adams, Thomas; Rosenkranz, J Amiel

    2016-06-01

    Children exposed to neglect or social deprivation are at heightened risk for psychiatric disorders and abnormal social patterns as adults. There is also evidence that prepubertal neglect in children causes abnormal metabolic activity in several brain regions, including the amygdala area. The medial nucleus of the amygdala (MeA) is a key region for performance of social behaviors and still undergoes maturation during the periadolescent period. As such, the normal development of this region may be disrupted by social deprivation. In rodents, postweaning social isolation causes a range of deficits in sexual and agonistic behaviors that normally rely on the posterior MeA (MeAp). However, little is known about the effects of social isolation on the function of MeA neurons. In this study, we tested whether postweaning social isolation caused abnormal activity of MeA neurons. We found that postweaning social isolation caused a decrease of in vivo firing activity of MeAp neurons, and reduced drive from excitatory afferents. In vitro electrophysiological studies found that postweaning social isolation caused a presynaptic impairment of excitatory input to the dorsal MeAp, but a progressive postsynaptic reduction of membrane excitability in the ventral MeAp. These results demonstrate discrete, subnucleus-specific effects of social deprivation on the physiology of MeAp neurons. This pathophysiology may contribute to the disruption of social behavior after developmental social deprivation, and may be a novel target to facilitate the treatment of social disorders.

  13. Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala

    PubMed Central

    Adams, Thomas; Rosenkranz, J Amiel

    2016-01-01

    Children exposed to neglect or social deprivation are at heightened risk for psychiatric disorders and abnormal social patterns as adults. There is also evidence that prepubertal neglect in children causes abnormal metabolic activity in several brain regions, including the amygdala area. The medial nucleus of the amygdala (MeA) is a key region for performance of social behaviors and still undergoes maturation during the periadolescent period. As such, the normal development of this region may be disrupted by social deprivation. In rodents, postweaning social isolation causes a range of deficits in sexual and agonistic behaviors that normally rely on the posterior MeA (MeAp). However, little is known about the effects of social isolation on the function of MeA neurons. In this study, we tested whether postweaning social isolation caused abnormal activity of MeA neurons. We found that postweaning social isolation caused a decrease of in vivo firing activity of MeAp neurons, and reduced drive from excitatory afferents. In vitro electrophysiological studies found that postweaning social isolation caused a presynaptic impairment of excitatory input to the dorsal MeAp, but a progressive postsynaptic reduction of membrane excitability in the ventral MeAp. These results demonstrate discrete, subnucleus-specific effects of social deprivation on the physiology of MeAp neurons. This pathophysiology may contribute to the disruption of social behavior after developmental social deprivation, and may be a novel target to facilitate the treatment of social disorders. PMID:26677945

  14. A calcium-permeable cGMP-activated cation conductance in hippocampal neurons

    NASA Technical Reports Server (NTRS)

    Leinders-Zufall, T.; Rosenboom, H.; Barnstable, C. J.; Shepherd, G. M.; Zufall, F.

    1995-01-01

    Whole-cell patch clamp recordings detected a previously unidentified cGMP-activated membrane conductance in cultured rat hippocampal neurons. This conductance is nonselectively permeable for cations and is completely but reversibly blocked by external Cd2+. The Ca2+ permeability of the hippocampal cGMP-activated conductance was examined in detail, indicating that the underlying ion channels display a high relative permeability for Ca2+. The results indicate that hippocampal neurons contain a cGMP-activated membrane conductance that has some properties similar to the cyclic nucleotide-gated channels previously shown in sensory receptor cells and retinal neurons. In hippocampal neurons this conductance similarly could mediate membrane depolarization and Ca2+ fluxes in response to intracellular cGMP elevation.

  15. Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys.

    PubMed

    Walton, Mark M G; Mustari, Michael J

    2015-08-01

    Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30° of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem. Copyright © 2015 the American Physiological Society.

  16. Salicylate-induced abnormal activity in the inferior colliculus of rats.

    PubMed

    Chen, G D; Jastreboff, P J

    1995-02-01

    The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10-16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.

  17. Cell Cycle Deregulation in the Neurons of Alzheimer’s Disease

    PubMed Central

    Moh, Calvin; Kubiak, Jacek Z.; Bajic, Vladan P.; Zhu, Xiongwei; Smith, Mark A.

    2018-01-01

    The cell cycle consists of four main phases: G1, S, G2, and M. Most cells undergo these cycles up to 40–60 times in their life. However, neurons remain in a nondividing, nonreplicating phase, G0. Neurons initiate but do not complete cell division, eventually entering apoptosis. Research has suggested that like cancer, Alzheimer’s disease (AD) involves dysfunction in neuronal cell cycle reentry, leading to the development of the two-hit hypothesis of AD. The first hit is abnormal cell cycle reentry, which typically results in neuronal apoptosis and prevention of AD. However, with the second hit of chronic oxidative damage preventing apoptosis, neurons gain “immortality” analogous to tumor cells. Once both of these hits are activated, AD can develop and produce senile plaques and neurofibrillary tangles throughout brain tissue. In this review, we propose a mechanism for neuronal cell cycle reentry and the development of AD. PMID:21630160

  18. Maternal immune activation and abnormal brain development across CNS disorders.

    PubMed

    Knuesel, Irene; Chicha, Laurie; Britschgi, Markus; Schobel, Scott A; Bodmer, Michael; Hellings, Jessica A; Toovey, Stephen; Prinssen, Eric P

    2014-11-01

    Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.

  19. Effects of intranasal administration of epitalon on neuron activity in the rat neocortex.

    PubMed

    Sibarov, D A; Vol'nova, A B; Frolov, D S; Nozdrachev, A D

    2007-11-01

    This report discusses the properties of the synthetic tetrapeptide epitalon (Ala-Glu-Asp-Gly), synthesized on the basis of an epiphyseal peptide extract. Intranasal administration of epitalon was selected as a noninvasive means of applying the agent to the CNS by bypassing the blood-brain barrier. The aim of the present work was to assess the characteristics of the action of epitalon on the frequency of spontaneous neuron activity in the cerebral cortex of white rats. Studies were performed using male Wistar rats anesthetized with urethane (1 g/kg). Extracellular activity of cortical neurons was recorded with a glass microelectrode of resistance 1-2 MOmega. Recording of spontaneous neuron discharges for 10-15 min was followed by intranasal administration of epitalon solution and recording of neuron activity to 30 min after doses of 30 ng per animal. Significant activation of neuron activity was seen several minutes after dosage, with an increase (by factors of 2-2.5) in discharge frequency. In some experiments, the effect of epitalon was multiphasic. The first peak of increased neuron discharge frequency at 5-7 min was followed by peaks at 11-12 and 17-18 min. The increase in discharge frequency occurred because of an increase in the discharge frequency of neurons which were already active and the recruitment of previously silent neurons. At least the first peak of increased neuron activity following exposure to epitalon was found to be associated with the direct action of the peptide on cortical cells.

  20. Neuronal pattern separation of motion-relevant input in LIP activity

    PubMed Central

    Berberian, Nareg; MacPherson, Amanda; Giraud, Eloïse; Richardson, Lydia

    2016-01-01

    In various regions of the brain, neurons discriminate sensory stimuli by decreasing the similarity between ambiguous input patterns. Here, we examine whether this process of pattern separation may drive the rapid discrimination of visual motion stimuli in the lateral intraparietal area (LIP). Starting with a simple mean-rate population model that captures neuronal activity in LIP, we show that overlapping input patterns can be reformatted dynamically to give rise to separated patterns of neuronal activity. The population model predicts that a key ingredient of pattern separation is the presence of heterogeneity in the response of individual units. Furthermore, the model proposes that pattern separation relies on heterogeneity in the temporal dynamics of neural activity and not merely in the mean firing rates of individual neurons over time. We confirm these predictions in recordings of macaque LIP neurons and show that the accuracy of pattern separation is a strong predictor of behavioral performance. Overall, results propose that LIP relies on neuronal pattern separation to facilitate decision-relevant discrimination of sensory stimuli. NEW & NOTEWORTHY A new hypothesis is proposed on the role of the lateral intraparietal (LIP) region of cortex during rapid decision making. This hypothesis suggests that LIP alters the representation of ambiguous inputs to reduce their overlap, thus improving sensory discrimination. A combination of computational modeling, theoretical analysis, and electrophysiological data shows that the pattern separation hypothesis links neural activity to behavior and offers novel predictions on the role of LIP during sensory discrimination. PMID:27881719

  1. Network activity of mirror neurons depends on experience.

    PubMed

    Ushakov, Vadim L; Kartashov, Sergey I; Zavyalova, Victoria V; Bezverhiy, Denis D; Posichanyuk, Vladimir I; Terentev, Vasliliy N; Anokhin, Konstantin V

    2013-03-01

    In this work, the investigation of network activity of mirror neurons systems in animal brains depending on experience (existence or absence performance of the shown actions) was carried out. It carried out the research of mirror neurons network in the C57/BL6 line mice in the supervision task of swimming mice-demonstrators in Morris water maze. It showed the presence of mirror neurons systems in the motor cortex M1, M2, cingular cortex, hippocampus in mice groups, having experience of the swimming and without it. The conclusion is drawn about the possibility of the new functional network systems formation by means of mirror neurons systems and the acquisition of new knowledge through supervision by the animals in non-specific tasks.

  2. Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

    PubMed Central

    Ding, Shengyuan; Wei, Wei

    2011-01-01

    GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (NaV) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, NaV channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming NaV1.1 and NaV1.6 subunits and regulatory NaVβ1 and Navβ4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming NaV channels conducting the transient NaV current (INaT), persistent Na current (INaP), and resurgent Na current (INaR). Nucleated patch-clamp recordings showed that INaT had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. INaT also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger INaR and INaP. Blockade of INaP induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that NaV channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities. PMID:21880943

  3. Development and characterization of NEX- Pten, a novel forebrain excitatory neuron-specific knockout mouse.

    PubMed

    Kazdoba, Tatiana M; Sunnen, C Nicole; Crowell, Beth; Lee, Gum Hwa; Anderson, Anne E; D'Arcangelo, Gabriella

    2012-01-01

    The phosphatase and tensin homolog located on chromosome 10 (PTEN) suppresses the activity of the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, a signaling cascade critically involved in the regulation of cell proliferation and growth. Human patients carrying germ line PTEN mutations have an increased predisposition to tumors, and also display a variety of neurological symptoms and increased risk of epilepsy and autism, implicating PTEN in neuronal development and function. Consistently, loss of Pten in mouse neural cells results in ataxia, seizures, cognitive abnormalities, increased soma size and synaptic abnormalities. To better understand how Pten regulates the excitability of principal forebrain neurons, a factor that is likely to be altered in cognitive disorders, epilepsy and autism, we generated a novel conditional knockout mouse line (NEX-Pten) in which Cre, under the control of the NEX promoter, drives the deletion of Pten specifically in early postmitotic, excitatory neurons of the developing forebrain. Homozygous mutant mice exhibited a massive enlargement of the forebrain, and died shortly after birth due to excessive mTOR activation. Analysis of the neonatal cerebral cortex further identified molecular defects resulting from Pten deletion that likely affect several aspects of neuronal development and excitability. Copyright © 2012 S. Karger AG, Basel.

  4. Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats.

    PubMed

    Suo, Guihai; Shen, Feifei; Sun, Baolan; Song, Honghua; Xu, Meiyu; Wu, Youjia

    2018-05-14

    EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically.

  5. FlyMAD: rapid thermogenetic control of neuronal activity in freely walking Drosophila.

    PubMed

    Bath, Daniel E; Stowers, John R; Hörmann, Dorothea; Poehlmann, Andreas; Dickson, Barry J; Straw, Andrew D

    2014-07-01

    Rapidly and selectively modulating the activity of defined neurons in unrestrained animals is a powerful approach in investigating the circuit mechanisms that shape behavior. In Drosophila melanogaster, temperature-sensitive silencers and activators are widely used to control the activities of genetically defined neuronal cell types. A limitation of these thermogenetic approaches, however, has been their poor temporal resolution. Here we introduce FlyMAD (the fly mind-altering device), which allows thermogenetic silencing or activation within seconds or even fractions of a second. Using computer vision, FlyMAD targets an infrared laser to freely walking flies. As a proof of principle, we demonstrated the rapid silencing and activation of neurons involved in locomotion, vision and courtship. The spatial resolution of the focused beam enabled preferential targeting of neurons in the brain or ventral nerve cord. Moreover, the high temporal resolution of FlyMAD allowed us to discover distinct timing relationships for two neuronal cell types previously linked to courtship song.

  6. Improved expression of halorhodopsin for light-induced silencing of neuronal activity

    PubMed Central

    Zhao, Shengli; Cunha, Catarina; Zhang, Feng; Liu, Qun; Gloss, Bernd; Deisseroth, Karl; Augustine, George J.; Feng, Guoping

    2011-01-01

    The ability to control and manipulate neuronal activity within an intact mammalian brain is of key importance for mapping functional connectivity and for dissecting the neural circuitry underlying behaviors. We have previously generated transgenic mice that express channelrhodopsin-2 for light-induced activation of neurons and mapping of neural circuits. Here we describe transgenic mice that express halorhodopsin (NpHR), a light-driven chloride pump, that can be used to silence neuronal activity via light. Using the Thy-1 promoter to target NpHR expression to neurons, we found that neurons in these mice expressed high levels of NpHR-YFP and that illumination of cortical pyramidal neurons expressing NpHR-YFP led to rapid, reversible photoinhibition of action potential firing in these cells. However, NpHR-YFP expression led to the formation of numerous intracellular blebs, which may disrupt neuronal function. Labeling of various subcellular markers indicated that the blebs arise from retention of NpHR-YFP in the endoplasmic reticulum. By improving the signal peptide sequence and adding an ER export signal to NpHR-YFP, we eliminated the formation of blebs and dramatically increased the membrane expression of NpHR-YFP. Thus, the improved version of NpHR should serve as an excellent tool for neuronal silencing in vitro and in vivo. PMID:18931914

  7. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

    PubMed Central

    Lu, Jackie W; Fenik, Victor B; Branconi, Jennifer L; Mann, Graziella L; Rukhadze, Irma; Kubin, Leszek

    2007-01-01

    Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 mm), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. PMID:17495048

  8. Role of Microglia Disturbances and Immune-Related Marker Abnormalities in Cortical Circuitry Dysfunction in Schizophrenia

    PubMed Central

    Volk, David W.

    2017-01-01

    Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia. PMID:28007586

  9. Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage.

    PubMed

    Liu, Fang; Rainosek, Shuo W; Frisch-Daiello, Jessica L; Patterson, Tucker A; Paule, Merle G; Slikker, William; Wang, Cheng; Han, Xianlin

    2015-10-01

    Sevoflurane is a volatile anesthetic that has been widely used in general anesthesia, yet its safety in pediatric use is a public concern. This study sought to evaluate whether prolonged exposure of infant monkeys to a clinically relevant concentration of sevoflurane is associated with any adverse effects on the developing brain. Infant monkeys were exposed to 2.5% sevoflurane for 9 h, and frontal cortical tissues were harvested for DNA microarray, lipidomics, Luminex protein, and histological assays. DNA microarray analysis showed that sevoflurane exposure resulted in a broad identification of differentially expressed genes (DEGs) in the monkey brain. In general, these genes were associated with nervous system development, function, and neural cell viability. Notably, a number of DEGs were closely related to lipid metabolism. Lipidomic analysis demonstrated that critical lipid components, (eg, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol) were significantly downregulated by prolonged exposure of sevoflurane. Luminex protein analysis indicated abnormal levels of cytokines in sevoflurane-exposed brains. Consistently, Fluoro-Jade C staining revealed more degenerating neurons after sevoflurane exposure. These data demonstrate that a clinically relevant concentration of sevoflurane (2.5%) is capable of inducing and maintaining an effective surgical plane of anesthesia in the developing nonhuman primate and that a prolonged exposure of 9 h resulted in profound changes in gene expression, cytokine levels, lipid metabolism, and subsequently, neuronal damage. Generally, sevoflurane-induced neuronal damage was also associated with changes in lipid content, composition, or both; and specific lipid changes could provide insights into the molecular mechanism(s) underlying anesthetic-induced neurotoxicity and may be sensitive biomarkers for the early detection of anesthetic-induced neuronal damage. Published by Oxford University Press on behalf of the

  10. BAD and KATP channels regulate neuron excitability and epileptiform activity.

    PubMed

    Martínez-François, Juan Ramón; Fernández-Agüera, María Carmen; Nathwani, Nidhi; Lahmann, Carolina; Burnham, Veronica L; Danial, Nika N; Yellen, Gary

    2018-01-25

    Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad ( B CL-2 a gonist of cell d eath) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (K ATP ) channels. Here we investigated the effect of BAD manipulation on K ATP channel activity and excitability in acute brain slices. We found that BAD's influence on neuronal K ATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal K ATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of K ATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a 'dentate gate' function that is reinforced by increased K ATP channel activity. © 2018, Martínez-François et al.

  11. Periodic activation function and a modified learning algorithm for the multivalued neuron.

    PubMed

    Aizenberg, Igor

    2010-12-01

    In this paper, we consider a new periodic activation function for the multivalued neuron (MVN). The MVN is a neuron with complex-valued weights and inputs/output, which are located on the unit circle. Although the MVN outperforms many other neurons and MVN-based neural networks have shown their high potential, the MVN still has a limited capability of learning highly nonlinear functions. A periodic activation function, which is introduced in this paper, makes it possible to learn nonlinearly separable problems and non-threshold multiple-valued functions using a single multivalued neuron. We call this neuron a multivalued neuron with a periodic activation function (MVN-P). The MVN-Ps functionality is much higher than that of the regular MVN. The MVN-P is more efficient in solving various classification problems. A learning algorithm based on the error-correction rule for the MVN-P is also presented. It is shown that a single MVN-P can easily learn and solve those benchmark classification problems that were considered unsolvable using a single neuron. It is also shown that a universal binary neuron, which can learn nonlinearly separable Boolean functions, and a regular MVN are particular cases of the MVN-P.

  12. Neuronal network models of epileptogenesis

    PubMed Central

    Abdullahi, Aminu T.; Adamu, Lawan H.

    2017-01-01

    Epilepsy is a chronic neurological condition, following some trigger, transforming a normal brain to one that produces recurrent unprovoked seizures. In the search for the mechanisms that best explain the epileptogenic process, there is a growing body of evidence suggesting that the epilepsies are network level disorders. In this review, we briefly describe the concept of neuronal networks and highlight 2 methods used to analyse such networks. The first method, graph theory, is used to describe general characteristics of a network to facilitate comparison between normal and abnormal networks. The second, dynamic causal modelling, is useful in the analysis of the pathways of seizure spread. We concluded that the end results of the epileptogenic process are best understood as abnormalities of neuronal circuitry and not simply as molecular or cellular abnormalities. The network approach promises to generate new understanding and more targeted treatment of epilepsy. PMID:28416779

  13. Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis.

    PubMed

    Alshikho, Mohamad J; Zürcher, Nicole R; Loggia, Marco L; Cernasov, Paul; Chonde, Daniel B; Izquierdo Garcia, David; Yasek, Julia E; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce R; Cudkowicz, Merit E; Hooker, Jacob M; Atassi, Nazem

    2016-12-13

    In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [ 11 C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [ 11 C]-PBR28 uptake. In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [ 11 C]-PBR28 binding in the left motor cortex was correlated with FA (r = -0.68, p < 0.05) and cortical thickness (r = -0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = -0.77, p < 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex. Increased uptake of the glial marker [ 11 C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS. © 2016 American Academy of Neurology.

  14. Manipulating neuronal activity with low frequency transcranial ultrasound

    NASA Astrophysics Data System (ADS)

    Moore, Michele Elizabeth

    Stimulation of the rodent cerebral cortex is used to investigate the underlying biological basis for the restorative effects of slow wave sleep. Neuronal activation by optogenetic and ultrasound stimulation elicits changes in action potentials across the cerebral cortex that are recorded as electroencephalograms. Optogenetic stimulation requires an invasive implantation procedure limiting its application in human studies. We sought to determine whether ultrasound stimulation could be as effective as optogenetic techniques currently used, in an effort to further understand the physiological and metabolic requirements of sleep. We successfully recorded electroencephalograms in response to transcranial ultrasound stimulation of the barrel cortex at 1 and 7 Hz frequencies, comparing them to those recorded in response to optogenetic stimuli applied at the same frequencies. Our results showed application of a 473 nm blue LED positioned 6 cm above the skull and ultrasound stimulation at an output voltage of 1000 mVpp produced electroencephalograms with physiological responses of similar amplitude. We concluded that there exists an intensity-proportionate response in the optogenetic stimulation, but not with ultrasound stimulation at the frequencies we surveyed. Activation of neuronal cells in response to optogenetic stimulation in a Thy1-ChR2 transgenic mouse line is specifically targeted to pyramidal cells in the cerebral cortex. ChR2 responses to optogenetic stimulation are mediated by a focal activation of neuronal ion channels. We measured electrophysiological responses to ultrasound stimulation, comparing them to those recorded from optogenetic stimuli. Our results show striking similarities between ultrasound-induced responses and optogenetically-induced responses, which may indicate that transcranial ultrasound stimulation is also mediated by ion channel dependent processes in cerebral cortical neurons. The biophysical substrates for electrical excitability of

  15. Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism.

    PubMed

    Novaira, Horacio J; Sonko, Momodou L; Hoffman, Gloria; Koo, Yongbum; Ko, Chemyong; Wolfe, Andrew; Radovick, Sally

    2014-02-01

    Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron-specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.

  16. Theta synchronizes the activity of medial prefrontal neurons during learning

    PubMed Central

    Paz, Rony; Bauer, Elizabeth P.; Paré, Denis

    2008-01-01

    Memory consolidation is thought to involve the gradual transfer of transient hippocampal-dependent traces to distributed neocortical sites via the rhinal cortices. Recently, medial prefrontal (mPFC) neurons were shown to facilitate this process when their activity becomes synchronized. However, the mechanisms underlying this enhanced synchrony remain unclear. Because the hippocampus projects to the mPFC, we tested whether theta oscillations contribute to synchronize mPFC neurons during learning. Thus, we obtained field (LFP) and unit recordings from multiple mPFC sites during the acquisition of a trace-conditioning task, where a visual conditioned stimulus (CS) predicted reward delivery. In quiet waking, the activity of mPFC neurons was modulated by theta oscillations. During conditioning, CS presentation caused an increase in mPFC theta power that augmented as the CS gained predictive value for reward delivery. This increased theta power coincided with a transient theta phase locking at distributed mPFC sites, an effect that was also manifest in the timing of mPFC unit activity. Overall, these results show that theta oscillations contribute to synchronize neuronal activity at distributed mPFC sites, suggesting that the hippocampus, by generating a stronger theta source during learning, can synchronize mPFC activity, in turn facilitating rhinal transfer of its activity to the neocortex. PMID:18612069

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

    PubMed

    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.

  18. Possible involvement of 12-lipoxygenase activation in glucose-deprivation/reload-treated neurons.

    PubMed

    Nagasawa, Kazuki; Kakuda, Taichi; Higashi, Youichirou; Fujimoto, Sadaki

    2007-12-18

    The aim of this study was to clarify whether 12-lipoxygenase (12-LOX) activation was involved in reactive oxygen species (ROS) generation, extensive poly(ADP-ribose) polymerase (PARP) activation and neuronal death induced by glucose-deprivation, followed by glucose-reload (GD/R). The decrease of neuronal viability and accumulation of poly(ADP-ribose) induced by GD/R were prevented 3-aminobenzamide, a representative PARP inhibitor, demonstrating this treatment protocol caused the same oxidative stress with the previously reported one. The PARP activation, ROS generation and decrease of neuron viability induced by GD/R treatment were almost completely abolished by an extracellular zinc chelator, CaEDTA. p47(phox), a cytosolic component of NADPH oxidase was translocated the membrane fraction by GD/R, indicating its activation, but it did not generate detectable ROS. Surprisingly, pharmacological inhibition of NADPH oxidase with apocynin and AEBSF further decreased the decreased neuron viability induced by GD/R. On the other hand, AA861, a 12-LOX inhibitor, prevented ROS generation and decrease of neuron viability caused by GD/R. Interestingly, an antioxidant, N-acetyl-l-cysteine rescued the neurons from GD/R-induced oxidative stress, implying effectiveness of antioxidant administration. These findings suggested that activation of 12-LOX, but not NADPH oxidase, following to zinc release might play an important role in ROS generation and decrease of viability in GD/R-treated neurons.

  19. Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement.

    PubMed

    Adamsky, Adar; Kol, Adi; Kreisel, Tirzah; Doron, Adi; Ozeri-Engelhard, Nofar; Melcer, Talia; Refaeli, Ron; Horn, Henrike; Regev, Limor; Groysman, Maya; London, Michael; Goshen, Inbal

    2018-05-18

    Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    PubMed Central

    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 of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the prefrontal cortex in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia. PMID:23769891

  1. Excessive Astrocyte-Derived Neurotrophin-3 Contributes to the Abnormal Neuronal Dendritic Development in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Guo, Yan-yan; Liu, Shui-bing; Wu, Yu-mei; Li, Xiao-qiang; Zhao, Ming-gao

    2012-01-01

    Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA–binding motifs and is involved in translational regulation. RNA–binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS. PMID:23300470

  2. Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis

    PubMed Central

    Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

    2013-01-01

    Summary Background Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Results Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, while neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized, but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Conclusions Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. PMID:23103189

  3. Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis.

    PubMed

    Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

    2012-11-06

    Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Automated system for analyzing the activity of individual neurons

    NASA Technical Reports Server (NTRS)

    Bankman, Isaac N.; Johnson, Kenneth O.; Menkes, Alex M.; Diamond, Steve D.; Oshaughnessy, David M.

    1993-01-01

    This paper presents a signal processing system that: (1) provides an efficient and reliable instrument for investigating the activity of neuronal assemblies in the brain; and (2) demonstrates the feasibility of generating the command signals of prostheses using the activity of relevant neurons in disabled subjects. The system operates online, in a fully automated manner and can recognize the transient waveforms of several neurons in extracellular neurophysiological recordings. Optimal algorithms for detection, classification, and resolution of overlapping waveforms are developed and evaluated. Full automation is made possible by an algorithm that can set appropriate decision thresholds and an algorithm that can generate templates on-line. The system is implemented with a fast IBM PC compatible processor board that allows on-line operation.

  5. Spontaneous olfactory receptor neuron activity determines follower cell response properties

    PubMed Central

    Joseph, Joby; Dunn, Felice A.; Stopfer, Mark

    2012-01-01

    Noisy or spontaneous activity is common in neural systems and poses a challenge to detecting and discriminating signals. Here we use the locust to answer fundamental questions about noise in the olfactory system: Where does spontaneous activity originate? How is this activity propagated or reduced throughout multiple stages of neural processing? What mechanisms favor the detection of signals despite the presence of spontaneous activity? We found that spontaneous activity long observed in the secondary projection neurons (PNs) originates almost entirely from the primary olfactory receptor neurons (ORNs) rather than from spontaneous circuit interactions in the antennal lobe, and that spontaneous activity in ORNs tonically depolarizes the resting membrane potentials of their target PNs and local neurons (LNs), and indirectly tonically depolarizes tertiary Kenyon cells (KCs). However, because these neurons have different response thresholds, in the absence of odor stimulation, ORNs and PNs display a high spontaneous firing rate but KCs are nearly silent. Finally, we used a simulation of the olfactory network to show that discrimination of signal and noise in the KCs is best when threshold levels are set so that baseline activity in PNs persists. Our results show how the olfactory system benefits from making a signal detection decision after a point of maximal information convergence, e.g., after KCs pool inputs from many PNs. PMID:22357872

  6. Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.

    PubMed

    Sotoyama, Hidekazu; Namba, Hisaaki; Chiken, Satomi; Nambu, Atsushi; Nawa, Hiroyuki

    2013-08-01

    Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia. © 2013 International Society for Neurochemistry.

  7. Neuronal Activation After Prolonged Immobilization: Do the Same or Different Neurons Respond to a Novel Stressor?

    PubMed

    Marín-Blasco, Ignacio; Muñoz-Abellán, Cristina; Andero, Raül; Nadal, Roser; Armario, Antonio

    2018-04-01

    Despite extensive research on the impact of emotional stressors on brain function using immediate-early genes (e.g., c-fos), there are still important questions that remain unanswered such as the reason for the progressive decline of c-fos expression in response to prolonged stress and the neuronal populations activated by different stressors. This study tackles these 2 questions by evaluating c-fos expression in response to 2 different emotional stressors applied sequentially, and performing a fluorescent double labeling of c-Fos protein and c-fos mRNA on stress-related brain areas. Results were complemented with the assessment of the hypothalamic-pituitary-adrenal axis activation. We showed that the progressive decline of c-fos expression could be related to 2 differing mechanisms involving either transcriptional repression or changes in stimulatory inputs. Moreover, the neuronal populations that respond to the different stressors appear to be predominantly separated in high-level processing areas (e.g., medial prefrontal cortex). However, in low-hierarchy areas (e.g., paraventricular nucleus of the hypothalamus) neuronal populations appear to respond unspecifically. The data suggest that the distinct physiological and behavioral consequences of emotional stressors, and their implication in the development of psychopathologies, are likely to be closely associated with neuronal populations specifically activated by each stressor.

  8. Axonal degeneration in Alzheimer’s disease: When signaling abnormalities meet the axonal transport system

    PubMed Central

    Kanaan, Nicholas M.; Pigino, Gustavo F.; Brady, Scott T.; Lazarov, Orly; Binder, Lester I.; Morfini, Gerardo A.

    2012-01-01

    Alzheimer’s disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD. PMID:22721767

  9. Cultured Neuronal Networks Express Complex Patterns of Activity and Morphological Memory

    NASA Astrophysics Data System (ADS)

    Raichman, Nadav; Rubinsky, Liel; Shein, Mark; Baruchi, Itay; Volman, Vladislav; Ben-Jacob, Eshel

    The following sections are included: * Cultured Neuronal Networks * Recording the Network Activity * Network Engineering * The Formation of Synchronized Bursting Events * The Characterization of the SBEs * Highly-Active Neurons * Function-Form Relations in Cultured Networks * Analyzing the SBEs Motifs * Network Repertoire * Network under Hypothermia * Summary * Acknowledgments * References

  10. Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

    PubMed Central

    Lim, Sanghee; Kwak, Minhye; Gray, Christy D.; Xu, Michael; Choi, Jun H.; Junn, Sue; Kim, Jieun; Xu, Jing; Schaefer, Michele; Johns, Roger A.; Song, Hongjun; Ming, Guo-Li; Mintz, C. David

    2017-01-01

    Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. PMID:28683067

  11. Primary motor cortex of the parkinsonian monkey: altered encoding of active movement

    PubMed Central

    Pasquereau, Benjamin; DeLong, Mahlon R.

    2016-01-01

    Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson’s disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (−22%), speed (−40%), acceleration (−49%) and hand position (−33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (−50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes

  12. TorsinA dysfunction causes persistent neuronal nuclear pore defects.

    PubMed

    Pappas, Samuel S; Liang, Chun-Chi; Kim, Sumin; Rivera, CheyAnne O; Dauer, William T

    2018-02-01

    A critical challenge to deciphering the pathophysiology of neurodevelopmental disease is identifying which of the myriad abnormalities that emerge during CNS maturation persist to contribute to long-term brain dysfunction. Childhood-onset dystonia caused by a loss-of-function mutation in the AAA+ protein torsinA exemplifies this challenge. Neurons lacking torsinA develop transient nuclear envelope (NE) malformations during CNS maturation, but no NE defects are described in mature torsinA null neurons. We find that during postnatal CNS maturation torsinA null neurons develop mislocalized and dysfunctional nuclear pore complexes (NPC) that lack NUP358, normally added late in NPC biogenesis. SUN1, a torsinA-related molecule implicated in interphase NPC biogenesis, also exhibits localization abnormalities. Whereas SUN1 and associated nuclear membrane abnormalities resolve in juvenile mice, NPC defects persist into adulthood. These findings support a role for torsinA function in NPC biogenesis during neuronal maturation and implicate altered NPC function in dystonia pathophysiology. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. AMPK activation by Tanshinone IIA protects neuronal cells from oxygen-glucose deprivation

    PubMed Central

    Weng, Yingfeng; Lin, Jixian; Liu, Hui; Wu, Hui; Yan, Zhimin; Zhao, Jing

    2018-01-01

    The current study tested the potential neuroprotective function of Tanshinone IIA (ThIIA) in neuronal cells with oxygen-glucose deprivation (ODG) and re-oxygenation (OGDR). In SH-SY5Y neuronal cells and primary murine cortical neurons, ThIIA pre-treatment attenuated OGDR-induced viability reduction and apoptosis. Further, OGDR-induced mitochondrial depolarization, reactive oxygen species production, lipid peroxidation and DNA damages in neuronal cells were significantly attenuated by ThIIA. ThIIA activated AMP-activated protein kinase (AMPK) signaling, which was essential for neuroprotection against OGDR. AMPKα1 knockdown or complete knockout in SH-SY5Y cells abolished ThIIA-induced AMPK activation and neuroprotection against OGDR. Further studies found that ThIIA up-regulated microRNA-135b to downregulate the AMPK phosphatase Ppm1e. Notably, knockdown of Ppm1e by targeted shRNA or forced microRNA-135b expression also activated AMPK and protected SH-SY5Y cells from OGDR. Together, AMPK activation by ThIIA protects neuronal cells from OGDR. microRNA-135b-mediated silence of Ppm1e could be the key mechanism of AMPK activation by ThIIA. PMID:29435120

  14. Self-organization of synchronous activity propagation in neuronal networks driven by local excitation

    PubMed Central

    Bayati, Mehdi; Valizadeh, Alireza; Abbassian, Abdolhossein; Cheng, Sen

    2015-01-01

    Many experimental and theoretical studies have suggested that the reliable propagation of synchronous neural activity is crucial for neural information processing. The propagation of synchronous firing activity in so-called synfire chains has been studied extensively in feed-forward networks of spiking neurons. However, it remains unclear how such neural activity could emerge in recurrent neuronal networks through synaptic plasticity. In this study, we investigate whether local excitation, i.e., neurons that fire at a higher frequency than the other, spontaneously active neurons in the network, can shape a network to allow for synchronous activity propagation. We use two-dimensional, locally connected and heterogeneous neuronal networks with spike-timing dependent plasticity (STDP). We find that, in our model, local excitation drives profound network changes within seconds. In the emergent network, neural activity propagates synchronously through the network. This activity originates from the site of the local excitation and propagates through the network. The synchronous activity propagation persists, even when the local excitation is removed, since it derives from the synaptic weight matrix. Importantly, once this connectivity is established it remains stable even in the presence of spontaneous activity. Our results suggest that synfire-chain-like activity can emerge in a relatively simple way in realistic neural networks by locally exciting the desired origin of the neuronal sequence. PMID:26089794

  15. Neuronal activity determines distinct gliotransmitter release from a single astrocyte

    PubMed Central

    Covelo, Ana

    2018-01-01

    Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses. PMID:29380725

  16. Human Temporal Cortical Single Neuron Activity During Working Memory Maintenance

    PubMed Central

    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

  17. Modeling schizophrenia using hiPSC neurons

    PubMed Central

    Brennand, Kristen; Simone, Anthony; Jou, Jessica; Gelboin-Burkhart, Chelsea; Tran, Ngoc; Sangar, Sarah; Li, Yan; Mu, Yangling; Chen, Gong; Yu, Diana; McCarthy, Shane; Sebat, Jonathan; Gage, Fred H.

    2012-01-01

    SUMMARY Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%1. Though postmortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue2 and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD3, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (SI Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cAMP and WNT signaling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic Loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood4–6. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder (SI Table 1). PMID:21490598

  18. Dynamic synchronization of ongoing neuronal activity across spinal segments regulates sensory information flow

    PubMed Central

    Contreras-Hernández, E; Chávez, D; Rudomin, P

    2015-01-01

    Previous studies on the correlation between spontaneous cord dorsum potentials recorded in the lumbar spinal segments of anaesthetized cats suggested the operation of a population of dorsal horn neurones that modulates, in a differential manner, transmission along pathways mediating Ib non-reciprocal postsynaptic inhibition and pathways mediating primary afferent depolarization and presynaptic inhibition. In order to gain further insight into the possible neuronal mechanisms that underlie this process, we have measured changes in the correlation between the spontaneous activity of individual dorsal horn neurones and the cord dorsum potentials associated with intermittent activation of these inhibitory pathways. We found that high levels of neuronal synchronization within the dorsal horn are associated with states of incremented activity along the pathways mediating presynaptic inhibition relative to pathways mediating Ib postsynaptic inhibition. It is suggested that ongoing changes in the patterns of functional connectivity within a distributed ensemble of dorsal horn neurones play a relevant role in the state-dependent modulation of impulse transmission along inhibitory pathways, among them those involved in the central control of sensory information. This feature would allow the same neuronal network to be involved in different functional tasks. Key points We have examined, in the spinal cord of the anaesthetized cat, the relationship between ongoing correlated fluctuations of dorsal horn neuronal activity and state-dependent activation of inhibitory reflex pathways. We found that high levels of synchronization between the spontaneous activity of dorsal horn neurones occur in association with the preferential activation of spinal pathways leading to primary afferent depolarization and presynaptic inhibition relative to activation of pathways mediating Ib postsynaptic inhibition. It is suggested that changes in synchronization of ongoing activity within a

  19. Delay activity of saccade-related neurons in the caudal dentate nucleus of the macaque cerebellum

    PubMed Central

    Sommer, Marc A.

    2013-01-01

    The caudal dentate nucleus (DN) in lateral cerebellum is connected with two visual/oculomotor areas of the cerebrum: the frontal eye field and lateral intraparietal cortex. Many neurons in frontal eye field and lateral intraparietal cortex produce “delay activity” between stimulus and response that correlates with processes such as motor planning. Our hypothesis was that caudal DN neurons would have prominent delay activity as well. From lesion studies, we predicted that this activity would be related to self-timing, i.e., the triggering of saccades based on the internal monitoring of time. We recorded from neurons in the caudal DN of monkeys (Macaca mulatta) that made delayed saccades with or without a self-timing requirement. Most (84%) of the caudal DN neurons had delay activity. These neurons conveyed at least three types of information. First, their activity was often correlated, trial by trial, with saccade initiation. Correlations were found more frequently in a task that required self-timing of saccades (53% of neurons) than in a task that did not (27% of neurons). Second, the delay activity was often tuned for saccade direction (in 65% of neurons). This tuning emerged continuously during a trial. Third, the time course of delay activity associated with self-timed saccades differed significantly from that associated with visually guided saccades (in 71% of neurons). A minority of neurons had sensory-related activity. None had presaccadic bursts, in contrast to DN neurons recorded more rostrally. We conclude that caudal DN neurons convey saccade-related delay activity that may contribute to the motor preparation of when and where to move. PMID:23365182

  20. Effect of light on the activity of motor cortex neurons during locomotion

    PubMed Central

    Armer, Madison C.; Nilaweera, Wijitha U.; Rivers, Trevor J.; Dasgupta, Namrata M.; Beloozerova, Irina N.

    2013-01-01

    The motor cortex plays a critical role in accurate visually guided movements such as reaching and target stepping. However, the manner in which vision influences the movement-related activity of neurons in the motor cortex is not well understood. In this study we have investigated how the locomotion-related activity of neurons in the motor cortex is modified when subjects switch between walking in the darkness and in light. Three adult cats were trained to walk through corridors of an experimental chamber for a food reward. On randomly selected trials, lights were extinguished for approximately four seconds when the cat was in a straight portion of the chamber's corridor. Discharges of 146 neurons from layer V of the motor cortex, including 51 pyramidal tract cells (PTNs), were recorded and compared between light and dark conditions. It was found that while cats’ movements during locomotion in light and darkness were similar (as judged from the analysis of three-dimensional limb kinematics and the activity of limb muscles), the firing behavior of 49% (71/146) of neurons was different between the two walking conditions. This included differences in the mean discharge rate (19%, 28/146 of neurons), depth of stride-related frequency modulation (24%, 32/131), duration of the period of elevated firing ([PEF], 19%, 25/131), and number of PEFs among stride-related neurons (26%, 34/131). 20% of responding neurons exhibited more than one type of change. We conclude that visual input plays a very significant role in determining neuronal activity in the motor cortex during locomotion by altering one, or occasionally multiple, parameters of locomotion-related discharges of its neurons. PMID:23680161

  1. Non-chemosensitive parafacial neurons simultaneously regulate active expiration and airway patency under hypercapnia in rats.

    PubMed

    de Britto, Alan A; Moraes, Davi J A

    2017-03-15

    Hypercapnia or parafacial respiratory group (pFRG) disinhibition at normocapnia evokes active expiration in rats by recruitment of pFRG late-expiratory (late-E) neurons. We show that hypercapnia simultaneously evoked active expiration and exaggerated glottal dilatation by late-E synaptic excitation of abdominal, hypoglossal and laryngeal motoneurons. Simultaneous rhythmic expiratory activity in previously silent pFRG late-E neurons, which did not express the marker of ventral medullary CO 2 -sensitive neurons (transcription factor Phox2b), was also evoked by hypercapnia. Hypercapnia-evoked active expiration, neural and neuronal late-E activities were eliminated by pFRG inhibition, but not after blockade of synaptic excitation. Hypercapnia produces disinhibition of non-chemosensitive pFRG late-E neurons to evoke active expiration and concomitant cranial motor respiratory responses controlling the oropharyngeal and upper airway patency. Hypercapnia produces active expiration in rats and the recruitment of late-expiratory (late-E) neurons located in the parafacial respiratory group (pFRG) of the ventral medullary brainstem. We tested the hypothesis that hypercapnia produces active expiration and concomitant cranial respiratory motor responses controlling the oropharyngeal and upper airway patency by disinhibition of pFRG late-E neurons, but not via synaptic excitation. Phrenic nerve, abdominal nerve (AbN), cranial respiratory motor nerves, subglottal pressure, and medullary and spinal neurons/motoneurons were recorded in in situ preparations of juvenile rats. Hypercapnia evoked AbN active expiration, exaggerated late-E discharges in cranial respiratory motor outflows, and glottal dilatation via late-E synaptic excitation of abdominal, hypoglossal and laryngeal motoneurons. Simultaneous rhythmic late-E activity in previously silent pFRG neurons, which did not express the marker of ventral medullary CO 2 -sensitive neurons (transcription factor Phox2b), was also evoked

  2. Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity.

    PubMed

    Unal, Gunes; Crump, Michael G; Viney, Tim J; Éltes, Tímea; Katona, Linda; Klausberger, Thomas; Somogyi, Peter

    2018-03-03

    Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

  3. Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures.

    PubMed

    Lantoine, Joséphine; Grevesse, Thomas; Villers, Agnès; Delhaye, Geoffrey; Mestdagh, Camille; Versaevel, Marie; Mohammed, Danahe; Bruyère, Céline; Alaimo, Laura; Lacour, Stéphanie P; Ris, Laurence; Gabriele, Sylvain

    2016-05-01

    The ability to construct easily in vitro networks of primary neurons organized with imposed topologies is required for neural tissue engineering as well as for the development of neuronal interfaces with desirable characteristics. However, accumulating evidence suggests that the mechanical properties of the culture matrix can modulate important neuronal functions such as growth, extension, branching and activity. Here we designed robust and reproducible laminin-polylysine grid micropatterns on cell culture substrates that have similar biochemical properties but a 100-fold difference in Young's modulus to investigate the role of the matrix rigidity on the formation and activity of cortical neuronal networks. We found that cell bodies of primary cortical neurons gradually accumulate in circular islands, whereas axonal extensions spread on linear tracks to connect circular islands. Our findings indicate that migration of cortical neurons is enhanced on soft substrates, leading to a faster formation of neuronal networks. Furthermore, the pre-synaptic density was two times higher on stiff substrates and consistently the number of action potentials and miniature synaptic currents was enhanced on stiff substrates. Taken together, our results provide compelling evidence to indicate that matrix stiffness is a key parameter to modulate the growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks, thus providing useful information on scaffold design for neural tissue engineering. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model

    PubMed Central

    Nakao, Kazuhito; Nakazawa, Kazu

    2014-01-01

    In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20 s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The “paradoxically” high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception. PMID:25018691

  5. Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis

    PubMed Central

    Alshikho, Mohamad J.; Zürcher, Nicole R.; Loggia, Marco L.; Cernasov, Paul; Chonde, Daniel B.; Izquierdo Garcia, David; Yasek, Julia E.; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce R.; Cudkowicz, Merit E.

    2016-01-01

    Objective: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Methods: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. Results: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = −0.68, p < 0.05) and cortical thickness (r = −0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = −0.77, p < 0.05), and cortical thickness (r = −0.75, p < 0.05) in the motor cortex. Conclusions: Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS. PMID:27837005

  6. ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons

    PubMed Central

    Noh, Kyung-Min; Zhao, Dan; Xiang, Bin; Wenderski, Wendy; Lewis, Peter W.; Shen, Li; Li, Haitao; Allis, C. David

    2015-01-01

    ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of “repressive” histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX’s ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this “methyl/phos” switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction. PMID:25538301

  7. ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons.

    PubMed

    Noh, Kyung-Min; Maze, Ian; Zhao, Dan; Xiang, Bin; Wenderski, Wendy; Lewis, Peter W; Shen, Li; Li, Haitao; Allis, C David

    2015-06-02

    ATRX (the alpha thalassemia/mental retardation syndrome X-linked protein) is a member of the switch2/sucrose nonfermentable2 (SWI2/SNF2) family of chromatin-remodeling proteins and primarily functions at heterochromatic loci via its recognition of "repressive" histone modifications [e.g., histone H3 lysine 9 tri-methylation (H3K9me3)]. Despite significant roles for ATRX during normal neural development, as well as its relationship to human disease, ATRX function in the central nervous system is not well understood. Here, we describe ATRX's ability to recognize an activity-dependent combinatorial histone modification, histone H3 lysine 9 tri-methylation/serine 10 phosphorylation (H3K9me3S10ph), in postmitotic neurons. In neurons, this "methyl/phos" switch occurs exclusively after periods of stimulation and is highly enriched at heterochromatic repeats associated with centromeres. Using a multifaceted approach, we reveal that H3K9me3S10ph-bound Atrx represses noncoding transcription of centromeric minor satellite sequences during instances of heightened activity. Our results indicate an essential interaction between ATRX and a previously uncharacterized histone modification in the central nervous system and suggest a potential role for abnormal repetitive element transcription in pathological states manifested by ATRX dysfunction.

  8. Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration.

    PubMed

    Lin, Tiffany V; Hsieh, Lawrence; Kimura, Tomoki; Malone, Taylor J; Bordey, Angélique

    2016-10-04

    Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity. Importantly, we found that decreasing cap-dependent translation by expressing a constitutively active mutant of the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) prevents neuronal misplacement and soma enlargement, while partially rescuing dendritic hypertrophy induced by hyperactive mTORC1. Furthermore, overactivation of translation alone through knockdown of 4E-BP2 was sufficient to induce neuronal misplacement. These data show that many aspects of abnormal brain cytoarchitecture can be prevented by manipulating a single intracellular process downstream of mTORC1, cap-dependent translation.

  9. Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation.

    PubMed

    Xie, Zhi; Ding, Sheng-quan; Shen, Ya-fang

    2014-11-14

    In this study, we explored the cytoprotective potential of silibinin against oxygen-glucose deprivation (OGD)-induced neuronal cell damages, and studied underling mechanisms. In vitro model of ischemic stroke was created by keeping neuronal cells (SH-SY5Y cells and primary mouse cortical neurons) in an OGD condition followed by re-oxygenation. Pre-treatment of silibinin significantly inhibited OGD/re-oxygenation-induced necrosis and apoptosis of neuronal cells. OGD/re-oxygenation-induced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) reduction were also inhibited by silibinin. At the molecular level, silibinin treatment in SH-SY5Y cells and primary cortical neurons led to significant AMP-activated protein kinase (AMPK) signaling activation, detected by phosphorylations of AMPKα1, its upstream kinase liver kinase B1 (LKB1) and the downstream target acetyl-CoA Carboxylase (ACC). Pharmacological inhibition or genetic depletion of AMPK alleviated the neuroprotective ability of silibinin against OGD/re-oxygenation. Further, ROS scavenging ability by silibinin was abolished with AMPK inhibition or silencing. While A-769662, the AMPK activator, mimicked silibinin actions and suppressed ROS production and neuronal cell death following OGD/re-oxygenation. Together, these results show that silibinin-mediated neuroprotection requires activation of AMPK signaling. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons.

    PubMed

    Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

    2017-01-01

    The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K + channel modulators.

  11. Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons

    PubMed Central

    Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

    2017-01-01

    The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K+ channel modulators. PMID:29311835

  12. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons

    PubMed Central

    Wang, W.; Wildes, C. P.; Pattarabanjird, T.; Sanchez, M. I.; Glober, G.F.; Matthews, G. A.; Tye, K. M.; Ting, A. Y

    2017-01-01

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically-encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally-applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high-to-low calcium signal ratio of 10 after 10 minutes of stimulation. Channelrhodopsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium. PMID:28650461

  13. A light- and calcium-gated transcription factor for imaging and manipulating activated neurons.

    PubMed

    Wang, Wenjing; Wildes, Craig P; Pattarabanjird, Tanyaporn; Sanchez, Mateo I; Glober, Gordon F; Matthews, Gillian A; Tye, Kay M; Ting, Alice Y

    2017-09-01

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high- to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium.

  14. Vasoactive intestinal peptide and electrical activity influence neuronal survival

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Brenneman, D.E.; Eiden, L.E.

    1986-02-01

    Blockage of electrical activity in dissociated spinal cord cultures results in a significant loss of neurons during a critical period in development. Decreases in neuronal cell numbers and SVI-labeled tetanus toxin fixation produced by electrical blockage with tetrodotoxin (TTX) were prevented by addition of vasoactive intestinal peptide (VIP) to the nutrient medium. The most effective concentration of VIP was 0.1 nM. At higher concentrations, the survival-enhancing effect of VIP on TTX-treated cultures was attenuated. Addition of the peptide alone had no significant effect on neuronal cell counts or tetanus toxin fixation. With the same experimental conditions, two closely related peptides,more » PHI-27 (peptide, histidyl-isoleucine amide) and secretin, were found not to increase the number of neurons in TTX-treated cultures. Interference with VIP action by VIP antiserum resulted in neuronal losses that were not significantly different from those observed after TTX treatment. These data indicate that under conditions of electrical blockade a neurotrophic action of VIP on neuronal survival can be demonstrated.« less

  15. Post-movement beta rebound abnormality as indicator of mirror neuron system dysfunction in autistic spectrum disorder: an MEG study.

    PubMed

    Honaga, Eiko; Ishii, Ryouhei; Kurimoto, Ryu; Canuet, Leonides; Ikezawa, Koji; Takahashi, Hidetoshi; Nakahachi, Takayuki; Iwase, Masao; Mizuta, Ichiro; Yoshimine, Toshiki; Takeda, Masatoshi

    2010-07-12

    The mu rhythm is regarded as a physiological indicator of the human mirror neuron system (MNS). The dysfunctional MNS hypothesis in patients with autistic spectrum disorder (ASD) has often been tested using EEG and MEG, targeting mu rhythm suppression during action observation/execution, although with controversial results. We explored neural activity related to the MNS in patients with ASD, focusing on power increase in the beta frequency band after observation and execution of movements, known as post-movement beta rebound (PMBR). Multiple source beamformer (MSBF) and BrainVoyager QX were used for MEG source imaging and statistical group analysis, respectively. Seven patients with ASD and ten normal subjects participated in this study. During the MEG recordings, the subjects were asked to observe and later execute object-related hand actions performed by an experimenter. We found that both groups exhibited pronounced PMBR exceeding 20% when observing and executing actions with a similar topographic distribution of maximal activity. However, significantly reduced PMBR was found only during the observation condition in the patients relative to controls in cortical regions within the MNS, namely the sensorimotor area, premotor cortex and superior temporal gyrus. Reduced PMBR during the observation condition was also found in the medial prefrontal cortex. These results support the notion of a dysfunctional execution/observation matching system related to MNS impairment in patients with ASD, and the feasibility of using MEG to detect neural activity, in particular PMBR abnormalities, as an index of MNS dysfunction during performance of motor or cognitive tasks. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  16. Effect of light on the activity of motor cortex neurons during locomotion.

    PubMed

    Armer, Madison C; Nilaweera, Wijitha U; Rivers, Trevor J; Dasgupta, Namrata M; Beloozerova, Irina N

    2013-08-01

    The motor cortex plays a critical role in accurate visually guided movements such as reaching and target stepping. However, the manner in which vision influences the movement-related activity of neurons in the motor cortex is not well understood. In this study we have investigated how the locomotion-related activity of neurons in the motor cortex is modified when subjects switch between walking in the darkness and in light. Three adult cats were trained to walk through corridors of an experimental chamber for a food reward. On randomly selected trials, lights were extinguished for approximately 4s when the cat was in a straight portion of the chamber's corridor. Discharges of 146 neurons from layer V of the motor cortex, including 51 pyramidal tract cells (PTNs), were recorded and compared between light and dark conditions. It was found that while cats' movements during locomotion in light and darkness were similar (as judged from the analysis of three-dimensional limb kinematics and the activity of limb muscles), the firing behavior of 49% (71/146) of neurons was different between the two walking conditions. This included differences in the mean discharge rate (19%, 28/146 of neurons), depth of stride-related frequency modulation (24%, 32/131), duration of the period of elevated firing ([PEF], 19%, 25/131), and number of PEFs among stride-related neurons (26%, 34/131). 20% of responding neurons exhibited more than one type of change. We conclude that visual input plays a very significant role in determining neuronal activity in the motor cortex during locomotion by altering one, or occasionally multiple, parameters of locomotion-related discharges of its neurons. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Neuronal activity in ontogeny and oncology

    PubMed Central

    Venkatesh, Humsa; Monje, Michelle

    2017-01-01

    The nervous system plays a central role in regulating the stem cell niche in many organs and thereby critically modulates development, homeostasis and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. Here, we review what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues and discuss emerging principles of neural regulation of development and cancer. PMID:28718448

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

    PubMed Central

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

    2016-01-01

    The larval brain of Drosophila melanogaster provides an excellent system for the study of the neurocircuitry mechanism of memory. Recent development of neurogenetic techniques in fruit flies enables manipulations of neuronal activities in freely behaving animals. This protocol describes detailed steps for artificial induction of olfactory associative memory in Drosophila larvae. In this protocol, the natural reward signal is substituted by thermogenetic activation of octopaminergic neurons in the brain. In parallel, the odor signal is substituted by optogenetic activation of a specific class of olfactory receptor neurons. Association of reward and odor stimuli is achieved with the concomitant application of blue light and heat that leads to activation of both sets of neurons in living transgenic larvae. Given its operational simplicity and robustness, this method could be utilized to further our knowledge on the neurocircuitry mechanism of memory in the fly brain. PMID:27445732

  19. Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia.

    PubMed

    Kita, Hitoshi; Kita, Takako

    2011-07-13

    The motor cortex (MC) sends massive projections to the basal ganglia. Motor disabilities in patients and animal models of Parkinson's disease (PD) may be caused by dopamine (DA)-depleted basal ganglia that abnormally process the information originating from MC. To study how DA depletion alters signal transfer in the basal ganglia, MC stimulation-induced (MC-induced) unitary responses were recorded from the basal ganglia of control and 6-hydroxydopamine-treated hemi-parkinsonian rats anesthetized with isoflurane. This report describes new findings about how DA depletion alters MC-induced responses. MC stimulation evokes an excitation in normally quiescent striatal (Str) neurons projecting to the globus pallidus external segment (GPe). After DA-depletion, the spontaneous firing of Str-GPe neurons increases, and MC stimulation evokes a shorter latency excitation followed by a long-lasting inhibition that was invisible under normal conditions. The increased firing activity and the newly exposed long inhibition generate tonic inhibition and a disfacilitation in GPe. The disfacilitation in GPe is then amplified in basal ganglia circuitry and generates a powerful long inhibition in the basal ganglia output nucleus, the globus pallidus internal segment. Intra-Str injections of a behaviorally effective dose of DA precursor l-3,4-dihydroxyphenylalanine effectively reversed these changes. These newly observed mechanisms also support the generation of pauses and burst activity commonly observed in the basal ganglia of parkinsonian subjects. These results suggest that the generation of abnormal response sequences in the basal ganglia contributes to the development of motor disabilities in PD and that intra-Str DA supplements effectively suppress abnormal signal transfer.

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

    PubMed Central

    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

  1. Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus

    PubMed Central

    Chali, Farah; Djelti, Fathia; Eugene, Emmanuel; Valderrama, Mario; Marquer, Catherine; Aubourg, Patrick; Duykaerts, Charles; Miles, Richard; Cartier, Nathalie; Navarro, Vincent

    2015-01-01

    Elevations in neuronal cholesterol have been associated with several degenerative diseases. An enhanced excitability and synchronous firing in surviving neurons are among the sequels of neuronal death in these diseases and also in some epileptic syndromes. Here, we attempted to increase neuronal cholesterol levels, using a short hairpin RNA (shRNA) to suppress expression of the enzyme CYP46A1. This protein hydroxylates cholesterol and so facilitates trans-membrane extrusion. A sh-RNA CYP46A1construction coupled to an adeno-associated virus (AAV5) was injected focally and unilaterally into mouse hippocampus. It was selectively expressed first in neurons of the CA3a region. Cytoplasmic and membrane cholesterol increased, neuronal soma volume increased and then decreased before pyramidal cells died. As CA3a pyramidal cells died, inter-ictal EEG events occurred during exploration and non-REM sleep. With time, neuronal death spread to involve pyramidal cells and interneurons of the CA1 region. CA1 neuronal death was correlated with a delayed local expression of phosphorylated tau. Astrocytes were activated throughout the hippocampus and microglial activation was specific to regions of neuronal death. CA1 neuronal death was correlated with distinct aberrant EEG activity. During exploratory behaviour and rapid eye movement sleep, EEG oscillations at 7-10 Hz (theta) could accelerate to 14-21 Hz (beta) waves. They were accompanied by low amplitude, high-frequency oscillations of peak power at ~300Hz and a range of 250-350 Hz. While episodes of EEG acceleration were not correlated with changes in exploratory behaviour, they were followed in some animals by structured seizure-like discharges. These data strengthen links between increased cholesterol, neuronal sclerosis and epileptic behavior PMID:25847620

  2. Peptidergic Agonists of Activity-Dependent Neurotrophic Factor Protect Against Prenatal Alcohol-Induced Neural Tube Defects and Serotonin Neuron Loss

    PubMed Central

    Zhou, Feng C.; Fang, Yuan; Goodlett, Charles

    2009-01-01

    Introduction Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development. Methods Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe. Results Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in

  3. Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner.

    PubMed

    Mitew, Stanislaw; Gobius, Ilan; Fenlon, Laura R; McDougall, Stuart J; Hawkes, David; Xing, Yao Lulu; Bujalka, Helena; Gundlach, Andrew L; Richards, Linda J; Kilpatrick, Trevor J; Merson, Tobias D; Emery, Ben

    2018-01-22

    Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear. Here we demonstrate that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons display an increased probability of being myelinated compared to neighboring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing reduces axonal myelination in a selective activity-dependent manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.

  4. Inward rectifier potassium current IKir promotes intrinsic pacemaker activity of thalamocortical neurons.

    PubMed

    Amarillo, Yimy; Tissone, Angela I; Mato, Germán; Nadal, Marcela S

    2018-06-01

    Slow repetitive burst firing by hyperpolarized thalamocortical (TC) neurons correlates with global slow rhythms (<4 Hz), which are the physiological oscillations during non-rapid eye movement sleep or pathological oscillations during idiopathic epilepsy. The pacemaker activity of TC neurons depends on the expression of several subthreshold conductances, which are modulated in a behaviorally dependent manner. Here we show that upregulation of the small and neglected inward rectifier potassium current I Kir induces repetitive burst firing at slow and delta frequency bands. We demonstrate this in mouse TC neurons in brain slices by manipulating the Kir maximum conductance with dynamic clamp. We also performed a thorough theoretical analysis that explains how the unique properties of I Kir enable this current to induce slow periodic bursting in TC neurons. We describe a new ionic mechanism based on the voltage- and time-dependent interaction of I Kir and hyperpolarization-activated cationic current I h that endows TC neurons with the ability to oscillate spontaneously at very low frequencies, even below 0.5 Hz. Bifurcation analysis of conductance-based models of increasing complexity demonstrates that I Kir induces bistability of the membrane potential at the same time that it induces sustained oscillations in combination with I h and increases the robustness of low threshold-activated calcium current I T -mediated oscillations. NEW & NOTEWORTHY The strong inwardly rectifying potassium current I Kir of thalamocortical neurons displays a region of negative slope conductance in the current-voltage relationship that generates potassium currents activated by hyperpolarization. Bifurcation analysis shows that I Kir induces bistability of the membrane potential; generates sustained subthreshold oscillations by interacting with the hyperpolarization-activated cationic current I h ; and increases the robustness of oscillations mediated by the low threshold-activated calcium

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

    PubMed

    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

  6. Ran-dependent TPX2 activation promotes acentrosomal microtubule nucleation in neurons

    PubMed Central

    Chen, Wen-Shin; Chen, Yi-Ju; Huang, Yung-An; Hsieh, Bing-Yuan; Chiu, Ho-Chieh; Kao, Pei-Ying; Chao, Chih-Yuan; Hwang, Eric

    2017-01-01

    The microtubule (MT) cytoskeleton is essential for the formation of morphologically appropriate neurons. The existence of the acentrosomal MT organizing center in neurons has been proposed but its identity remained elusive. Here we provide evidence showing that TPX2 is an important component of this acentrosomal MT organizing center. First, neurite elongation is compromised in TPX2-depleted neurons. In addition, TPX2 localizes to the centrosome and along the neurite shaft bound to MTs. Depleting TPX2 decreases MT formation frequency specifically at the tip and the base of the neurite, and these correlate precisely with the regions where active GTP-bound Ran proteins are enriched. Furthermore, overexpressing the downstream effector of Ran, importin, compromises MT formation and neuronal morphogenesis. Finally, applying a Ran-importin signaling interfering compound phenocopies the effect of TPX2 depletion on MT dynamics. Together, these data suggest a model in which Ran-dependent TPX2 activation promotes acentrosomal MT nucleation in neurons. PMID:28205572

  7. Optogenetic Activation of Zebrafish Somatosensory Neurons using ChEF-tdTomato

    PubMed Central

    Palanca, Ana Marie S.; Sagasti, Alvaro

    2013-01-01

    Larval zebrafish are emerging as a model for describing the development and function of simple neural circuits. Due to their external fertilization, rapid development, and translucency, zebrafish are particularly well suited for optogenetic approaches to investigate neural circuit function. In this approach, light-sensitive ion channels are expressed in specific neurons, enabling the experimenter to activate or inhibit them at will and thus assess their contribution to specific behaviors. Applying these methods in larval zebrafish is conceptually simple but requires the optimization of technical details. Here we demonstrate a procedure for expressing a channelrhodopsin variant in larval zebrafish somatosensory neurons, photo-activating single cells, and recording the resulting behaviors. By introducing a few modifications to previously established methods, this approach could be used to elicit behavioral responses from single neurons activated up to at least 4 days post-fertilization (dpf). Specifically, we created a transgene using a somatosensory neuron enhancer, CREST3, to drive the expression of the tagged channelrhodopsin variant, ChEF-tdTomato. Injecting this transgene into 1-cell stage embryos results in mosaic expression in somatosensory neurons, which can be imaged with confocal microscopy. Illuminating identified cells in these animals with light from a 473 nm DPSS laser, guided through a fiber optic cable, elicits behaviors that can be recorded with a high-speed video camera and analyzed quantitatively. This technique could be adapted to study behaviors elicited by activating any zebrafish neuron. Combining this approach with genetic or pharmacological perturbations will be a powerful way to investigate circuit formation and function. PMID:23407374

  8. The interplay of microRNA and neuronal activity in health and disease

    PubMed Central

    Eacker, Stephen M.; Dawson, Ted M.; Dawson, Valina L.

    2013-01-01

    MicroRNAs (miRNAs) are small 19–23 nucleotide regulatory RNAs that function by modulating mRNA translation and/or turnover in a sequence-specific fashion. In the nervous system, miRNAs regulate the production of numerous proteins involved in synaptic transmission. In turn, neuronal activity can regulate the production and turnover of miRNA through a variety of mechanisms. In this way, miRNAs and neuronal activity are in a reciprocal homeostatic relationship that balances neuronal function. The miRNA function is critical in pathological states related to overexcitation such as epilepsy and stroke, suggesting miRNA’s potential as a therapeutic target. We review the current literature relating the interplay of miRNA and neuronal activity and provide future directions for defining miRNA’s role in disease. PMID:23986658

  9. PhotoMEA: an opto-electronic biosensor for monitoring in vitro neuronal network activity.

    PubMed

    Ghezzi, Diego; Pedrocchi, Alessandra; Menegon, Andrea; Mantero, Sara; Valtorta, Flavia; Ferrigno, Giancarlo

    2007-02-01

    PhotoMEA is a biosensor useful for the analysis of an in vitro neuronal network, fully based on optical methods. Its function is based on the stimulation of neurons with caged glutamate and the recording of neuronal activity by Voltage-Sensitive fluorescent Dyes (VSD). The main advantage is that it will be possible to stimulate even at sub-single neuron level and to record with high resolution the activity of the entire network in the culture. A large-scale view of neuronal intercommunications offers a unique opportunity for testing the ability of drugs to affect neuronal properties as well as alterations in the behaviour of the entire network. The concept and a prototype for validation is described here in detail.

  10. Patterns of fast synaptic cholinergic activation of neurons in the celiac ganglia of cats.

    PubMed

    Niel, J P; Clerc, N; Jule, Y

    1988-12-01

    Fast nicotinic transmission was studied in vitro in neurons of isolated cat celiac ganglia. In the absence of nerve stimulation, neurons could be classified into three types: silent neurons, synaptically activated neurons, and spontaneously discharging neurons. In all three types, fast synaptic activation could be obtained in single neurons by stimulating with a single pulse both the splanchnic nerves or one of the peripheral nerves connected to the ganglia. During repetitive nerve stimulation, a gradual depression of the central and peripheral fast nicotinic activation occurred, which was not affected by phentolamine plus propranolol, domperidone, atropine, or naloxone. Repetitive nerve stimulation was followed by a long lasting discharge of excitatory postsynaptic potentials and action potentials that decreased gradually with time. This discharge, which was probably due to presynaptic or prejunctional facilitation of acetylcholine release from cholinergic terminals, was reduced by the application of phentolamine plus propranolol, domperidone, or atropine and increased with naloxone. The existence of the mechanisms described in this study reflects the complexity of the integrative processes at work in neurons of the cat celiac ganglia that involve fast synaptic cholinergic activation.

  11. Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

    PubMed Central

    Pierrot, Nathalie; Tyteca, Donatienne; D'auria, Ludovic; Dewachter, Ilse; Gailly, Philippe; Hendrickx, Aurélie; Tasiaux, Bernadette; Haylani, Laetitia El; Muls, Nathalie; N'Kuli, Francisca; Laquerrière, Annie; Demoulin, Jean-Baptiste; Campion, Dominique; Brion, Jean-Pierre; Courtoy, Pierre J; Kienlen-Campard, Pascal; Octave, Jean-Noël

    2013-01-01

    Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity. PMID:23554170

  12. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    PubMed Central

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  13. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation

    PubMed Central

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J.

    2016-01-01

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1–D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated. PMID:27337658

  14. Glutamine-mediated protection from neuronal cell death depends on mitochondrial activity.

    PubMed

    Stelmashook, E V; Lozier, E R; Goryacheva, E S; Mergenthaler, P; Novikova, S V; Zorov, D B; Isaev, N K

    2010-09-27

    The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  15. Varenicline and Abnormal Sleep Related Events

    PubMed Central

    Savage, Ruth L.; Zekarias, Alem; Caduff-Janosa, Pia

    2015-01-01

    Study Objectives: To assess adverse drug reaction reports of “abnormal sleep related events” associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. Design: Twenty-seven reports of “abnormal sleep related events” often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. Measurements and Results: These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. Conclusions: The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events. Citation: Savage RL, Zekarias A, Caduff-Janosa P. Varenicline and abnormal sleep related events. SLEEP 2015

  16. Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons

    PubMed Central

    Kirschen, Gregory W.; Shen, Jia; Wang, Jia; Man, Guoming; Wu, Song

    2017-01-01

    The continuous addition of new dentate granule cells (DGCs), which is regulated exquisitely by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to affect the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca2+ imaging to track the real-time activity of individual DGCs in freely behaving mice. For the first time, we found that active DGCs responded to a novel experience by increasing their Ca2+ event frequency preferentially. This elevated activity, which we found to be associated with object exploration, returned to baseline by 1 h in the same environment, but could be dishabituated via introduction to a novel environment. To transition seamlessly between environments, we next established a freely controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences increased the number of newborn neurons accumulatively compared with a single experience. Finally, optogenetic silencing of existing DGCs during novel environmental exploration perturbed experience-induced neuronal addition. Our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active DGCs. SIGNIFICANCE STATEMENT Adult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca2+ imaging of dentate granule neurons with a novel, unrestrained virtual reality system for rodents, we discovered that a new experience increased firing of active dentate granule neurons rapidly and robustly

  17. Abnormal patterns of displacement activities: a review and reinterpretation.

    PubMed

    Anselme, Patrick

    2008-09-01

    A series of important theoretical contributions flourished in the years 1950-1970 about displacement activities -- those 'out-of-context' actions expressed by organisms in stressful situations. Nothing really new has appeared thereafter. Although the models address different issues, such as causal factors of displacement, it appears obvious that they do not provide a unified (coherent) approach; they often explain the same phenomena using very different means and turn out to be contradictory on several points. In addition, some problems currently remain unsolved, especially concerning the fact that displacement activities exhibit 'abnormalities' of expression in comparison with the same activities performed in usual context. Each model is here described and criticized in order to evaluate its explanatory power and allow the identification of specific limits. A new, integrative model -- the Anticipatory Dynamics Model (or ADM) -- then attempts to overcome the failures of previous models. The ADM suggests that abnormal patterns of displacement activities result from attentional interference caused by a thwarting experience or conflicting motivations. At least one theoretical prediction of the ADM can be differentiated from that of any other model.

  18. Neuronal activity related to spontaneous and capsaicin-induced rhythmical jaw movements in the rat.

    PubMed

    Ohta, M; Sasamoto, K; Kobayashi, J

    1998-02-01

    Intraoral capsaicin induced rhythmical jaw movements (RJM) in anesthetized rats. Neurons in the trigeminal spinal nucleus caudalis or the cortico-peduncular (CP) axons were extracellularly recorded. Capsaicin excited dose-dependently most caudalis neurons, which were activated by stimulation of the oral cavity and/or the tooth pulp and activated during spontaneous or induced RJM. Ten of 55 CP axons were antidromically activated by stimulation of the contralateral trigeminal motor nucleus. All antidromic and 29 other CP axons discharged prior to the spontaneous RJM, but most of them did not during capsaicin-induced RJM. These neuronal activities possibly initiate spontaneous RJM although the activities of caudalis neurons are necessary for capsicin-induced RJM.

  19. Egalitarian reward contingency in competitive games and primate prefrontal neuronal activity.

    PubMed

    Hosokawa, Takayuki; Watanabe, Masataka

    2015-01-01

    How people work to obtain a reward depends on the context of the reward delivery, such as the presence/absence of competition and the contingency of reward delivery. Since resources are limited, winning a competition is critically important for organisms' obtaining a reward. People usually expect ordinary performance-reward contingency, with better performers obtaining better rewards. Unordinary reward contingency, such as egalitarianism (equal rewards/no-rewards to both good and poor performers), dampens people's motivation. We previously reported that monkeys were more motivated, and neurons in the lateral prefrontal cortex (LPFC) showed higher outcome-related activity in a competitive than in a noncompetitive game (Hosokawa and Watanabe, 2012). However, monkey's behavior and LPFC neuronal activity have not been examined in a competitive situation with an unordinary performance-reward contingency. Also, the fixed performance-reward contingency in the previous study did not allow us to examine effects of win/loss separately from those of reward/no-reward on prefrontal neuronal activity. Here, we employed the egalitarian competitive situation in which both the winner and loser, or neither of them, got a reward as well as the normal competitive situation in which only the winner got a reward. Monkey's behavioral performance greatly deteriorated in trials with the egalitarian outcome conditions. LPFC neurons showed activities that reflected the normal or egalitarian outcome condition while very few neurons coded win/loss independent of reward/no-reward. Importantly, we found neurons that showed reward-related activity in the normal, but not in the egalitarian outcome conditions, even though the same reward was given to the animal. These results indicate that LPFC may play an important role in monitoring the current reward contingency and integrating it with the performance outcome (win-loss) for better performing the competitive game, and thus for better survival.

  20. Neuron matters: electric activation of neuronal tissue is dependent on the interaction between the neuron and the electric field.

    PubMed

    Ye, Hui; Steiger, Amanda

    2015-08-12

    In laboratory research and clinical practice, externally-applied electric fields have been widely used to control neuronal activity. It is generally accepted that neuronal excitability is controlled by electric current that depolarizes or hyperpolarizes the excitable cell membrane. What determines the amount of polarization? Research on the mechanisms of electric stimulation focus on the optimal control of the field properties (frequency, amplitude, and direction of the electric currents) to improve stimulation outcomes. Emerging evidence from modeling and experimental studies support the existence of interactions between the targeted neurons and the externally-applied electric fields. With cell-field interaction, we suggest a two-way process. When a neuron is positioned inside an electric field, the electric field will induce a change in the resting membrane potential by superimposing an electrically-induced transmembrane potential (ITP). At the same time, the electric field can be perturbed and re-distributed by the cell. This cell-field interaction may play a significant role in the overall effects of stimulation. The redistributed field can cause secondary effects to neighboring cells by altering their geometrical pattern and amount of membrane polarization. Neurons excited by the externally-applied electric field can also affect neighboring cells by ephaptic interaction. Both aspects of the cell-field interaction depend on the biophysical properties of the neuronal tissue, including geometric (i.e., size, shape, orientation to the field) and electric (i.e., conductivity and dielectricity) attributes of the cells. The biophysical basis of the cell-field interaction can be explained by the electromagnetism theory. Further experimental and simulation studies on electric stimulation of neuronal tissue should consider the prospect of a cell-field interaction, and a better understanding of tissue inhomogeneity and anisotropy is needed to fully appreciate the neural

  1. Activation of oral trigeminal neurons by fatty acids is dependent upon intracellular calcium.

    PubMed

    Yu, Tian; Shah, Bhavik P; Hansen, Dane R; Park-York, MieJung; Gilbertson, Timothy A

    2012-08-01

    The chemoreception of dietary fat in the oral cavity has largely been attributed to activation of the somatosensory system that conveys the textural properties of fat. However, the ability of fatty acids, which are believed to represent the proximate stimulus for fat taste, to stimulate rat trigeminal neurons has remained unexplored. Here, we found that several free fatty acids are capable of activating trigeminal neurons with different kinetics. Further, a polyunsaturated fatty acid, linoleic acid (LA), activates trigeminal neurons by increasing intracellular calcium concentration and generating depolarizing receptor potentials. Ion substitution and pharmacological approaches reveal that intracellular calcium store depletion is crucial for LA-induced signaling in a subset of trigeminal neurons. Using pseudorabies virus (PrV) as a live cell tracer, we identified a subset of lingual nerve-innervated trigeminal neurons that respond to different subsets of fatty acids. Quantitative real-time PCR of several transient receptor potential channel markers in individual neurons validated that PrV labeled a subset but not the entire population of lingual-innervated trigeminal neurons. We further confirmed that the LA-induced intracellular calcium rise is exclusively coming from the release of calcium stores from the endoplasmic reticulum in this subset of lingual nerve-innervated trigeminal neurons.

  2. Activation of Oral Trigeminal Neurons by Fatty Acids is Dependent upon Intracellular Calcium

    PubMed Central

    Yu, Tian; Shah, Bhavik P.; Hansen, Dane R.; Park-York, MieJung; Gilbertson, Timothy A.

    2012-01-01

    The chemoreception of dietary fat in the oral cavity has largely been attributed to activation of the somatosensory system that conveys the textural properties of fat. However, the ability of fatty acids, which are believed to represent the proximate stimulus for fat taste, to stimulate rat trigeminal neurons has remained unexplored. Here, we found that several free fatty acids are capable of activating trigeminal neurons with different kinetics. Further, a polyunsaturated fatty acid, linoleic acid (LA), activates trigeminal neurons by increasing intracellular calcium concentration and generating depolarizing receptor potentials. Ion substitution and pharmacological approaches reveal that intracellular calcium store depletion is crucial for LA-induced signaling in a subset of trigeminal neurons. Using pseudorabies virus (PrV) as a live cell tracer, we identified a subset of lingual nerve-innervated trigeminal neurons that respond to different subsets of fatty acids. Quantitative real-time PCR of several transient receptor potential (TRP) channel markers in individual neurons validated that PrV labeled a subset but not the entire population of lingual-innervated trigeminal neurons. We further confirmed that the LA-induced intracellular calcium rise is exclusively coming from the release of calcium stores from the endoplasmic reticulum in this subset of lingual nerve-innervated trigeminal neurons. PMID:22644615

  3. Activation of hypothalamic RIP-Cre neurons promotes beiging of WAT via sympathetic nervous system.

    PubMed

    Wang, Baile; Li, Ang; Li, Xiaomu; Ho, Philip Wl; Wu, Donghai; Wang, Xiaoqi; Liu, Zhuohao; Wu, Kelvin Kl; Yau, Sonata Sy; Xu, Aimin; Cheng, Kenneth Ky

    2018-04-01

    Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat-insulin-promoter-Cre (RIP-Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT Genetic ablation of APPL2 in RIP-Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP-Cre neurons, inactivation of VMH AMPK, or treatment with a β3-adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP-Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP-Cre neurons, in which the APPL2-AMPK signaling axis is crucial for this defending mechanism to cold and obesity. © 2018 The Authors.

  4. Developmental and hormonal regulation of thermosensitive neuron potential activity in rat brain.

    PubMed

    Belugin, S; Akino, K; Takamura, N; Mine, M; Romanovsky, D; Fedoseev, V; Kubarko, A; Kosaka, M; Yamashita, S

    1999-08-01

    To understand the involvement of thyroid hormone on the postnatal development of hypothalamic thermosensitive neurons, we focused on the analysis of thermosensitive neuronal activity in the preoptic and anterior hypothalamic (PO/AH) regions of developing rats with and without hypothyroidism. In euthyroid rats, the distribution of thermosensitive neurons in PO/AH showed that in 3-week-old rats (46 neurons tested), 19.5% were warm-sensitive and 80.5% were nonsensitive. In 5- to 12-week-old euthyroid rats (122 neurons), 33.6% were warm-sensitive and 66.4% were nonsensitive. In 5- to 12-week-old hypothyroid rats (108 neurons), however, 18.5% were warm-sensitive and 81.5% were nonsensitive. Temperature thresholds of warm-sensitive neurons were lower in 12-week-old euthyroid rats (36.4+/-0.2 degrees C, n = 15, p<0.01,) than in 3-week-old and in 5-week-old euthyroid rats (38.5+/-0.5 degrees C, n = 9 and 38.0+/-0.3 degrees C, n = 15, respectively). The temperature thresholds of warm-sensitive neurons in 12-week-old hypothyroid rats (39.5+/-0.3 degrees C, n = 8) were similar to that of warm-sensitive neurons of 3-week-old raats (euthyroid and hypothyroid). In contrast, there was no difference in the thresholds of warm-sensitive neurons between hypothyroid and euthyroid rats at the age of 3-5 weeks. In conclusion, monitoring the thermosensitive neuronal tissue activity demonstrated the evidence that thyroid hormone regulates the maturation of warm-sensitive hypothalamic neurons in developing rat brain by electrophysiological analysis.

  5. Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

    PubMed Central

    Steinert, Joern R.; Robinson, Susan W.; Tong, Huaxia; Haustein, Martin D.; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D.

    2011-01-01

    Summary Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. PMID:21791288

  6. Hippocampal neuronal subtypes develop abnormal dendritic arbors in the presence of Fragile X astrocytes.

    PubMed

    Jacobs, S; Cheng, C; Doering, L C

    2016-06-02

    Astrocytes are now recognized as key players in the neurobiology of neurodevelopmental disorders such as Fragile X syndrome. However, the nature of Fragile X astrocyte-mediated control of dendrite development in subtypes of hippocampal neurons is not yet known. We used a co-culture procedure in which wildtype primary hippocampal neurons were cultured with astrocytes from either a wildtype or Fragile X mouse, for either 7, 14 or 21 days. The neurons were processed for immunocytochemistry with the dendritic marker MAP2, classified by morphological criteria into one of five neuronal subtypes, and subjected to Sholl analyses. Both linear and semi-log methods of Sholl analyses were applied to the neurons in order to provide an in depth analysis of the dendritic arborizations. We found that Fragile X astrocytes affect the development of dendritic arborization of all subtypes of wildtype hippocampal neurons. Furthermore, we show that hippocampal neurons with spiny stellate neuron morphology exhibit the most pervasive developmental delays, with significant dendritic arbor alterations persisting at 21 days in culture. The results further dictate the critical role astrocytes play in governing neuronal morphology including altered dendrite development in Fragile X. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

    PubMed Central

    Jolivet, Renaud; Coggan, Jay S.; Allaman, Igor; Magistretti, Pierre J.

    2015-01-01

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

  8. Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.

    PubMed

    Jolivet, Renaud; Coggan, Jay S; Allaman, Igor; Magistretti, Pierre J

    2015-02-01

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

  9. Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons

    PubMed Central

    Kraft, Andrew D.; Kaltenbach, Linda S.; Lo, Donald C.; Harry, G. Jean

    2011-01-01

    In Huntington's disease (HD), mutated huntingtin (mhtt) causes striatal neurodegeneration which is paralleled by elevated microglia cell numbers. In vitro cortico-striatal slice and primary neuronal culture models, in which neuronal expression of mhtt fragments drives HD-like neurotoxicity, were employed to examine wild type microglia during both the initiation and progression of neuronal pathology. As neuronal pathology progressed, microglia initially localized in the vicinity of neurons expressing mhtt fragments increased in number, demonstrated morphological evidence of activation, and expressed the proliferation marker, Ki67. These microglia were positioned along irregular neurites, but did not localize with mhtt inclusions nor exacerbate mhtt fragment-induced neurotoxicity. Prior to neuronal pathology, microglia upregulated Iba1, signaling a functional shift. With neurodegeneration, interleukin-6 and complement component 1q were increased. The results suggest a stimulatory, proliferative signal for microglia present at the onset of mhtt fragment-induced neurodegeneration. Thus, microglia effect a localized inflammatory response to neuronal mhtt expression that may serve to direct microglial removal of dysfunctional neurites or aberrant synapses, as is required for reparative actions in vivo. PMID:21482444

  10. Neuronal activity in somatosensory cortex related to tactile exploration

    PubMed Central

    Fortier-Poisson, Pascal

    2015-01-01

    The very light contact forces (∼0.60 N) applied by the fingertips during tactile exploration reveal a clearly optimized sensorimotor strategy. To investigate the cortical mechanisms involved with this behavior, we recorded 230 neurons in the somatosensory cortex (S1), as two monkeys scanned different surfaces with the fingertips in search of a tactile target without visual feedback. During the exploration, the monkeys, like humans, carefully controlled the finger forces. High-friction surfaces offering greater tangential shear force resistance to the skin were associated with decreased normal contact forces. The activity of one group of neurons was modulated with either the normal or tangential force, with little or no influence from the orthogonal force component. A second group responded to kinetic friction or the ratio of tangential to normal forces rather than responding to a specific parameter, such as force magnitude or direction. A third group of S1 neurons appeared to respond to particular vectors of normal and tangential force on the skin. Although 45 neurons correlated with scanning speed, 32 were also modulated by finger forces, suggesting that forces on the finger should be considered as the primary parameter encoding the skin compliance and that finger speed is a secondary parameter that co-varies with finger forces. Neurons (102) were also tested with different textures, and the activity of 62 of these increased or decreased in relation to the surface friction. PMID:26467519

  11. Activating STAT3 Alpha for Promoting Healing of Neurons

    NASA Technical Reports Server (NTRS)

    Conway, Greg

    2008-01-01

    A method of promoting healing of injured or diseased neurons involves pharmacological activation of the STAT3 alpha protein. Usually, injured or diseased neurons heal incompletely or not at all for two reasons: (1) they are susceptible to apoptosis (cell death); and (2) they fail to engage in axogenesis that is, they fail to re-extend their axons to their original targets (e.g., muscles or other neurons) because of insufficiency of compounds, denoted neurotrophic factors, needed to stimulate such extension. The present method (see figure) of treatment takes advantage of prior research findings to the effect that the STAT3 alpha protein has anti-apoptotic and pro-axogenic properties.

  12. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

    PubMed

    Miyazaki, Kayoko W; Miyazaki, Katsuhiko; Tanaka, Kenji F; Yamanaka, Akihiro; Takahashi, Aki; Tabuchi, Sawako; Doya, Kenji

    2014-09-08

    Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14]. However, the therapeutic effects of serotonin signal-enhancing medications have been difficult to reconcile with this theory [15, 16]. In contrast, a more recent theory states that serotonin facilitates long-term optimal behaviors and suppresses impulsive behaviors [17-21]. To test these theories, we developed optogenetic mice that selectively express channelrhodopsin in serotonin neurons and tested how the activation of serotonergic neurons in the DRN affects animal behavior during a delayed reward task. The activation of serotonin neurons reduced the premature cessation of waiting for conditioned cues and food rewards. In reward omission trials, serotonin neuron stimulation prolonged the time animals spent waiting. This effect was observed specifically when the animal was engaged in deciding whether to keep waiting and was not due to motor inhibition. Control experiments showed that the prolonged waiting times observed with optogenetic stimulation were not due to behavioral inhibition or the reinforcing effects of serotonergic activation. These results show, for the first time, that the timed activation of serotonin neurons during waiting promotes animals' patience to wait for a delayed reward. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte-neuron interactions.

    PubMed

    L'Episcopo, F; Drouin-Ouellet, J; Tirolo, C; Pulvirenti, A; Giugno, R; Testa, N; Caniglia, S; Serapide, M F; Cisbani, G; Barker, R A; Cicchetti, F; Marchetti, B

    2016-04-28

    Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2-4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr(216) being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3β-Tyr(216) was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD.

  14. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte–neuron interactions

    PubMed Central

    L'Episcopo, F; Drouin-Ouellet, J; Tirolo, C; Pulvirenti, A; Giugno, R; Testa, N; Caniglia, S; Serapide, M F; Cisbani, G; Barker, R A; Cicchetti, F; Marchetti, B

    2016-01-01

    Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2–4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr216 being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3β-Tyr216 was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD. PMID:27124580

  15. U-Shape Suppressive Effect of Phenol Red on the Epileptiform Burst Activity via Activation of Estrogen Receptors in Primary Hippocampal Culture

    PubMed Central

    Liu, Xu; Chen, Ben; Chen, Lulan; Ren, Wan-Ting; Liu, Juan; Wang, Guoxiang; Fan, Wei; Wang, Xin; Wang, Yun

    2013-01-01

    Phenol red is widely used in cell culture as a pH indicator. Recently, it also has been reported to have estrogen-like bioactivity and be capable of promoting cell proliferation in different cell lines. However, the effect of phenol red on primary neuronal culture has never been investigated. By using patch clamp technique, we demonstrated that hippocampal pyramidal neurons cultured in neurobasal medium containing no phenol red had large depolarization-associated epileptiform bursting activities, which were rarely seen in neurons cultured in phenol red-containing medium. Further experiment data indicate that the suppressive effect of the phenol red on the abnormal epileptiform burst neuronal activities was U-shape dose related, with the most effective concentration at 28 µM. In addition, this concentration related inhibitory effect of phenol red on the epileptiform neuronal discharges was mimicked by 17-β-estradiol, an estrogen receptor agonist, and inhibited by ICI-182,780, an estrogen receptor antagonist. Our results suggest that estrogen receptor activation by phenol red in the culture medium prevents formation of abnormal, epileptiform burst activity. These studies highlight the importance of phenol red as estrogen receptor stimulator and cautions of careful use of phenol red in cell culture media. PMID:23560076

  16. Activating neurons by light in free-moving adult flies

    NASA Astrophysics Data System (ADS)

    Wu, Ming-Chin; Hsiao, Po-Yen; Chu, Li-An; Lin, Yen-Yin; Fu, Chien-Chung; Chiang, Ann-Shyn

    2015-01-01

    In this presentation, we show our preliminary results which is related to neurons activation in vivo by laser. A laser scanning system was adopted to guide laser beam to an assigned fly and an assigned position. A 473-nm laser can be a heat punishment source to restrain a wild-type fly's moving area. Furthermore, neurons in optogenetics transgene flies can be triggered by the blue laser in this system.

  17. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture.

    PubMed

    Paşca, Anca M; Sloan, Steven A; Clarke, Laura E; Tian, Yuan; Makinson, Christopher D; Huber, Nina; Kim, Chul Hoon; Park, Jin-Young; O'Rourke, Nancy A; Nguyen, Khoa D; Smith, Stephen J; Huguenard, John R; Geschwind, Daniel H; Barres, Ben A; Paşca, Sergiu P

    2015-07-01

    The human cerebral cortex develops through an elaborate succession of cellular events that, when disrupted, can lead to neuropsychiatric disease. The ability to reprogram somatic cells into pluripotent cells that can be differentiated in vitro provides a unique opportunity to study normal and abnormal corticogenesis. Here, we present a simple and reproducible 3D culture approach for generating a laminated cerebral cortex-like structure, named human cortical spheroids (hCSs), from pluripotent stem cells. hCSs contain neurons from both deep and superficial cortical layers and map transcriptionally to in vivo fetal development. These neurons are electrophysiologically mature, display spontaneous activity, are surrounded by nonreactive astrocytes and form functional synapses. Experiments in acute hCS slices demonstrate that cortical neurons participate in network activity and produce complex synaptic events. These 3D cultures should allow a detailed interrogation of human cortical development, function and disease, and may prove a versatile platform for generating other neuronal and glial subtypes in vitro.

  18. Modulation and detection of single neuron activity using spin transfer nano-oscillators

    NASA Astrophysics Data System (ADS)

    Algarin, Jose Miguel; Ramaswamy, Bharath; Venuti, Lucy; Swierzbinski, Matthew; Villar, Pablo; Chen, Yu-Jin; Krivorotov, Ilya; Weinberg, Irving N.; Herberholz, Jens; Araneda, Ricardo; Shapiro, Benjamin; Waks, Edo

    2017-09-01

    The brain is a complex network of interconnected circuits that exchange electrical signals with each other. These electrical signals provide insight on how neural circuits code information, and give rise to sensations, thoughts, emotions and actions. Currents methods to detect and modulate these electrical signals use implanted electrodes or optical fields with light sensitive dyes in the brain. These techniques require complex surgeries or suffer low resolution. In this talk we explore a new method to both image and stimulate single neurons using spintronics. We propose using a Spin Transfer Nano-Oscillators (STNOs) as a nanoscale sensor that converts neuronal action potentials to microwave field oscillations that can be detected wirelessly by magnetic induction. We will describe our recent proof-of-concept demonstration of both detection and wireless modulation of neuronal activity using STNOs. For detection we use electrodes to connect a STNO to a lateral giant crayfish neuron. When we stimulate the neuron, the STNO responds to the neuronal activity with a corresponding microwave signal. For modulation, we stimulate the STNOs wirelessly using an inductively coupled solenoid. The STNO rectifies the induced microwave signal to produce a direct voltage. This direct voltage from the STNO, when applied in the vicinity of a mammalian neuron, changes the frequency of electrical signals produced by the neuron.

  19. Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations.

    PubMed

    Zhong, Ping; Hu, Zhixing; Jiang, Houbo; Yan, Zhen; Feng, Jian

    2017-05-02

    Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Amitriptyline Activates TrkA to Aid Neuronal Growth and Attenuate Anesthesia-Induced Neurodegeneration in Rat Dorsal Root Ganglion Neurons.

    PubMed

    Zheng, Xiaochun; Chen, Feng; Zheng, Ting; Huang, Fengyi; Chen, Jianghu; Tu, Wenshao

    2016-05-01

    Tricyclic antidepressant amitriptyline (AM) has been shown to exert neurotrophic activity on neurons. We thus explored whether AM may aid the neuronal development and protect anesthesia-induced neuro-injury in young spinal cord dorsal root ganglion (DRG) neurons.The DRG explants were prepared from 1-day-old rats. The effect of AM on aiding DRG neural development was examined by immunohistochemistry at dose-dependent manner. AM-induced changes in gene and protein expressions, and also phosphorylation states of tyrosine kinases receptor A (TrkA) and B (TrkB) in DRG, were examined by quantitative real-time polymerase chain reaction and western blot. The effect of AM on attenuating lidocaine-induced DRG neurodegeneration was examined by immunohistochemistry, and small interfering RNA (siRNA)-mediated TrkA/B down-regulation.Amitriptyline stimulated DRG neuronal development in dose-dependent manner, but exerted toxic effect at concentrations higher than 10 M. AM activated TrkA in DRG through phosphorylation, whereas it had little effect on TrkB-signaling pathway. AM reduced lidocaine-induced DRG neurodegeneration by regenerating neurites and growth cones. Moreover, the neuroprotection of AM on lidocaine-injured neurodegeneration was blocked by siRNA-mediated TrkA down-regulation, but not by TrkB down-regulation.Amitriptyline facilitated neuronal development and had protective effect on lidocaine-induced neurodegeneration, very likely through the activation of TrkA-signaling pathway in DRG.

  1. Amitriptyline Activates TrkA to Aid Neuronal Growth and Attenuate Anesthesia-Induced Neurodegeneration in Rat Dorsal Root Ganglion Neurons

    PubMed Central

    Zheng, Xiaochun; Chen, Feng; Zheng, Ting; Huang, Fengyi; Chen, Jianghu; Tu, Wenshao

    2016-01-01

    Abstract Tricyclic antidepressant amitriptyline (AM) has been shown to exert neurotrophic activity on neurons. We thus explored whether AM may aid the neuronal development and protect anesthesia-induced neuro-injury in young spinal cord dorsal root ganglion (DRG) neurons. The DRG explants were prepared from 1-day-old rats. The effect of AM on aiding DRG neural development was examined by immunohistochemistry at dose-dependent manner. AM-induced changes in gene and protein expressions, and also phosphorylation states of tyrosine kinases receptor A (TrkA) and B (TrkB) in DRG, were examined by quantitative real-time polymerase chain reaction and western blot. The effect of AM on attenuating lidocaine-induced DRG neurodegeneration was examined by immunohistochemistry, and small interfering RNA (siRNA)-mediated TrkA/B down-regulation. Amitriptyline stimulated DRG neuronal development in dose-dependent manner, but exerted toxic effect at concentrations higher than 10 M. AM activated TrkA in DRG through phosphorylation, whereas it had little effect on TrkB-signaling pathway. AM reduced lidocaine-induced DRG neurodegeneration by regenerating neurites and growth cones. Moreover, the neuroprotection of AM on lidocaine-injured neurodegeneration was blocked by siRNA-mediated TrkA down-regulation, but not by TrkB down-regulation. Amitriptyline facilitated neuronal development and had protective effect on lidocaine-induced neurodegeneration, very likely through the activation of TrkA-signaling pathway in DRG. PMID:27149473

  2. The importance of regulation of blood glucose levels through activation of peripheral 5'-AMP-activated protein kinase on ischemic neuronal damage.

    PubMed

    Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

    2010-09-10

    5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in energy homeostasis. Recently, it was reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In addition, we have previously reported that the development of post-ischemic glucose intolerance could be one of the triggers for the aggravation of neuronal damage. In this study, we focused on effect of activation of peripheral or central AMPK on the development of ischemic neuronal damage. Male ddY mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histological and behavioral analysis after MCAO. In the liver and skeletal muscle, AMPK activity was not affected by MCAO. But, application of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly suppressed the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, application of intracerebroventricular metformin (25, 100 microg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO, in a dose-dependent manner. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK was activated by ischemic stress per se, however, peripheral AMPK was not altered. Furthermore, the regulation of post-ischemic glucose intolerance by activation of peripheral AMPK is of assistance for the suppression of cerebral ischemic neuronal damage. 2010 Elsevier B.V. All rights reserved.

  3. Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

    PubMed

    Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

    2015-01-21

    Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

  4. Abnormal Neural Activation to Faces in the Parents of Children with Autism

    PubMed Central

    Yucel, G. H.; Belger, A.; Bizzell, J.; Parlier, M.; Adolphs, R.; Piven, J.

    2015-01-01

    Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the “Broad Autism Phenotype ” (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally in autism parents with aloof personality (“BAP+”). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP. PMID:25056573

  5. Nucleus Ambiguus Cholinergic Neurons Activated by Acupuncture: Relation to Enkephalin

    PubMed Central

    Guo, Zhi-Ling; Li, Min; Longhurst, John C.

    2012-01-01

    Acupuncture regulates autonomic function. Our previous studies have shown that electroacupuncture (EA) at the Jianshi–Neiguan acupoints (P5–P6, underlying the median nerve) inhibits central sympathetic outflow and attenuates excitatory cardiovascular reflexes, in part, through an opioid mechanism. It is unknown if EA at these acupoints influences the parasympathetic system. Thus, using c-Fos expression, we examined activation of nucleus ambiguus (NAmb) neurons by EA, their relation to cholinergic (preganglionic parasympathetic) neurons and those containing enkephalin. To enhance detection of cell bodies containing enkephalin, colchicine (90–100 μg/kg) was administered into the subarachnoid space of cats 30 hr prior to EA or sham-operated controls for EA. Following bilateral barodenervation and cervical vagotomy, either EA for 30 min at P5–P6 acupoints or control stimulation (needle placement at P5–P6 without stimulation) was applied. While perikarya containing enkephalin were observed in some medullary nuclei (e.g., râphe), only enkephalin-containing neuronal processes were found in the NAmb. Compared to controls (n=4), more c-Fos immunoreactivity, located principally in close proximity to fibers containing enkephalin was noted in the NAmb of EA-treated cats (n=5; P<0.01). Moreover, neurons double-labeled with c-Fos and choline acetyltransferase in the NAmb were identified in EA-treated, but not the control animals. These data demonstrate for the first time that EA activates preganglionic parasympathetic neurons in the NAmb. Because of their close proximity, these EA-activated neurons likely interact with nerve fibers containing enkephalin. These results suggest that EA at the P5–P6 acupoints has the potential to influence parasympathetic outflow and cardiovascular function, likely through an enkephalinergic mechanism. PMID:22306033

  6. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

    PubMed Central

    Kaushal, V; Dye, R; Pakavathkumar, P; Foveau, B; Flores, J; Hyman, B; Ghetti, B; Koller, B H; LeBlanc, A C

    2015-01-01

    Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1−/− and Casp1−/− mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration. PMID:25744023

  7. Motor neuronal activity varies least among individuals when it matters most for behavior

    PubMed Central

    Cullins, Miranda J.; Shaw, Kendrick M.; Gill, Jeffrey P.

    2014-01-01

    How does motor neuronal variability affect behavior? To explore this question, we quantified activity of multiple individual identified motor neurons mediating biting and swallowing in intact, behaving Aplysia californica by recording from the protractor muscle and the three nerves containing the majority of motor neurons controlling the feeding musculature. We measured multiple motor components: duration of the activity of identified motor neurons as well as their relative timing. At the same time, we measured behavioral efficacy: amplitude of grasping movement during biting and amplitude of net inward food movement during swallowing. We observed that the total duration of the behaviors varied: Within animals, biting duration shortened from the first to the second and third bites; between animals, biting and swallowing durations varied. To study other sources of variation, motor components were divided by behavior duration (i.e., normalized). Even after normalization, distributions of motor component durations could distinguish animals as unique individuals. However, the degree to which a motor component varied among individuals depended on the role of that motor component in a behavior. Motor neuronal activity that was essential for the expression of biting or swallowing was similar among animals, whereas motor neuronal activity that was not essential for that behavior varied more from individual to individual. These results suggest that motor neuronal activity that matters most for the expression of a particular behavior may vary least from individual to individual. Shaping individual variability to ensure behavioral efficacy may be a general principle for the operation of motor systems. PMID:25411463

  8. Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons

    PubMed Central

    Ashhad, Sufyan

    2016-01-01

    An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-d-aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron–astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP3) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide–gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtype-specific receptor blockers during paired neuron–astrocyte recordings, we provide evidence that GluN2B- and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place

  9. Abnormalities of thalamic activation and cognition in schizophrenia.

    PubMed

    Andrews, Jessica; Wang, Lei; Csernansky, John G; Gado, Mokhtar H; Barch, Deanna M

    2006-03-01

    Functional and structural magnetic resonance imaging (MRI) was used to investigate relationships among structure, functional activation, and cognitive deficits related to the thalamus in individuals with schizophrenia and healthy comparison subjects. Thirty-six schizophrenia subjects and 28 healthy comparison subjects matched by age, gender, race, and parental socioeconomic status underwent structural and functional MRI while performing a series of memory tasks, including an N-back task (working memory), intentional memorization of a series of pictures or words (episodic encoding), and a yes/no recognition task. Functional activation magnitudes in seven regions of interest within the thalamic complex, as defined by anatomical and functional criteria, were computed for each group. Participants with schizophrenia exhibited decreased activation within the whole thalamus, the anterior nuclei, and the medial dorsal nucleus. These nuclei overlap with subregions of the thalamic surface that the authors previously reported to exhibit morphological abnormalities in schizophrenia. However, there were no significant correlations between specific dimensions of thalamic shape variation (i.e., eigenvectors) and the activation patterns within thalamic regions of interest. Better performance on the working memory task among individuals with schizophrenia was significantly associated with increased activation in the anterior nuclei, the centromedian nucleus, the pulvinar, and the ventrolateral nuclei. These results suggest that there are limited relationships between morphological and functional abnormalities of the thalamus in schizophrenia subjects and highlight the importance of investigating relationships between brain structure and function.

  10. The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival

    PubMed Central

    Wijayatunge, Ranjula; Chen, Liang-Fu; Cha, Young May; Zannas, Anthony S.; Frank, Christopher L.; West, Anne E.

    2014-01-01

    Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic+4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic+4AP induced preconditioning of neuronal survival. Prior exposure to Bic+4AP promoted neuronal survival in control neurons upon growth factor withdrawal, however this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity. PMID:24983519

  11. Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution

    PubMed Central

    Herculano-Houzel, Suzana

    2011-01-01

    It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution. PMID:21390261

  12. Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution.

    PubMed

    Herculano-Houzel, Suzana

    2011-03-01

    It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.

  13. Nociceptive Afferent Activity Alters the SI RA Neuron Response to Mechanical Skin Stimulation

    PubMed Central

    Favorov, O.V.; Li, Y.; Lee, J.; Quibrera, P.M.; Tommerdahl, M.

    2010-01-01

    Procedures that reliably evoke cutaneous pain in humans (i.e., 5–7 s skin contact with a 47–51 °C probe, intradermal algogen injection) are shown to decrease the mean spike firing rate (MFR) and degree to which the rapidly adapting (RA) neurons in areas 3b/1 of squirrel monkey primary somatosensory cortex (SI) entrain to a 25-Hz stimulus to the receptive field center (RFcenter) when stimulus amplitude is “near-threshold” (i.e., 10–50 μm). In contrast, RA neuron MFR and entrainment are either unaffected or enhanced by 47–51 °C contact or intradermal algogen injection when the amplitude of 25-Hz stimulation is 100–200 μm (suprathreshold). The results are attributed to an “activity dependence” of γ-aminobutyric acid (GABA) action on the GABAA receptors of RA neurons. The nociceptive afferent drive triggered by skin contact with a 47–51 °C probe or intradermal algogen is proposed to activate nociresponsive neurons in area 3a which, via corticocortical connections, leads to the release of GABA in areas 3b/1. It is hypothesized that GABA is hyperpolarizing/inhibitory and suppresses stimulus-evoked RA neuron MFR and entrainment whenever RA neuron activity is low (as when the RFcenter stimulus is weak/near-threshold) but is depolarizing/excitatory and augments MFR and entrainment when RA neuron activity is high (when the stimulus is strong/suprathreshold). PMID:20308203

  14. Toward a complex system understanding of bipolar disorder: A chaotic model of abnormal circadian activity rhythms in euthymic bipolar disorder.

    PubMed

    Hadaeghi, Fatemeh; Hashemi Golpayegani, Mohammad Reza; Jafari, Sajad; Murray, Greg

    2016-08-01

    In the absence of a comprehensive neural model to explain the underlying mechanisms of disturbed circadian function in bipolar disorder, mathematical modeling is a helpful tool. Here, circadian activity as a response to exogenous daily cycles is proposed to be the product of interactions between neuronal networks in cortical (cognitive processing) and subcortical (pacemaker) areas of the brain. To investigate the dynamical aspects of the link between disturbed circadian activity rhythms and abnormalities of neurotransmitter functioning in frontal areas of the brain, we developed a novel mathematical model of a chaotic system which represents fluctuations in circadian activity in bipolar disorder as changes in the model's parameters. A novel map-based chaotic system was developed to capture disturbances in circadian activity across the two extreme mood states of bipolar disorder. The model uses chaos theory to characterize interplay between neurotransmitter functions and rhythm generation; it aims to illuminate key activity phenomenology in bipolar disorder, including prolonged sleep intervals, decreased total activity and attenuated amplitude of the diurnal activity rhythm. To test our new cortical-circadian mathematical model of bipolar disorder, we utilized previously collected locomotor activity data recorded from normal subjects and bipolar patients by wrist-worn actigraphs. All control parameters in the proposed model have an important role in replicating the different aspects of circadian activity rhythm generation in the brain. The model can successfully replicate deviations in sleep/wake time intervals corresponding to manic and depressive episodes of bipolar disorder, in which one of the excitatory or inhibitory pathways is abnormally dominant. Although neuroimaging research has strongly implicated a reciprocal interaction between cortical and subcortical regions as pathogenic in bipolar disorder, this is the first model to mathematically represent this

  15. ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity*

    PubMed Central

    Kim, Yoonju; Lee, Sang-Eun; Park, Joohyun; Kim, Minhyung; Lee, Boyoon; Hwang, Daehee; Chang, Sunghoe

    2015-01-01

    Recent studies have reported conflicting results regarding the role of ARF6 in dendritic spine development, but no clear answer for the controversy has been suggested. We found that ADP-ribosylation factor 6 (ARF6) either positively or negatively regulates dendritic spine formation depending on neuronal maturation and activity. ARF6 activation increased the spine formation in developing neurons, whereas it decreased spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite patterns of expression of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via the phospholipase D pathway is the coincident factor in both stages, but the antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using tetrodotoxin or enhancing the activity in mature neurons using picrotoxin or chemical long term potentiation reversed the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated spine structures may play a role in structural plasticity of mature neurons. PMID:25605715

  16. Persistently active neurons in human medial frontal and medial temporal lobe support working memory

    PubMed Central

    Kamiński, J; Sullivan, S; Chung, JM; Ross, IB; Mamelak, AN; Rutishauser, U

    2017-01-01

    Persistent neural activity is a putative mechanism for the maintenance of working memories. Persistent activity relies on the activity of a distributed network of areas, but the differential contribution of each area remains unclear. We recorded single neurons in the human medial frontal cortex and the medial temporal lobe while subjects held up to three items in memory. We found persistently active neurons in both areas. Persistent activity of hippocampal and amygdala neurons was stimulus-specific, formed stable attractors, and was predictive of memory content. Medial frontal cortex persistent activity, on the other hand, was modulated by memory load and task set but was not stimulus-specific. Trial-by-trial variability in persistent activity in both areas was related to memory strength, because it predicted the speed and accuracy by which stimuli were remembered. This work reveals, in humans, direct evidence for a distributed network of persistently active neurons supporting working memory maintenance. PMID:28218914

  17. Brain lactate kinetics: Modeling evidence for neuronal lactate uptake upon activation.

    PubMed

    Aubert, Agnès; Costalat, Robert; Magistretti, Pierre J; Pellerin, Luc

    2005-11-08

    A critical issue in brain energy metabolism is whether lactate produced within the brain by astrocytes is taken up and metabolized by neurons upon activation. Although there is ample evidence that neurons can efficiently use lactate as an energy substrate, at least in vitro, few experimental data exist to indicate that it is indeed the case in vivo. To address this question, we used a modeling approach to determine which mechanisms are necessary to explain typical brain lactate kinetics observed upon activation. On the basis of a previously validated model that takes into account the compartmentalization of energy metabolism, we developed a mathematical model of brain lactate kinetics, which was applied to published data describing the changes in extracellular lactate levels upon activation. Results show that the initial dip in the extracellular lactate concentration observed at the onset of stimulation can only be satisfactorily explained by a rapid uptake within an intraparenchymal cellular compartment. In contrast, neither blood flow increase, nor extracellular pH variation can be major causes of the lactate initial dip, whereas tissue lactate diffusion only tends to reduce its amplitude. The kinetic properties of monocarboxylate transporter isoforms strongly suggest that neurons represent the most likely compartment for activation-induced lactate uptake and that neuronal lactate utilization occurring early after activation onset is responsible for the initial dip in brain lactate levels observed in both animals and humans.

  18. Genetically encoded proton sensors reveal activity-dependent pH changes in neurons.

    PubMed

    Raimondo, Joseph V; Irkle, Agnese; Wefelmeyer, Winnie; Newey, Sarah E; Akerman, Colin J

    2012-01-01

    The regulation of hydrogen ion concentration (pH) is fundamental to cell viability, metabolism, and enzymatic function. Within the nervous system, the control of pH is also involved in diverse and dynamic processes including development, synaptic transmission, and the control of network excitability. As pH affects neuronal activity, and can also itself be altered by neuronal activity, the existence of tools to accurately measure hydrogen ion fluctuations is important for understanding the role pH plays under physiological and pathological conditions. Outside of their use as a marker of synaptic release, genetically encoded pH sensors have not been utilized to study hydrogen ion fluxes associated with network activity. By combining whole-cell patch clamp with simultaneous two-photon or confocal imaging, we quantified the amplitude and time course of neuronal, intracellular, acidic transients evoked by epileptiform activity in two separate in vitro models of temporal lobe epilepsy. In doing so, we demonstrate the suitability of three genetically encoded pH sensors: deGFP4, E(2)GFP, and Cl-sensor for investigating activity-dependent pH changes at the level of single neurons.

  19. [Infantile autism and mirror neurons].

    PubMed

    Cornelio-Nieto, J O

    2009-02-27

    Infantile autism is a disorder that is characterised by alterations affecting reciprocal social interactions, abnormal verbal and non-verbal communication, poor imaginative activity and a restricted repertoire of activities and interests. The causes of autism remain unknown, but there are a number of different approaches that attempt to explain the neurobiological causes of the syndrome. A recent theory that has been considered is that of a dysfunction in the mirror neuron system (MNS). The MNS is a neuronal complex, originally described in monkeys and also found in humans, that is related with our movements and which offers specific responses to the movements and intended movements of other subjects. This system is believed to underlie processes of imitation and our capacity to learn by imitation. It is also thought to play a role in language acquisition, in expressing the emotions, in understanding what is happening to others and in empathy. Because these functions are altered in children with autism, it has been suggested that there is some dysfunction present in the MNS of those with autism. Dysfunction of the MNS could account for the symptoms that are observed in children with autism.

  20. Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.

    PubMed

    Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti; Kumar, Asok; Nixon, Ralph A

    2016-04-01

    Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, α-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST

  1. Activation state of the hyperpolarization-activated current modulates temperature-sensitivity of firing in locus coeruleus neurons from bullfrogs.

    PubMed

    Santin, Joseph M; Hartzler, Lynn K

    2015-06-15

    Locus coeruleus neurons of anuran amphibians contribute to breathing control and have spontaneous firing frequencies that, paradoxically, increase with cooling. We previously showed that cooling inhibits a depolarizing membrane current, the hyperpolarization-activated current (I h) in locus coeruleus neurons from bullfrogs, Lithobates catesbeianus (Santin JM, Watters KC, Putnam RW, Hartzler LK. Am J Physiol Regul Integr Comp Physiol 305: R1451-R1464, 2013). This suggests an unlikely role for I h in generating cold activation, but led us to hypothesize that inhibition of I h by cooling functions as a physiological brake to limit the cold-activated response. Using whole cell electrophysiology in brain slices, we employed 2 mM Cs(+) (an I h antagonist) to isolate the role of I h in spontaneous firing and cold activation in neurons recorded with either control or I h agonist (cyclic AMP)-containing artificial intracellular fluid. I h did not contribute to the membrane potential (V m) and spontaneous firing at 20°C. Although voltage-clamp analysis confirmed that cooling inhibits I h, its lack of involvement in setting baseline firing and V m precluded its ability to regulate cold activation as hypothesized. In contrast, neurons dialyzed with cAMP exhibited greater baseline firing frequencies at 20°C due to I h activation. Our hypothesis was supported when the starting level of I h was enhanced by elevating cAMP because cold activation was converted to more ordinary cold inhibition. These findings indicate that situations leading to enhancement of I h facilitate firing at 20°C, yet the hyperpolarization associated with inhibiting a depolarizing cation current by cooling blunts the net V m response to cooling to oppose normal cold-depolarizing factors. This suggests that the influence of I h activation state on neuronal firing varies in the poikilothermic neuronal environment. Copyright © 2015 the American Physiological Society.

  2. Inhibition of cyclin-dependent kinase activity triggers neuronal differentiation of mouse neuroblastoma cells.

    PubMed

    Kranenburg, O; Scharnhorst, V; Van der Eb, A J; Zantema, A

    1995-10-01

    Studies on the molecular mechanisms underlying neuronal differentiation are frequently performed using cell lines established from neuroblastomas. In this study we have used mouse N1E-115 neuroblastoma cells that undergo neuronal differentiation in response to DMSO. During differentiation, cyclin-dependent kinase (cdk) activities decline and phosphorylation of the retinoblastoma gene product (pRb) is lost, leading to the appearance of a pRb-containing E2F DNA-binding complex. The loss of cdk2 activity is due to a decrease in cdk2 abundance whereas loss of cdk4 activity is caused by strong association with the cdk inhibitor (CKI) p27KIP1 and concurrent loss of cdk4 phosphorylation. Moreover, neuronal differentiation can be induced by overexpression of p27KIP1 or pRb, suggesting that inhibition of cdk activity leading to loss of pRb phosphorylation, is the major determinant for neuronal differentiation.

  3. Synaptic activation of putative sensory neurons by hexamethonium-sensitive nerve pathways in mouse colon.

    PubMed

    Hibberd, Timothy J; Travis, Lee; Wiklendt, Lukasz; Costa, Marcello; Brookes, Simon J H; Hu, Hongzhen; Keating, Damien J; Spencer, Nick J

    2018-01-01

    The gastrointestinal tract contains its own independent population of sensory neurons within the gut wall. These sensory neurons have been referred to as intrinsic primary afferent neurons (IPANs) and can be identified by immunoreactivity to calcitonin gene-related peptide (CGRP) in mice. A common feature of IPANs is a paucity of fast synaptic inputs observed during sharp microelectrode recordings. Whether this is observed using different recording techniques is of particular interest for understanding the physiology of these neurons and neural circuit modeling. Here, we imaged spontaneous and evoked activation of myenteric neurons in isolated whole preparations of mouse colon and correlated recordings with CGRP and nitric oxide synthase (NOS) immunoreactivity, post hoc. Calcium indicator fluo 4 was used for this purpose. Calcium responses were recorded in nerve cell bodies located 5-10 mm oral to transmural electrical nerve stimuli. A total of 618 recorded neurons were classified for CGRP or NOS immunoreactivity. Aboral electrical stimulation evoked short-latency calcium transients in the majority of myenteric neurons, including ~90% of CGRP-immunoreactive Dogiel type II neurons. Activation of Dogiel type II neurons had a time course consistent with fast synaptic transmission and was always abolished by hexamethonium (300 μM) and by low-calcium Krebs solution. The nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (during synaptic blockade) directly activated Dogiel type II neurons. The present study suggests that murine colonic Dogiel type II neurons receive prominent fast excitatory synaptic inputs from hexamethonium-sensitive neural pathways. NEW & NOTEWORTHY Myenteric neurons in isolated mouse colon were recorded using calcium imaging and then neurochemically defined. Short-latency calcium transients were detected in >90% of calcitonin gene-related peptide-immunoreactive neurons to electrical stimulation of hexamethonium-sensitive pathways

  4. Basal Ganglia Neuronal Activity during Scanning Eye Movements in Parkinson’s Disease

    PubMed Central

    Sieger, Tomáš; Bonnet, Cecilia; Serranová, Tereza; Wild, Jiří; Novák, Daniel; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen; Gaymard, Bertrand; Jech, Robert

    2013-01-01

    The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control. PMID:24223158

  5. Synaptic plasticity and levodopa-induced dyskinesia: electrophysiological and structural abnormalities.

    PubMed

    Picconi, Barbara; De Leonibus, Elvira; Calabresi, Paolo

    2018-02-28

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons located in the midbrain. The gold-standard therapy for PD is the restoration of dopamine (DA) levels through the chronic administration of the DA precursor levodopa (L-DOPA). Although levodopa therapy is the main therapeutic approach for PD, its use is limited by the development of very disabling dyskinetic movements, mainly due to the fluctuation of DA cerebral content. Experimental animal models of PD identified in DA D1/ERK-signaling pathway aberrant activation, occurring in striatal projection neurons, coupled with structural spines abnormalities, the molecular and neuronal basis of L-DOPA-induced dyskinesia (LIDs) occurrence. Different electrophysiological approaches allowed the identification of  the alteration of homeostatic structural and synaptic changes, the neuronal bases of LIDs either in vivo in parkinsonian patients or in vitro in experimental animals. Here, we report the most recent studies showing electrophysiological and morphological evidence of aberrant synaptic plasticity in parkinsonian patients during LIDs in different basal ganglia nuclei and also in cortical transmission, accounting for the complexity of the synaptic changes during dyskinesias. All together, these studies suggest that LIDs are associated with a loss of homeostatic synaptic mechanisms.

  6. Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones

    PubMed Central

    Corlew, Rebekah; Bosma, Martha M; Moody, William J

    2004-01-01

    Spontaneous [Ca2+]i transients were measured in the mouse neocortex from embryonic day 16 (E16) to postnatal day 6 (P6). On the day of birth (P0), cortical neurones generated widespread, highly synchronous [Ca2+]i transients over large areas. On average, 52% of neurones participated in these transients, and in 20% of slices, an average of 80% participated. These transients were blocked by TTX and nifedipine, indicating that they resulted from Ca2+ influx during electrical activity, and occurred at a mean frequency of 0.91 min−1. The occurrence of this activity was highly centred at P0: at E16 and P2 an average of only 15% and 24% of neurones, respectively, participated in synchronous transients, and they occurred at much lower frequencies at both E16 and P2 than at P0. The overall frequency of [Ca2+]i transients in individual cells did not change between E16 and P2, just the degree of their synchronicity. The onset of this spontaneous, synchronous activity correlated with a large increase in Na+ current density that occurred just before P0, and its cessation with a large decrease in resting resistance that occurred just after P2. This widespread, synchronous activity may serve a variety of functions in the neonatal nervous system. PMID:15297578

  7. Progesterone Directly and Rapidly Inhibits GnRH Neuronal Activity via Progesterone Receptor Membrane Component 1

    PubMed Central

    Bashour, Nicholas Michael

    2012-01-01

    GnRH neurons are essential for reproduction, being an integral component of the hypothalamic-pituitary-gonadal axis. Progesterone (P4), a steroid hormone, modulates reproductive behavior and is associated with rapid changes in GnRH secretion. However, a direct action of P4 on GnRH neurons has not been previously described. Receptors in the progestin/adipoQ receptor family (PAQR), as well as progesterone receptor membrane component 1 (PgRMC1) and its partner serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1) mRNA binding protein 1 (SERBP1), have been shown to mediate rapid progestin actions in various tissues, including the brain. This study shows that PgRMC1 and SERBP1, but not PAQR, are expressed in prenatal GnRH neurons. Expression of PgRMC1 and SERBP1 was verified in adult mouse GnRH neurons. To investigate the effect of P4 on GnRH neuronal activity, calcium imaging was used on primary GnRH neurons maintained in explants. Application of P4 significantly decreased the activity of GnRH neurons, independent of secretion of gamma-aminobutyric acidergic and glutamatergic input, suggesting a direct action of P4 on GnRH neurons. Inhibition was not blocked by RU486, an antagonist of the classic nuclear P4 receptor. Inhibition was also maintained after uncoupling of the inhibitory regulative G protein (Gi/o), the signal transduction pathway used by PAQR. However, AG-205, a PgRMC1 ligand and inhibitor, blocked the rapid P4-mediated inhibition, and inhibition of protein kinase G, thought to be activated downstream of PgRMC1, also blocked the inhibitory activity of P4. These data show for the first time that P4 can act directly on GnRH neurons through PgRMC1 to inhibit neuronal activity. PMID:22822163

  8. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia.

    PubMed

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-06-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

  9. Isolated dorsal root ganglion neurones inhibit receptor-dependent adenylyl cyclase activity in associated glial cells

    PubMed Central

    Ng, KY; Yeung, BHS; Wong, YH; Wise, H

    2013-01-01

    Background and Purpose Hyper-nociceptive PGE2 EP4 receptors and prostacyclin (IP) receptors are present in adult rat dorsal root ganglion (DRG) neurones and glial cells in culture. The present study has investigated the cell-specific expression of two other Gs-protein coupled hyper-nociceptive receptor systems: β-adrenoceptors and calcitonin gene-related peptide (CGRP) receptors in isolated DRG cells and has examined the influence of neurone–glial cell interactions in regulating adenylyl cyclase (AC) activity. Experimental Approach Agonist-stimulated AC activity was determined in mixed DRG cell cultures from adult rats and compared with activity in DRG neurone-enriched cell cultures and pure DRG glial cell cultures. Key Results Pharmacological analysis showed the presence of Gs-coupled β2-adrenoceptors and CGRP receptors, but not β1-adrenoceptors, in all three DRG cell preparations. Agonist-stimulated AC activity was weakest in DRG neurone-enriched cell cultures. DRG neurones inhibited IP receptor-stimulated glial cell AC activity by a process dependent on both cell–cell contact and neurone-derived soluble factors, but this is unlikely to involve purine or glutamine receptor activation. Conclusions and Implications Gs-coupled hyper-nociceptive receptors are readily expressed on DRG glial cells in isolated cell cultures and the activity of CGRP, EP4 and IP receptors, but not β2-adrenoceptors, in glial cells is inhibited by DRG neurones. Studies using isolated DRG cells should be aware that hyper-nociceptive ligands may stimulate receptors on glial cells in addition to neurones, and that variable numbers of neurones and glial cells will influence absolute measures of AC activity and affect downstream functional responses. PMID:22924655

  10. Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction.

    PubMed

    Nakao, Kazuhito; Jeevakumar, Vivek; Jiang, Sunny Zhihong; Fujita, Yuko; Diaz, Noelia B; Pretell Annan, Carlos A; Eskow Jaunarajs, Karen L; Hashimoto, Kenji; Belforte, Juan E; Nakazawa, Kazu

    2018-01-31

    Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex (PFC) is a hallmark of schizophrenia pathophysiology. Although N-methyl-D-aspartate receptor (NMDAR) hypofunction is also implicated in schizophrenia, it remains unclear whether NMDAR hypofunction leads to dopamine release abnormalities. We previously demonstrated schizophrenia-like phenotypes in GABAergic neuron-specific NMDAR hypofunctional mutant mice, in which Ppp1r2-Cre dependent deletion of indispensable NMDAR channel subunit Grin1 is induced in corticolimbic GABAergic neurons including parvalbumin (PV)-positive neurons, in postnatal development, but not in adulthood. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: nucleus accumbens (NAc) dopamine release was enhanced by amphetamine in postnatal Ppp1r2-Cre/Grin1 knockout (KO) mice, whereas dopamine release was dramatically reduced in the medial PFC (mPFC) compared to controls. Basal tissue dopamine levels in both the NAc and mPFC were unaffected. Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area (VTA). These effects appear to be both developmentally and cell-type specifically modulated, since PV-specific Grin1 KO mice could induce the same effects as seen in postnatal-onset Ppp1r2-Cre/Grin1 KO mice, but no such abnormalities were observed in somatostatin-Cre/Grin1 KO mice or adult-onset Ppp1r2-Cre/Grin1 KO mice. These results suggest that PV GABAergic neuron-NMDAR hypofunction in postnatal development confers bidirectional NAc hyper- and mPFC hypo-sensitivity to amphetamine-induced dopamine release, similar to that classically observed in schizophrenia pathophysiology. © The Author(s) 2018. Published by Oxford University

  11. A receptor and neuron that activate a circuit limiting sucrose consumption.

    PubMed

    Joseph, Ryan M; Sun, Jennifer S; Tam, Edric; Carlson, John R

    2017-03-23

    The neural control of sugar consumption is critical for normal metabolism. In contrast to sugar-sensing taste neurons that promote consumption, we identify a taste neuron that limits sucrose consumption in Drosophila . Silencing of the neuron increases sucrose feeding; optogenetic activation decreases it. The feeding inhibition depends on the IR60b receptor, as shown by behavioral analysis and Ca 2+ imaging of an IR60b mutant. The IR60b phenotype shows a high degree of chemical specificity when tested with a broad panel of tastants. An automated analysis of feeding behavior in freely moving flies shows that IR60b limits the duration of individual feeding bouts. This receptor and neuron provide the molecular and cellular underpinnings of a new element in the circuit logic of feeding regulation. We propose a dynamic model in which sucrose acts via IR60b to activate a circuit that inhibits feeding and prevents overconsumption.

  12. A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.

    PubMed

    Kong, Dong; Dagon, Yossi; Campbell, John N; Guo, Yikun; Yang, Zongfang; Yi, Xinchi; Aryal, Pratik; Wellenstein, Kerry; Kahn, Barbara B; Sabatini, Bernardo L; Lowell, Bradford B

    2016-07-06

    AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Protease-Activated Receptor 2 Activation Inhibits N-Type Ca2+ Currents in Rat Peripheral Sympathetic Neurons

    PubMed Central

    Kim, Young-Hwan; Ahn, Duck-Sun; Kim, Myeong Ok; Joeng, Ji-Hyun; Chung, Seungsoo

    2014-01-01

    The protease-activated receptor (PAR)-2 is highly expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although several mechanisms have been suggested to explain PAR-2-induced hypotension, the precise mechanism remains to be elucidated. To investigate this possibility, we investigated the effects of PAR-2 activation on N-type Ca2+ currents (ICa-N) in isolated neurons of the celiac ganglion (CG), which is involved in the sympathetic regulation of mesenteric artery vascular tone. PAR-2 agonists irreversibly diminished voltage-gated Ca2+ currents (ICa), measured using the patch-clamp method, in rat CG neurons, whereas thrombin had little effect on ICa. This PAR-2-induced inhibition was almost completely prevented by ω-CgTx, a potent N-type Ca2+ channel blocker, suggesting the involvement of N-type Ca2+ channels in PAR-2-induced inhibition. In addition, PAR-2 agonists inhibited ICa–N in a voltage-independent manner in rat CG neurons. Moreover, PAR-2 agonists reduced action potential (AP) firing frequency as measured using the current-clamp method in rat CG neurons. This inhibition of AP firing induced by PAR-2 agonists was almost completely prevented by ω-CgTx, indicating that PAR-2 activation may regulate the membrane excitability of peripheral sympathetic neurons through modulation of N-type Ca2+ channels. In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type Ca2+ channel activity, which appears to be involved in PAR-2-induced hypotension, in peripheral sympathetic nerve terminals. PMID:25410909

  14. Trigeminal Medullary Dorsal Horn Neurons Activated by Nasal Stimulation Coexpress AMPA, NMDA, and NK1 Receptors

    PubMed Central

    McCulloch, P. F.; DiNovo, K. M.; Westerhaus, D. J.; Vizinas, T. A.; Peevey, J. F.; Lach, M. A.; Czarnocki, P.

    2013-01-01

    Afferent information initiating the cardiorespiratory responses during nasal stimulation projects from the nasal passages to neurons within the trigeminal medullary dorsal horn (MDH) via the anterior ethmoidal nerve (AEN). Central AEN terminals are thought to release glutamate to activate the MDH neurons. This study was designed to determine which neurotransmitter receptors (AMPA, kainate, or NMDA glutamate receptor subtypes or the Substance P receptor NK1) are expressed by these activated MDH neurons. Fos was used as a neuronal marker of activated neurons, and immunohistochemistry combined with epifluorescent microscopy was used to determine which neurotransmitter receptor subunits were coexpressed by activated MDH neurons. Results indicate that, during nasal stimulation with ammonia vapors in urethane-anesthetized Sprague-Dawley rats, activated neurons within the superficial MDH coexpress the AMPA glutamate receptor subunits GluA1 (95.8%) and GluA2/3 (88.2%), the NMDA glutamate receptor subunits GluN1 (89.1%) and GluN2A (41.4%), and NK1 receptors (64.0%). It is therefore likely that during nasal stimulation the central terminals of the AEN release glutamate and substance P that then produces activation of these MDH neurons. The involvement of AMPA and NMDA receptors may mediate fast and slow neurotransmission, respectively, while NK1 receptor involvement may indicate activation of a nociceptive pathway. PMID:24967301

  15. Activation of anorexigenic pro-opiomelanocortin neurones during refeeding is independent of vagal and brainstem inputs.

    PubMed

    Fekete, C; Zséli, G; Singru, P S; Kádár, A; Wittmann, G; Füzesi, T; El-Bermani, W; Lechan, R M

    2012-11-01

    After fasting, satiety is observed within 2 h after reintroducing food, accompanied by activation of anorexigenic, pro-opiomelanocortin (POMC)-synthesising neurones in the arcuate nucleus (ARC), indicative of the critical role that α-melanocyte-stimulating hormone has in the regulation of meal size during refeeding. To determine whether refeeding-induced activation of POMC neurones in the arcuate is dependent upon the vagus nerve and/or ascending brainstem pathways, bilateral subdiaphragmatic vagotomy or transection of the afferent brainstem input to one side of the ARC was performed. One day after vagotomy or 2 weeks after brain surgery, animals were fasted and then refed for 2 h. Sections containing the ARC from vagotomised animals or animals with effective transection were immunostained for c-Fos and POMC to detect refeeding-induced activation of POMC neurones. Quantitative analyses of double-labelled preparations demonstrated that sham-operated and vagotomised animals markedly increased the number of c-Fos-immunoreactive (-IR) POMC neurones with refeeding. Furthermore, transection of the ascending brainstem pathway had no effect on diminishing c-Fos-immunoreactivity in POMC neurones on either side of the ARC, although it did diminish activation in a separate, subpopulation of neurones in the dorsomedial posterior ARC (dmpARC) on the transected side. We conclude that inputs mediated via the vagus nerve and/or arising from the brainstem do not have a primary role in refeeding-induced activation of POMC neurones in the ARC, and propose that these neurones may be activated solely by direct effects of circulating hormones/metabolites during refeeding. Activation of the dmpARC by refeeding indicates a previously unrecognised role for these neurones in appetite regulation in the rat. © 2012 The Authors. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology.

  16. Abnormal Neural Activation to Faces in the Parents of Children with Autism.

    PubMed

    Yucel, G H; Belger, A; Bizzell, J; Parlier, M; Adolphs, R; Piven, J

    2015-12-01

    Parents of children with an autism spectrum disorder (ASD) show subtle deficits in aspects of social behavior and face processing, which resemble those seen in ASD, referred to as the "Broad Autism Phenotype " (BAP). While abnormal activation in ASD has been reported in several brain structures linked to social cognition, little is known regarding patterns in the BAP. We compared autism parents with control parents with no family history of ASD using 2 well-validated face-processing tasks. Results indicated increased activation in the autism parents to faces in the amygdala (AMY) and the fusiform gyrus (FG), 2 core face-processing regions. Exploratory analyses revealed hyper-activation of lateral occipital cortex (LOC) bilaterally in autism parents with aloof personality ("BAP+"). Findings suggest that abnormalities of the AMY and FG are related to underlying genetic liability for ASD, whereas abnormalities in the LOC and right FG are more specific to behavioral features of the BAP. Results extend our knowledge of neural circuitry underlying abnormal face processing beyond those previously reported in ASD to individuals with shared genetic liability for autism and a subset of genetically related individuals with the BAP. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Electrophysiological evidence showing muscarinic agonist-antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons.

    PubMed

    Sugawara, Yuto; Kikuchi, Yui; Yoneda, Mitsugu; Ohno-Shosaku, Takako

    2016-07-01

    The atypical antipsychotic clozapine is widely used for treatment-resistant schizophrenic patients. Clozapine and its major active metabolite, N-desmethylclozapine (NDMC), have complex pharmacological properties, and interact with various neurotransmitter receptors. There are several biochemical studies reporting that NDMC exhibits a partial agonist profile at the human recombinant M1 muscarinic receptors. However, direct electrophysiological evidence showing the ability of NDMC to activate native M1 receptors in intact neurons is poor. Using rat hippocampal neurons, we previously demonstrated that activation of muscarinic receptors by a muscarinic agonist, oxotremorine M (oxo-M), induces a decrease in outward K(+)current at -40mV. In the present study, using this muscarinic current response we assessed agonist and antagonist activities of clozapine and NDMC at native muscarinic receptors in intact hippocampal excitatory and inhibitory neurons. Suppression of the oxo-M-induced current response by the M1 antagonist pirenzepine was evident only in excitatory neurons, while the M3 antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC. These results demonstrate that NDMC has the ability to activate native M1 receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic antagonist activity. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Electrophysiological characterization of harmane-induced activation of mesolimbic dopamine neurons.

    PubMed

    Arib, Ouafa; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; Faure, Philippe; de Beaurepaire, Renaud

    2010-03-10

    It has been suggested that the beta-carbolines harmane and norharmane may be involved in the pathophysiology of Parkinson's disease, psychosis and addiction, but the mechanisms of these possible effects remain to be elucidated. In the present study, the effects of the two compounds were examined by using in vivo extracellular recordings of ventral tegmental dopamine neurons. The effects of harmane (2mg/kg) and norharmane (2mg/kg), were compared to those of nicotine (11microg/kg), of cotinine (0.5mg/kg), of the monoamine-oxidase-A inhibitor befloxatone (0.12mg/kg), and of the monoamine-oxidase-B inhibitor selegiline (0.5mg/kg). The effects of harmane were also tested after pre-treatment with the nicotine receptor antagonist mecamylamine. The results show that all substances, except befloxatone, activate the firing and/or burst activity of dopamine neurons. The increase in firing rate produced by harmane was approximately 18 times greater than that produced by nicotine. Such powerful excitation of dopamine neurons by harmane may in part explain its involvement in neurotoxicity, psychosis and addiction. The absence of effect of befloxatone supports the hypothesis that the effect of harmane is not related to its monoamine-oxidase-A inhibitory properties. Mecamylamine inhibited by approximately 80% the activity of harmane, indicating that the activating effect of harmane on dopamine neurons involves several mechanisms, among which activation of nicotinic receptors likely has a prominent importance. The results of the present study support the hypothesis that harmane could be a tobacco (or smoke) component other than nicotine involved in tobacco dependence. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  19. Varenicline and abnormal sleep related events.

    PubMed

    Savage, Ruth L; Zekarias, Alem; Caduff-Janosa, Pia

    2015-05-01

    To assess adverse drug reaction reports of "abnormal sleep related events" associated with varenicline, a partial agonist to the α4β2 subtype of nicotinic acetylcholine receptors on neurones, indicated for smoking cessation. Twenty-seven reports of "abnormal sleep related events" often associated with abnormal dreams, nightmares, or somnambulism, which are known to be associated with varenicline use, were identified in the World Health Organisation (WHO) Global Individual Case Safety Reports Database. Original anonymous reports were obtained from the four national pharmacovigilance centers that submitted these reports and assessed for reaction description and causality. These 27 reports include 10 of aggressive activity occurring during sleep and seven of other sleep related harmful or potentially harmful activities, such as apparently deliberate self-harm, moving a child or a car, or lighting a stove or a cigarette. Assessment of these 17 reports of aggression or other actual or potential harm showed that nine patients recovered or were recovering on varenicline withdrawal and there were no consistent alternative explanations. Thirteen patients experienced single events, and two had multiple events. Frequency was not stated for the remaining two patients. The descriptions of the reports of aggression during sleep with violent dreaming are similar to those of rapid eye movement sleep behavior disorder and also nonrapid eye movement (NREM) sleep parasomnias in some adults. Patients who experience somnambulism or dreams of a violent nature while taking varenicline should be advised to consult their health providers. Consideration should be given to clarifying the term sleep disorders in varenicline product information and including sleep related harmful and potentially harmful events. © 2015 Associated Professional Sleep Societies, LLC.

  20. Defects formation and spiral waves in a network of neurons in presence of electromagnetic induction.

    PubMed

    Rostami, Zahra; Jafari, Sajad

    2018-04-01

    Complex anatomical and physiological structure of an excitable tissue (e.g., cardiac tissue) in the body can represent different electrical activities through normal or abnormal behavior. Abnormalities of the excitable tissue coming from different biological reasons can lead to formation of some defects. Such defects can cause some successive waves that may end up to some additional reorganizing beating behaviors like spiral waves or target waves. In this study, formation of defects and the resulting emitted waves in an excitable tissue are investigated. We have considered a square array network of neurons with nearest-neighbor connections to describe the excitable tissue. Fundamentally, electrophysiological properties of ion currents in the body are responsible for exhibition of electrical spatiotemporal patterns. More precisely, fluctuation of accumulated ions inside and outside of cell causes variable electrical and magnetic field. Considering undeniable mutual effects of electrical field and magnetic field, we have proposed the new Hindmarsh-Rose (HR) neuronal model for the local dynamics of each individual neuron in the network. In this new neuronal model, the influence of magnetic flow on membrane potential is defined. This improved model holds more bifurcation parameters. Moreover, the dynamical behavior of the tissue is investigated in different states of quiescent, spiking, bursting and even chaotic state. The resulting spatiotemporal patterns are represented and the time series of some sampled neurons are displayed, as well.

  1. A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations

    PubMed Central

    Lin, Shih-Chieh; Nicolelis, Miguel A. L.

    2011-01-01

    The medial septum-vertical limb of the diagonal band of Broca (MSvDB) is important for normal hippocampal functions and theta oscillations. Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing <4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15∼30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these “pro-arousal” neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation. PMID:21865435

  2. Inhibition of cyclin-dependent kinase activity triggers neuronal differentiation of mouse neuroblastoma cells

    PubMed Central

    1995-01-01

    Studies on the molecular mechanisms underlying neuronal differentiation are frequently performed using cell lines established from neuroblastomas. In this study we have used mouse N1E-115 neuroblastoma cells that undergo neuronal differentiation in response to DMSO. During differentiation, cyclin-dependent kinase (cdk) activities decline and phosphorylation of the retinoblastoma gene product (pRb) is lost, leading to the appearance of a pRb-containing E2F DNA-binding complex. The loss of cdk2 activity is due to a decrease in cdk2 abundance whereas loss of cdk4 activity is caused by strong association with the cdk inhibitor (CKI) p27KIP1 and concurrent loss of cdk4 phosphorylation. Moreover, neuronal differentiation can be induced by overexpression of p27KIP1 or pRb, suggesting that inhibition of cdk activity leading to loss of pRb phosphorylation, is the major determinant for neuronal differentiation. PMID:7559779

  3. Contribution of amygdala CRF neurons to chronic pain.

    PubMed

    Andreoli, Matthew; Marketkar, Tanvi; Dimitrov, Eugene

    2017-12-01

    We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail-flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and ΔFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX-DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased ΔFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice. The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation

  4. Response of Cultured Neuronal Network Activity After High-Intensity Power Frequency Magnetic Field Exposure

    PubMed Central

    Saito, Atsushi; Takahashi, Masayuki; Makino, Kei; Suzuki, Yukihisa; Jimbo, Yasuhiko; Nakasono, Satoshi

    2018-01-01

    High-intensity and low frequency (1–100 kHz) time-varying electromagnetic fields stimulate the human body through excitation of the nervous system. In power frequency range (50/60 Hz), a frequency-dependent threshold of the external electric field-induced neuronal modulation in cultured neuronal networks was used as one of the biological indicator in international guidelines; however, the threshold of the magnetic field-induced neuronal modulation has not been elucidated. In this study, we exposed rat brain-derived neuronal networks to a high-intensity power frequency magnetic field (hPF-MF), and evaluated the modulation of synchronized bursting activity using a multi-electrode array (MEA)-based extracellular recording technique. As a result of short-term hPF-MF exposure (50–400 mT root-mean-square (rms), 50 Hz, sinusoidal wave, 6 s), the synchronized bursting activity was increased in the 400 mT-exposed group. On the other hand, no change was observed in the 50–200 mT-exposed groups. In order to clarify the mechanisms of the 400 mT hPF-MF exposure-induced neuronal response, we evaluated it after blocking inhibitory synapses using bicuculline methiodide (BMI); subsequently, increase in bursting activity was observed with BMI application, and the response of 400 mT hPF-MF exposure disappeared. Therefore, it was suggested that the response of hPF-MF exposure was involved in the inhibitory input. Next, we screened the inhibitory pacemaker-like neuronal activity which showed autonomous 4–10 Hz firing with CNQX and D-AP5 application, and it was confirmed that the activity was reduced after 400 mT hPF-MF exposure. Comparison of these experimental results with estimated values of the induced electric field (E-field) in the culture medium revealed that the change in synchronized bursting activity occurred over 0.3 V/m, which was equivalent to the findings of a previous study that used the external electric fields. In addition, the results suggested that the

  5. Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

    PubMed Central

    Hull, Michael J.; Soffe, Stephen R.; Willshaw, David J.; Roberts, Alan

    2016-01-01

    What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition. PMID:26824331

  6. Neuronal plasticity and neurotrophic factors in drug responses

    PubMed Central

    Castrén, Eero; Antila, Hanna

    2017-01-01

    Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs directly activate neurotrophins and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate: the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of

  7. AP4M1 is abnormally expressed in oxygen-glucose deprived hippocampal neurons.

    PubMed

    Zhang, J; Cheng, X Y; Sheng, G Y

    2014-03-20

    AP4M1 mutations have been suggested to be associated with autosomal recessive cerebral palsy syndrome. But the pathogenic mechanism remains uncertain. The purpose of this study is to investigate whether and how AP4M1 expression is changed in injured neurons. Primary cultured hippocampal neurons were prepared for this experiment. They were subjected to oxygen-glucose deprivation (OGD) leading to apoptosis, mimicking brain ischemia. Neuron-specific enolase (NSE) was labeled immunofluorescently to confirm that the purity of neuron was higher than 90%. Real-time PCR and western blotting were performed to measure the gene expression. AP4M1 was labeled with MAP2 or Tau-1 to observe the distribution. We found that the AP4M1 protein levels immediately after the procedure were similar between the OGD group and the sham group. However, down-regulation was observed 12h after the reperfusion, and became more notable at 24h. The real-time PCR showed similar results, except that the down-regulation of mRNA was able to be detected immediately after the OGD. Immunofluorescent labeling revealed AP4M1 distributed in the dendrites of normal neurons, but it redistributed to the axons after the OGD procedure. In conclusion, AP4M1 is not only down-regulated at both the mRNA and protein levels, but also redistributed from dendrites to axons in oxygen-glucose deprived hippocampal neurons. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Brain lactate kinetics: Modeling evidence for neuronal lactate uptake upon activation

    PubMed Central

    Aubert, Agnès; Costalat, Robert; Magistretti, Pierre J.; Pellerin, Luc

    2005-01-01

    A critical issue in brain energy metabolism is whether lactate produced within the brain by astrocytes is taken up and metabolized by neurons upon activation. Although there is ample evidence that neurons can efficiently use lactate as an energy substrate, at least in vitro, few experimental data exist to indicate that it is indeed the case in vivo. To address this question, we used a modeling approach to determine which mechanisms are necessary to explain typical brain lactate kinetics observed upon activation. On the basis of a previously validated model that takes into account the compartmentalization of energy metabolism, we developed a mathematical model of brain lactate kinetics, which was applied to published data describing the changes in extracellular lactate levels upon activation. Results show that the initial dip in the extracellular lactate concentration observed at the onset of stimulation can only be satisfactorily explained by a rapid uptake within an intraparenchymal cellular compartment. In contrast, neither blood flow increase, nor extracellular pH variation can be major causes of the lactate initial dip, whereas tissue lactate diffusion only tends to reduce its amplitude. The kinetic properties of monocarboxylate transporter isoforms strongly suggest that neurons represent the most likely compartment for activation-induced lactate uptake and that neuronal lactate utilization occurring early after activation onset is responsible for the initial dip in brain lactate levels observed in both animals and humans. PMID:16260743

  9. A new era for functional labeling of neurons: activity-dependent promoters have come of age

    PubMed Central

    Kawashima, Takashi; Okuno, Hiroyuki; Bito, Haruhiko

    2014-01-01

    Genetic labeling of neurons with a specific response feature is an emerging technology for precise dissection of brain circuits that are functionally heterogeneous at the single-cell level. While immediate early gene mapping has been widely used for decades to identify brain regions which are activated by external stimuli, recent characterization of the promoter and enhancer elements responsible for neuronal activity-dependent transcription have opened new avenues for live imaging of active neurons. Indeed, these advancements provided the basis for a growing repertoire of novel experiments to address the role of active neuronal networks in cognitive behaviors. In this review, we summarize the current literature on the usage and development of activity-dependent promoters and discuss the future directions of this expanding new field. PMID:24795570

  10. Interplay of activation kinetics and the derivative conductance determines resonance properties of neurons

    NASA Astrophysics Data System (ADS)

    Pena, Rodrigo F. O.; Ceballos, Cesar C.; Lima, Vinicius; Roque, Antonio C.

    2018-04-01

    In a neuron with hyperpolarization activated current (Ih), the correct input frequency leads to an enhancement of the output response. This behavior is known as resonance and is well described by the neuronal impedance. In a simple neuron model we derive equations for the neuron's resonance and we link its frequency and existence with the biophysical properties of Ih. For a small voltage change, the component of the ratio of current change to voltage change (d I /d V ) due to the voltage-dependent conductance change (d g /d V ) is known as derivative conductance (GhDer). We show that both GhDer and the current activation kinetics (characterized by the activation time constant τh) are mainly responsible for controlling the frequency and existence of resonance. The increment of both factors (GhDer and τh) greatly contributes to the appearance of resonance. We also demonstrate that resonance is voltage dependent due to the voltage dependence of GhDer. Our results have important implications and can be used to predict and explain resonance properties of neurons with the Ih current.

  11. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia

    PubMed Central

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-01-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that—against general belief—neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress. PMID:24569689

  12. Calcium imaging of neuronal activity in the most rostral parafacial respiratory group of the newborn rat.

    PubMed

    Onimaru, Hiroshi; Dutschmann, Mathias

    2012-01-01

    The parafacial respiratory group (pFRG) is thought to be involved in respiratory rhythm generation in neonates. This subgroup expresses the transcription factor, Phox2b, and contains intrinsically CO(2) sensitive neurons. Calcium imaging has been widely used for analysis of neuronal activity at the cellular and network level. In the present study, we applied calcium imaging to analyze neuronal activity of the most-rostral pFRG in an in vitro brainstem-spinal cord preparation from neonatal rats. We detected strong pre-inspiratory neuron activity in the most rostral pFRG, suggesting that significant numbers of pre-inspiratory neurons are localized in the ventrolateral medulla near the rostral end of the medulla. We show that usage of calcium imaging would be very useful for analysis of neuronal activity over different time scales, and discuss the advantages and disadvantages of this method.

  13. A novel framework for intelligent surveillance system based on abnormal human activity detection in academic environments.

    PubMed

    Al-Nawashi, Malek; Al-Hazaimeh, Obaida M; Saraee, Mohamad

    2017-01-01

    Abnormal activity detection plays a crucial role in surveillance applications, and a surveillance system that can perform robustly in an academic environment has become an urgent need. In this paper, we propose a novel framework for an automatic real-time video-based surveillance system which can simultaneously perform the tracking, semantic scene learning, and abnormality detection in an academic environment. To develop our system, we have divided the work into three phases: preprocessing phase, abnormal human activity detection phase, and content-based image retrieval phase. For motion object detection, we used the temporal-differencing algorithm and then located the motions region using the Gaussian function. Furthermore, the shape model based on OMEGA equation was used as a filter for the detected objects (i.e., human and non-human). For object activities analysis, we evaluated and analyzed the human activities of the detected objects. We classified the human activities into two groups: normal activities and abnormal activities based on the support vector machine. The machine then provides an automatic warning in case of abnormal human activities. It also embeds a method to retrieve the detected object from the database for object recognition and identification using content-based image retrieval. Finally, a software-based simulation using MATLAB was performed and the results of the conducted experiments showed an excellent surveillance system that can simultaneously perform the tracking, semantic scene learning, and abnormality detection in an academic environment with no human intervention.

  14. Differential receptor activation by cockroach adipokinetic hormones produces differential effects on ion currents, neuronal activity, and locomotion.

    PubMed

    Wicher, Dieter; Agricola, Hans-Jürgen; Söhler, Sandra; Gundel, Matthias; Heinemann, Stefan H; Wollweber, Leo; Stengl, Monika; Derst, Christian

    2006-04-01

    Adipokinetic hormone (AKH) peptides in insects serve the endocrine control of energy supply. They also produce, however, neuronal, vegetative, and motor effects, suggesting that AKHs orchestrate adaptive behavior by multiple actions. We have cloned, for Periplaneta americana, the AKH receptor to determine its localization and, based on current measurements in neurons and heterologous expression systems, the mechanisms of AKH actions. Apart from fat body, various neurons express the AKH receptor, among them abdominal dorsal unpaired median (DUM) neurons, which release the biogenic amine octopamine. They are part of the arousal system and are involved in the control of circulation and respiration. Both the two Periplaneta AKHs activate the Gs pathway, and AKH I also potently activates Gq. AKH I and--with much less efficacy--AKH II accelerate spiking of DUM neurons through an increase of the pacemaking Ca2+ current. Because the AKHs are released from the corpora cardiaca into the hemolymph, they must penetrate the blood-brain barrier for acting on neurons. That this happens was shown electrophysiologically by applying AKH I to an intact ganglion. Systemically injected AKH I stimulates locomotion potently in striking contrast to AKH II. This behavioral difference can be traced back conclusively to the different effectiveness of the AKHs on the level of G proteins. Our findings also show that AKHs act through the same basic mechanisms on neuronal and nonneuronal cells, and they support an integration of metabolic and neuronal effects in homoeostatic mechanisms.

  15. Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons.

    PubMed

    Ji, Sheng-Jian; Zhuang, BinQuan; Falco, Crystal; Schneider, André; Schuster-Gossler, Karin; Gossler, Achim; Sockanathan, Shanthini

    2006-09-01

    During embryonic development, the generation, diversification and maintenance of spinal motor neurons depend upon extrinsic signals that are tightly regulated. Retinoic acid (RA) is necessary for specifying the fates of forelimb-innervating motor neurons of the Lateral Motor Column (LMC), and the specification of LMC neurons into medial and lateral subtypes. Previous studies implicate motor neurons as the relevant source of RA for specifying lateral LMC fates at forelimb levels. However, at the time of LMC diversification, a significant amount of retinoids in the spinal cord originates from the adjacent paraxial mesoderm. Here we employ mouse genetics to show that RA derived from the paraxial mesoderm is required for lateral LMC induction at forelimb and hindlimb levels, demonstrating that mesodermally synthesized RA functions as a second source of signals to specify lateral LMC identity. Furthermore, reduced RA levels in postmitotic motor neurons result in a decrease of medial and lateral LMC neurons, and abnormal axonal projections in the limb; invoking additional roles for neuronally synthesized RA in motor neuron maintenance and survival. These findings suggest that during embryogenesis, mesodermal and neuronal retinoids act coordinately to establish and maintain appropriate cohorts of spinal motor neurons that innervate target muscles in the limb.

  16. Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors.

    PubMed

    Quintana, Albert; Sanz, Elisenda; Wang, Wengang; Storey, Granville P; Güler, Ali D; Wanat, Matthew J; Roller, Bryan A; La Torre, Anna; Amieux, Paul S; McKnight, G Stanley; Bamford, Nigel S; Palmiter, Richard D

    2012-11-01

    The striatum regulates motor control, reward and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G protein-coupled receptor GPR88 is robustly expressed in MSNs and is regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. We found that, in the absence of GPR88, MSNs showed increased glutamatergic excitation and reduced GABAergic inhibition, which promoted enhanced firing rates in vivo, resulting in hyperactivity, poor motor coordination and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescued the molecular and electrophysiological properties and normalized behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

  17. Light adaptation does not prevent early retinal abnormalities in diabetic rats

    PubMed Central

    Kur, Joanna; Burian, Michael A.; Newman, Eric A.

    2016-01-01

    The aetiology of diabetic retinopathy (DR), the leading cause of blindness in the developed world, remains controversial. One hypothesis holds that retinal hypoxia, exacerbated by the high O2 consumption of rod photoreceptors in the dark, is a primary cause of DR. Based on this prediction we investigated whether early retinal abnormalities in streptozotocin-induced diabetic rats are alleviated by preventing the rods from dark adapting. Diabetic rats and their non-diabetic littermates were housed in a 12:12 hour light-dim light photocycle (30 lux during the day and 3 lux at night). Progression of early retinal abnormalities in diabetic rats was assessed by monitoring the ERG b-wave and oscillatory potentials, Müller cell reactive gliosis, and neuronal cell death, as assayed by TUNEL staining and retinal thickness at 6 and 12 weeks after diabetes induction. Maintaining diabetic animals in a dim-adapting light did not slow the progression of these neuronal and glial changes when compared to diabetic rats maintained in a standard 12:12 hour light-dark photocycle (30 lux during the day and 0 lux at night). Our results indicate that neuronal and glial abnormalities in early stages of diabetes are not exacerbated by rod photoreceptor O2 consumption in the dark. PMID:26852722

  18. Curtailing effect of awakening on visual responses of cortical neurons by cholinergic activation of inhibitory circuits.

    PubMed

    Kimura, Rui; Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Kimura, Rie; Ebina, Teppei; Yanagawa, Yuchio; Sohya, Kazuhiro; Tsumoto, Tadaharu

    2014-07-23

    Visual responsiveness of cortical neurons changes depending on the brain state. Neural circuit mechanism underlying this change is unclear. By applying the method of in vivo two-photon functional calcium imaging to transgenic rats in which GABAergic neurons express fluorescent protein, we analyzed changes in visual response properties of cortical neurons when animals became awakened from anesthesia. In the awake state, the magnitude and reliability of visual responses of GABAergic neurons increased whereas the decay of responses of excitatory neurons became faster. To test whether the basal forebrain (BF) cholinergic projection is involved in these changes, we analyzed effects of electrical and optogenetic activation of BF on visual responses of mouse cortical neurons with in vivo imaging and whole-cell recordings. Electrical BF stimulation in anesthetized animals induced the same direction of changes in visual responses of both groups of neurons as awakening. Optogenetic activation increased the frequency of visually evoked action potentials in GABAergic neurons but induced the delayed hyperpolarization that ceased the late generation of action potentials in excitatory neurons. Pharmacological analysis in slice preparations revealed that photoactivation-induced depolarization of layer 1 GABAergic neurons was blocked by a nicotinic receptor antagonist, whereas non-fast-spiking layer 2/3 GABAergic neurons was blocked only by the application of both nicotinic and muscarinic receptor antagonists. These results suggest that the effect of awakening is mediated mainly through nicotinic activation of layer 1 GABAergic neurons and mixed nicotinic/muscarinic activation of layer 2/3 non-fast-spiking GABAergic neurons, which together curtails the visual responses of excitatory neurons. Copyright © 2014 the authors 0270-6474/14/3410122-12$15.00/0.

  19. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

    PubMed

    Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

    2013-08-01

    Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  20. Operant conditioning of synaptic and spiking activity patterns in single hippocampal neurons.

    PubMed

    Ishikawa, Daisuke; Matsumoto, Nobuyoshi; Sakaguchi, Tetsuya; Matsuki, Norio; Ikegaya, Yuji

    2014-04-02

    Learning is a process of plastic adaptation through which a neural circuit generates a more preferable outcome; however, at a microscopic level, little is known about how synaptic activity is patterned into a desired configuration. Here, we report that animals can generate a specific form of synaptic activity in a given neuron in the hippocampus. In awake, head-restricted mice, we applied electrical stimulation to the lateral hypothalamus, a reward-associated brain region, when whole-cell patch-clamped CA1 neurons exhibited spontaneous synaptic activity that met preset criteria. Within 15 min, the mice learned to generate frequently the excitatory synaptic input pattern that satisfied the criteria. This reinforcement learning of synaptic activity was not observed for inhibitory input patterns. When a burst unit activity pattern was conditioned in paired and nonpaired paradigms, the frequency of burst-spiking events increased and decreased, respectively. The burst reinforcement occurred in the conditioned neuron but not in other adjacent neurons; however, ripple field oscillations were concomitantly reinforced. Neural conditioning depended on activation of NMDA receptors and dopamine D1 receptors. Acutely stressed mice and depression model mice that were subjected to forced swimming failed to exhibit the neural conditioning. This learning deficit was rescued by repetitive treatment with fluoxetine, an antidepressant. Therefore, internally motivated animals are capable of routing an ongoing action potential series into a specific neural pathway of the hippocampal network.

  1. Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss through activating microglial NADPH oxidase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Yinxi; Liu, Dan; Zhang, Huifeng

    Background: Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. Methods: Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPHmore » oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. Results: In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100 μg/cm{sup 2} induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10 μg/cm{sup 2}) and rotenone (2 nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91{sup phox}, p47{sup phox} and p40{sup phox}); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47{sup phox} and p67{sup phox} translocation assembling active NADPH oxidase. Conclusion: ufCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to

  2. Attention-related changes in correlated neuronal activity arise from normalization mechanisms

    PubMed Central

    Verhoef, Bram-Ernst; Maunsell, John H.R.

    2017-01-01

    Attention is believed to enhance perception by altering the correlations between pairs of neurons. How attention changes neuronal correlations is unknown. Using multi-electrodes in primate visual cortex, we measured spike-count correlations when single or multiple stimuli were presented, and stimuli were attended or unattended. When stimuli were unattended, adding a suppressive, non-preferred, stimulus beside a preferred stimulus increased spike-count correlations between pairs of similarly-tuned neurons, but decreased spike-count correlations between pairs of oppositely-tuned neurons. These changes are explained by a stochastic normalization model containing populations of oppositely-tuned, mutually-suppressive neurons. Importantly, this model also explains why attention decreased (attend preferred stimulus) or increased (attend non-preferred stimulus) correlations: as an indirect consequence of attention-related changes in the inputs to normalization mechanisms. Our findings link normalization mechanisms to correlated neuronal activity and attention, showing that normalization mechanisms shape response correlations and that these correlations change when attention biases normalization mechanisms. PMID:28553943

  3. Activation of Brainstem Pro-opiomelanocortin Neurons Produces Opioidergic Analgesia, Bradycardia and Bradypnoea

    PubMed Central

    Hirschberg, Stefan; Hill, Rob; Balthasar, Nina; Pickering, Anthony E.

    2016-01-01

    Opioids are widely used medicinally as analgesics and abused for hedonic effects, actions that are each complicated by substantial risks such as cardiorespiratory depression. These drugs mimic peptides such as β-endorphin, which has a key role in endogenous analgesia. The β-endorphin in the central nervous system originates from pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and nucleus of the solitary tract (NTS). Relatively little is known about the NTSPOMC neurons but their position within the sensory nucleus of the vagus led us to test the hypothesis that they play a role in modulation of cardiorespiratory and nociceptive control. The NTSPOMC neurons were targeted using viral vectors in a POMC-Cre mouse line to express either opto-genetic (channelrhodopsin-2) or chemo-genetic (Pharmacologically Selective Actuator Modules). Opto-genetic activation of the NTSPOMC neurons in the working heart brainstem preparation (n = 21) evoked a reliable, titratable and time-locked respiratory inhibition (120% increase in inter-breath interval) with a bradycardia (125±26 beats per minute) and augmented respiratory sinus arrhythmia (58% increase). Chemo-genetic activation of NTSPOMC neurons in vivo was anti-nociceptive in the tail flick assay (latency increased by 126±65%, p<0.001; n = 8). All effects of NTSPOMC activation were blocked by systemic naloxone (opioid antagonist) but not by SHU9119 (melanocortin receptor antagonist). The NTSPOMC neurons were found to project to key brainstem structures involved in cardiorespiratory control (nucleus ambiguus and ventral respiratory group) and endogenous analgesia (periaqueductal gray and midline raphe). Thus the NTSPOMC neurons may be capable of tuning behaviour by an opioidergic modulation of nociceptive, respiratory and cardiac control. PMID:27077912

  4. Novel DLK-independent neuronal regeneration in Caenorhabditis elegans shares links with activity-dependent ectopic outgrowth

    PubMed Central

    Awal, Mehraj R.; Shay, James; McLoed, Melissa M.; Mazur, Eric; Gabel, Christopher V.

    2016-01-01

    During development, a neuron transitions from a state of rapid growth to a stable morphology, and neurons within the adult mammalian CNS lose their ability to effectively regenerate in response to injury. Here, we identify a novel form of neuronal regeneration, which is remarkably independent of DLK-1/DLK, KGB-1/JNK, and other MAPK signaling factors known to mediate regeneration in Caenorhabditis elegans, Drosophila, and mammals. This DLK-independent regeneration in C. elegans has direct genetic and molecular links to a well-studied form of endogenous activity-dependent ectopic axon outgrowth in the same neuron type. Both neuron outgrowth types are triggered by physical lesion of the sensory dendrite or mutations disrupting sensory activity, calcium signaling, or genes that restrict outgrowth during neuronal maturation, such as SAX-1/NDR kinase or UNC-43/CaMKII. These connections suggest that ectopic outgrowth represents a powerful platform for gene discovery in neuronal regeneration. Moreover, we note numerous similarities between C. elegans DLK-independent regeneration and lesion conditioning, a phenomenon producing robust regeneration in the mammalian CNS. Both regeneration types are triggered by lesion of a sensory neurite via reduction of neuronal activity and enhanced by disrupting L-type calcium channels or elevating cAMP. Taken as a whole, our study unites disparate forms of neuronal outgrowth to uncover fresh molecular insights into activity-dependent control of the adult nervous system’s intrinsic regenerative capacity. PMID:27078101

  5. Stress and Sucrose Intake Modulate Neuronal Activity in the Anterior Hypothalamic Area in Rats

    PubMed Central

    Mitra, Arojit; Guèvremont, Geneviève; Timofeeva, Elena

    2016-01-01

    The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter-lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS-inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non-stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry

  6. Stress and Sucrose Intake Modulate Neuronal Activity in the Anterior Hypothalamic Area in Rats.

    PubMed

    Mitra, Arojit; Guèvremont, Geneviève; Timofeeva, Elena

    2016-01-01

    The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter-lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS-inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non-stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry.

  7. Alterations of cortical GABA neurons and network oscillations in schizophrenia.

    PubMed

    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.

  8. Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats.

    PubMed

    Zold, Camila L; Ballion, Bérangère; Riquelme, Luis A; Gonon, François; Murer, M Gustavo

    2007-04-01

    There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.

  9. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity.

    PubMed

    Shi, Xuemei; Chacko, Shaji; Li, Feng; Li, Depei; Burrin, Douglas; Chan, Lawrence; Guan, Xinfu

    2017-11-01

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp. We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons NTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly. We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  10. Circadian Activators Are Expressed Days before They Initiate Clock Function in Late Pacemaker Neurons from Drosophila.

    PubMed

    Liu, Tianxin; Mahesh, Guruswamy; Houl, Jerry H; Hardin, Paul E

    2015-06-03

    Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. Copyright © 2015 the authors 0270-6474/15/358662-10$15.00/0.

  11. Common inputs in subthreshold membrane potential: The role of quiescent states in neuronal activity

    NASA Astrophysics Data System (ADS)

    Montangie, Lisandro; Montani, Fernando

    2018-06-01

    Experiments in certain regions of the cerebral cortex suggest that the spiking activity of neuronal populations is regulated by common non-Gaussian inputs across neurons. We model these deviations from random-walk processes with q -Gaussian distributions into simple threshold neurons, and investigate the scaling properties in large neural populations. We show that deviations from the Gaussian statistics provide a natural framework to regulate population statistics such as sparsity, entropy, and specific heat. This type of description allows us to provide an adequate strategy to explain the information encoding in the case of low neuronal activity and its possible implications on information transmission.

  12. Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

    PubMed

    Dulka, Eden A; Moenter, Suzanne M

    2017-11-01

    Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype. Copyright © 2017 Endocrine Society.

  13. Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice

    PubMed Central

    Yu, Tian; Taussig, Matthew D.; DiPatrizio, Nicholas V.; Astarita, Giuseppe; Piomelli, Daniele; Bergman, Bryan C.; Dell’Acqua, Mark L.; Eckel, Robert H.; Wang, Hong

    2015-01-01

    Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer’s disease. Lipoprotein lipase (LPL) hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS). Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/-) and 10 mo in heterozygous mice (NEXLPL+/-). In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid β accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA) in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation. PMID:26263173

  14. Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS.

    PubMed

    Yamashita, Takenari; Kwak, Shin

    2018-06-23

    TAR DNA-binding protein (TDP-43) pathology in the motor neurons is the most reliable pathological hallmark of amyotrophic lateral sclerosis (ALS), and motor neurons bearing TDP-43 pathology invariably exhibit failure in RNA editing at the GluA2 glutamine/arginine (Q/R) site due to down-regulation of adenosine deaminase acting on RNA 2 (ADAR2). Conditional ADAR2 knockout (AR2) mice display ALS-like phenotype, including progressive motor dysfunction due to loss of motor neurons. Motor neurons devoid of ADAR2 express Q/R site-unedited GluA2, and AMPA receptors with unedited GluA2 in their subunit assembly are abnormally permeable to Ca 2+ , which results in progressive neuronal death. Moreover, analysis of AR2 mice has demonstrated that exaggerated Ca 2+ influx through the abnormal AMPA receptors overactivates calpain, a Ca 2+ -dependent protease, that cleaves TDP-43 into aggregation-prone fragments, which serve as seeds for TDP-43 pathology. Activated calpain also disrupts nucleo-cytoplasmic transport and gene expression by cleaving molecules involved in nucleocytoplasmic transport, including nucleoporins. These lines of evidence prompted us to develop molecular targeting therapy for ALS by normalization of disrupted intracellular environment due to ADAR2 down-regulation. In this review, we have summarized the work from our group on the cell death cascade in sporadic ALS and discussed a potential therapeutic strategy for ALS. Copyright © 2018 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  15. Maintenance of neuronal size gradient in MNTB requires sound-evoked activity.

    PubMed

    Weatherstone, Jessica H; Kopp-Scheinpflug, Conny; Pilati, Nadia; Wang, Yuan; Forsythe, Ian D; Rubel, Edwin W; Tempel, Bruce L

    2017-02-01

    The medial nucleus of the trapezoid body (MNTB) is an important source of inhibition during the computation of sound location. It transmits fast and precisely timed action potentials at high frequencies; this requires an efficient calcium clearance mechanism, in which plasma membrane calcium ATPase 2 (PMCA2) is a key component. Deafwaddler ( dfw 2J ) mutant mice have a null mutation in PMCA2 causing deafness in homozygotes ( dfw 2J / dfw 2J ) and high-frequency hearing loss in heterozygotes (+/ dfw 2J ). Despite the deafness phenotype, no significant differences in MNTB volume or cell number were observed in dfw 2J homozygous mutants, suggesting that PMCA2 is not required for MNTB neuron survival. The MNTB tonotopic axis encodes high to low sound frequencies across the medial to lateral dimension. We discovered a cell size gradient along this axis: lateral neuronal somata are significantly larger than medially located somata. This size gradient is decreased in +/ dfw 2J and absent in dfw 2J / dfw 2J The lack of acoustically driven input suggests that sound-evoked activity is required for maintenance of the cell size gradient. This hypothesis was corroborated by selective elimination of auditory hair cell activity with either hair cell elimination in Pou4f3 DTR mice or inner ear tetrodotoxin (TTX) treatment. The change in soma size was reversible and recovered within 7 days of TTX treatment, suggesting that regulation of the gradient is dependent on synaptic activity and that these changes are plastic rather than permanent. NEW & NOTEWORTHY Neurons of the medial nucleus of the trapezoid body (MNTB) act as fast-spiking inhibitory interneurons within the auditory brain stem. The MNTB is topographically organized, with low sound frequencies encoded laterally and high frequencies medially. We discovered a cell size gradient along this axis: lateral neurons are larger than medial neurons. The absence of this gradient in deaf mice lacking plasma membrane calcium ATPase 2

  16. NG2 glial cells regulate neuroimmunological responses to maintain neuronal function and survival.

    PubMed

    Nakano, Masayuki; Tamura, Yasuhisa; Yamato, Masanori; Kume, Satoshi; Eguchi, Asami; Takata, Kumi; Watanabe, Yasuyoshi; Kataoka, Yosky

    2017-02-14

    NG2-expressing neural progenitor cells (i.e., NG2 glial cells) maintain their proliferative and migratory activities even in the adult mammalian central nervous system (CNS) and produce myelinating oligodendrocytes and astrocytes. Although NG2 glial cells have been observed in close proximity to neuronal cell bodies in order to receive synaptic inputs, substantive non-proliferative roles of NG2 glial cells in the adult CNS remain unclear. In the present study, we generated NG2-HSVtk transgenic rats and selectively ablated NG2 glial cells in the adult CNS. Ablation of NG2 glial cells produced defects in hippocampal neurons due to excessive neuroinflammation via activation of the interleukin-1 beta (IL-1β) pro-inflammatory pathway, resulting in hippocampal atrophy. Furthermore, we revealed that the loss of NG2 glial cell-derived hepatocyte growth factor (HGF) exacerbated these abnormalities. Our findings suggest that NG2 glial cells maintain neuronal function and survival via the control of neuroimmunological function.

  17. Layer-specific optogenetic activation of pyramidal neurons causes beta–gamma entrainment of neonatal networks

    PubMed Central

    Bitzenhofer, Sebastian H; Ahlbeck, Joachim; Wolff, Amy; Wiegert, J. Simon; Gee, Christine E.; Oertner, Thomas G.; Hanganu-Opatz, Ileana L.

    2017-01-01

    Coordinated activity patterns in the developing brain may contribute to the wiring of neuronal circuits underlying future behavioural requirements. However, causal evidence for this hypothesis has been difficult to obtain owing to the absence of tools for selective manipulation of oscillations during early development. We established a protocol that combines optogenetics with electrophysiological recordings from neonatal mice in vivo to elucidate the substrate of early network oscillations in the prefrontal cortex. We show that light-induced activation of layer II/III pyramidal neurons that are transfected by in utero electroporation with a high-efficiency channelrhodopsin drives frequency-specific spiking and boosts network oscillations within beta–gamma frequency range. By contrast, activation of layer V/VI pyramidal neurons causes nonspecific network activation. Thus, entrainment of neonatal prefrontal networks in fast rhythms relies on the activation of layer II/III pyramidal neurons. This approach used here may be useful for further interrogation of developing circuits, and their behavioural readout. PMID:28216627

  18. Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome.

    PubMed

    Wirth, Eva K; Roth, Stephan; Blechschmidt, Cristiane; Hölter, Sabine M; Becker, Lore; Racz, Ildiko; Zimmer, Andreas; Klopstock, Thomas; Gailus-Durner, Valerie; Fuchs, Helmut; Wurst, Wolfgang; Naumann, Thomas; Bräuer, Anja; de Angelis, Martin Hrabé; Köhrle, Josef; Grüters, Annette; Schweizer, Ulrich

    2009-07-29

    Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

  19. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons

    NASA Technical Reports Server (NTRS)

    Wurtman, R. J.

    1992-01-01

    The unique propensity of cholinergic neurons to use choline for two purposes--ACh and membrane phosphatidylcholine synthesis--may contribute to their selective vulnerability in Alzheimer's disease and other cholinergic neurodegenerative disorders. When physiologically active, the neurons use free choline taken from the 'reservoir' in membrane phosphatidylcholine to synthesize ACh; this can lead to an actual decrease in the quantity of membrane per cell. Alzheimer's disease (but not Down's syndrome, or other neurodegenerative disorders) is associated with characteristic neurochemical lesions involving choline and ethanolamine: brain levels of these compounds are diminished, while those of glycerophosphocholine and glycerophosphoethanolamine (breakdown products of their respective membrane phosphatides) are increased, both in cholinergic and noncholinergic brain regions. Perhaps this metabolic disturbance and the tendency of cholinergic neurons to 'export' choline--in the form of ACh--underlie the selective vulnerability of the neurons. Resulting changes in membrane composition could abnormally expose intramembraneous proteins such as amyloid precursor protein to proteases.

  20. Upregulation of Ih expressed in IB4-negative Aδ nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain

    PubMed Central

    Liu, Da-Lu; Lu, Na; Han, Wen-Juan; Chen, Rong-Gui; Cong, Rui; Xie, Rou-Gang; Zhang, Yu-Fei; Kong, Wei-Wei; Hu, San-Jue; Luo, Ceng

    2015-01-01

    Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4− Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4- Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy. PMID:26577374

  1. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  2. Nerve Growth Factor Gene Therapy Activates Neuronal Responses in Alzheimer’s Disease

    PubMed Central

    Tuszynski, Mark H.; Yang, Jennifer H.; Barba, David; U, H S.; Bakay, Roy; Pay, Mary M.; Masliah, Eliezer; Conner, James M.; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H.

    2016-01-01

    IMPORTANCE Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and lacks effective disease modifying therapies. In 2001 we initiated a clinical trial of Nerve Growth Factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in AD patients. We present post-mortem findings in 10 subjects with survival times ranging from 1 to 10 years post-treatment. OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS 10 patients with early AD underwent NGF gene therapy using either ex vivo or in vivo gene transfer. The brains of all eight patients in the first Phase 1 ex vivo trial and two patients in a subsequent Phase 1 in vivo trial were examined. MAIN OUTCOME MEASURES Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In two cases, NGF protein levels were measured by ELISA. RESULTS Degenerating neurons in the AD brain respond to NGF. All patients exhibited a trophic response to NGF, in the form of axonal sprouting toward the NGF source. Comparing treated and non-treated sides of the brain in three patients that underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P>0.05). Activation of cellular signaling and functional markers were present in two patients that underwent AAV2-mediated NGF gene transfer. Neurons exhibiting tau pathology as well as neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes with resulting activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE These findings indicate that

  3. An Improved Ivermectin-activated Chloride Channel Receptor for Inhibiting Electrical Activity in Defined Neuronal Populations*

    PubMed Central

    Lynagh, Timothy; Lynch, Joseph W.

    2010-01-01

    The ability to silence the electrical activity of defined neuronal populations in vivo is dramatically advancing our understanding of brain function. This technology may eventually be useful clinically for treating a variety of neuropathological disorders caused by excessive neuronal activity. Several neuronal silencing methods have been developed, with the bacterial light-activated halorhodopsin and the invertebrate allatostatin-activated G protein-coupled receptor proving the most successful to date. However, both techniques may be difficult to implement clinically due to their requirement for surgically implanted stimulus delivery methods and their use of nonhuman receptors. A third silencing method, an invertebrate glutamate-gated chloride channel receptor (GluClR) activated by ivermectin, solves the stimulus delivery problem as ivermectin is a safe, well tolerated drug that reaches the brain following systemic administration. However, the limitations of this method include poor functional expression, possibly due to the requirement to coexpress two different subunits in individual neurons, and the nonhuman origin of GluClR. Here, we describe the development of a modified human α1 glycine receptor as an improved ivermectin-gated silencing receptor. The crucial development was the identification of a mutation, A288G, which increased ivermectin sensitivity almost 100-fold, rendering it similar to that of GluClR. Glycine sensitivity was eliminated via the F207A mutation. Its large unitary conductance, homomeric expression, and human origin may render the F207A/A288G α1 glycine receptor an improved silencing receptor for neuroscientific and clinical purposes. As all known highly ivermectin-sensitive GluClRs contain an endogenous glycine residue at the corresponding location, this residue appears essential for exquisite ivermectin sensitivity. PMID:20308070

  4. MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling

    PubMed Central

    Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

    2014-01-01

    Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. PMID:25224226

  5. MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling.

    PubMed

    Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

    2014-11-01

    Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Neuropeptide secreted from a pacemaker activates neurons to control a rhythmic behavior.

    PubMed

    Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P; Dasgupta, Krishnakali; Knowles, James A; Schoofs, Liliane; Sieburth, Derek

    2013-05-06

    Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 s, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Here, we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G-protein-coupled receptor on the GABAergic neurons, as the receptor for NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Neuropeptide Secreted from a Pacemaker Activates Neurons to Control a Rhythmic Behavior

    PubMed Central

    Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P.; Dasgupta, Krishnakali; Knowles, James A.; Schoofs, Liliane; Sieburth, Derek

    2013-01-01

    Summary Background Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 seconds, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Results Here we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G protein-coupled receptor on the GABAergic neurons, as the receptor of NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Conclusions Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors. PMID:23583549

  8. Control of abdominal and expiratory intercostal muscle activity during vomiting - Role of ventral respiratory group expiratory neurons

    NASA Technical Reports Server (NTRS)

    Miller, Alan D.; Tan, L. K.; Suzuki, Ichiro

    1987-01-01

    The role of ventral respiratory group (VRG) expiratory (E) neurons in the control of abdominal and internal intercostal muscle activity during vomiting was investigated in cats. Two series of experiments were performed: in one, the activity of VRG E neurons was recorded during fictive vomiting in cats that were decerebrated, paralyzed, and artificially ventilated; in the second, the abdominal muscle activity during vomiting was compared before and after sectioning the axons of descending VRG E neurons in decerebrate spontaneously breathing cats. The results show that about two-thirds of VRG E neurons that project at least as far caudally as the lower thoracic cord contribute to internal intercostal muscle activity during vomiting. The remaining VRG E neurons contribute to abdominal muscle activation. As shown by severing the axons of the VRG E neurons, other, as yet unidenified, inputs (either descending from the brain stem or arising from spinal reflexes) can also produce abdominal muscle activation.

  9. [Effect of nootropic agents on impulse activity of cerebral cortex neurons].

    PubMed

    Iasnetsov, V V; Pravdivtsev, V A; Krylova, I N; Kozlov, S B; Provornova, N A; Ivanov, Iu V; Iasnetsov, V V

    2001-01-01

    The effect of nootropes (semax, mexidol, and GVS-111) on the activity of individual neurons in various cerebral cortex regions was studied by microelectrode and microionophoresis techniques in cats immobilized by myorelaxants. It was established that the inhibiting effect of mexidol upon neurons in more than half of cases is prevented or significantly decreased by the GABA antagonists bicuculline and picrotoxin. The inhibiting effect of semax and GVS-111 upon neurons in more than half of cases is related to stimulation of the M-choline and NMDA receptors, respectively.

  10. Behavioral State Modulates the Activity of Brainstem Sensorimotor Neurons

    PubMed Central

    McArthur, Kimberly L.

    2011-01-01

    Sensorimotor processing must be modulated according to the animal's behavioral state. A previous study demonstrated that motion responses were strongly state dependent in birds. Vestibular eye and head responses were significantly larger and more compensatory during simulated flight, and a flight-specific vestibular tail response was also characterized. In the current study, we investigated the neural substrates for these state-dependent vestibular behaviors by recording extracellularly from neurons in the vestibular nuclear complex and comparing their spontaneous activity and sensory responses during default and simulated flight states. We show that motion-sensitive neurons in the lateral vestibular nucleus are state dependent. Some neurons increased their spontaneous firing rates during flight, though their increased excitability was not reflected in higher sensory gains. However, other neurons exhibited state-dependent gating of sensory inputs, responding to rotational stimuli only during flight. These results demonstrate that vestibular processing in the brainstem is state dependent and lay the foundation for future studies to investigate the synaptic mechanisms responsible for these modifications. PMID:22090497

  11. Effect of acute stretch injury on action potential and network activity of rat neocortical neurons in culture.

    PubMed

    Magou, George C; Pfister, Bryan J; Berlin, Joshua R

    2015-10-22

    The basis for acute seizures following traumatic brain injury (TBI) remains unclear. Animal models of TBI have revealed acute hyperexcitablility in cortical neurons that could underlie seizure activity, but studying initiating events causing hyperexcitability is difficult in these models. In vitro models of stretch injury with cultured cortical neurons, a surrogate for TBI, allow facile investigation of cellular changes after injury but they have only demonstrated post-injury hypoexcitability. The goal of this study was to determine if neuronal hyperexcitability could be triggered by in vitro stretch injury. Controlled uniaxial stretch injury was delivered to a spatially delimited region of a spontaneously active network of cultured rat cortical neurons, yielding a region of stretch-injured neurons and adjacent regions of non-stretched neurons that did not directly experience stretch injury. Spontaneous electrical activity was measured in non-stretched and stretch-injured neurons, and in control neuronal networks not subjected to stretch injury. Non-stretched neurons in stretch-injured cultures displayed a three-fold increase in action potential firing rate and bursting activity 30-60 min post-injury. Stretch-injured neurons, however, displayed dramatically lower rates of action potential firing and bursting. These results demonstrate that acute hyperexcitability can be observed in non-stretched neurons located in regions adjacent to the site of stretch injury, consistent with reports that seizure activity can arise from regions surrounding the site of localized brain injury. Thus, this in vitro procedure for localized neuronal stretch injury may provide a model to study the earliest cellular changes in neuronal function associated with acute post-traumatic seizures. Copyright © 2015. Published by Elsevier B.V.

  12. Temperature influences neuronal activity and CO2/pH sensitivity of locus coeruleus neurons in the bullfrog, Lithobates catesbeianus.

    PubMed

    Santin, Joseph M; Watters, Kayla C; Putnam, Robert W; Hartzler, Lynn K

    2013-12-15

    The locus coeruleus (LC) is a chemoreceptive brain stem region in anuran amphibians and contains neurons sensitive to physiological changes in CO2/pH. The ventilatory and central sensitivity to CO2/pH is proportional to the temperature in amphibians, i.e., sensitivity increases with increasing temperature. We hypothesized that LC neurons from bullfrogs, Lithobates catesbeianus, would increase CO2/pH sensitivity with increasing temperature and decrease CO2/pH sensitivity with decreasing temperature. Further, we hypothesized that cooling would decrease, while warming would increase, normocapnic firing rates of LC neurons. To test these hypotheses, we used whole cell patch-clamp electrophysiology to measure firing rate, membrane potential (V(m)), and input resistance (R(in)) in LC neurons in brain stem slices from adult bullfrogs over a physiological range of temperatures during normocapnia and hypercapnia. We found that cooling reduced chemosensitive responses of LC neurons as temperature decreased until elimination of CO2/pH sensitivity at 10°C. Chemosensitive responses increased at elevated temperatures. Surprisingly, chemosensitive LC neurons increased normocapnic firing rate and underwent membrane depolarization when cooled and decreased normocapnic firing rate and underwent membrane hyperpolarization when warmed. These responses to temperature were not observed in nonchemosensitive LC neurons or neurons in a brain stem slice 500 μm rostral to the LC. Our results indicate that modulation of cellular chemosensitivity within the LC during temperature changes may influence temperature-dependent respiratory drive during acid-base disturbances in amphibians. Additionally, cold-activated/warm-inhibited LC neurons introduce paradoxical temperature sensitivity in respiratory control neurons of amphibians.

  13. Imaging of Neuronal Activity in Awake Mice by Measurements of Flavoprotein Autofluorescence Corrected for Cerebral Blood Flow.

    PubMed

    Takahashi, Manami; Urushihata, Takuya; Takuwa, Hiroyuki; Sakata, Kazumi; Takado, Yuhei; Shimizu, Eiji; Suhara, Tetsuya; Higuchi, Makoto; Ito, Hiroshi

    2017-01-01

    Green fluorescence imaging (e.g., flavoprotein autofluorescence imaging, FAI) can be used to measure neuronal activity and oxygen metabolism in living brains without expressing fluorescence proteins. It is useful for understanding the mechanism of various brain functions and their abnormalities in age-related brain diseases. However, hemoglobin in cerebral blood vessels absorbs green fluorescence, hampering accurate assessments of brain function in animal models with cerebral blood vessel dysfunctions and subsequent cerebral blood flow (CBF) alterations. In the present study, we developed a new method to correct FAI signals for hemoglobin-dependent green fluorescence reductions by simultaneous measurements of green fluorescence and intrinsic optical signals. Intrinsic optical imaging enabled evaluations of light absorption and scatters by hemoglobin, which could then be applied to corrections of green fluorescence intensities. Using this method, enhanced flavoprotein autofluorescence by sensory stimuli was successfully detected in the brains of awake mice, despite increases of CBF, and hemoglobin interference. Moreover, flavoprotein autofluorescence could be properly quantified in a resting state and during sensory stimulation by a CO 2 inhalation challenge, which modified vascular responses without overtly affecting neuronal activities. The flavoprotein autofluorescence signal data obtained here were in good agreement with the previous findings from a condition with drug-induced blockade of cerebral vasodilation, justifying the current assaying methodology. Application of this technology to studies on animal models of brain diseases with possible changes of CBF, including age-related neurological disorders, would provide better understanding of the mechanisms of neurovascular coupling in pathological circumstances.

  14. Optical Imaging of Neuronal Activity and Visualization of Fine Neural Structures in Non-Desheathed Nervous Systems

    PubMed Central

    Stein, Wolfgang

    2014-01-01

    Locating circuit neurons and recording from them with single-cell resolution is a prerequisite for studying neural circuits. Determining neuron location can be challenging even in small nervous systems because neurons are densely packed, found in different layers, and are often covered by ganglion and nerve sheaths that impede access for recording electrodes and neuronal markers. We revisited the voltage-sensitive dye RH795 for its ability to stain and record neurons through the ganglion sheath. Bath-application of RH795 stained neuronal membranes in cricket, earthworm and crab ganglia without removing the ganglion sheath, revealing neuron cell body locations in different ganglion layers. Using the pyloric and gastric mill central pattern generating neurons in the stomatogastric ganglion (STG) of the crab, Cancer borealis, we found that RH795 permeated the ganglion without major residue in the sheath and brightly stained somatic, axonal and dendritic membranes. Visibility improved significantly in comparison to unstained ganglia, allowing the identification of somata location and number of most STG neurons. RH795 also stained axons and varicosities in non-desheathed nerves, and it revealed the location of sensory cell bodies in peripheral nerves. Importantly, the spike activity of the sensory neuron AGR, which influences the STG motor patterns, remained unaffected by RH795, while desheathing caused significant changes in AGR activity. With respect to recording neural activity, RH795 allowed us to optically record membrane potential changes of sub-sheath neuronal membranes without impairing sensory activity. The signal-to-noise ratio was comparable with that previously observed in desheathed preparations and sufficiently high to identify neurons in single-sweep recordings and synaptic events after spike-triggered averaging. In conclusion, RH795 enabled staining and optical recording of neurons through the ganglion sheath and is therefore both a good anatomical

  15. Response of Electrical Activity in an Improved Neuron Model under Electromagnetic Radiation and Noise

    PubMed Central

    Zhan, Feibiao; Liu, Shenquan

    2017-01-01

    Electrical activities are ubiquitous neuronal bioelectric phenomena, which have many different modes to encode the expression of biological information, and constitute the whole process of signal propagation between neurons. Therefore, we focus on the electrical activities of neurons, which is also causing widespread concern among neuroscientists. In this paper, we mainly investigate the electrical activities of the Morris-Lecar (M-L) model with electromagnetic radiation or Gaussian white noise, which can restore the authenticity of neurons in realistic neural network. First, we explore dynamical response of the whole system with electromagnetic induction (EMI) and Gaussian white noise. We find that there are slight differences in the discharge behaviors via comparing the response of original system with that of improved system, and electromagnetic induction can transform bursting or spiking state to quiescent state and vice versa. Furthermore, we research bursting transition mode and the corresponding periodic solution mechanism for the isolated neuron model with electromagnetic induction by using one-parameter and bi-parameters bifurcation analysis. Finally, we analyze the effects of Gaussian white noise on the original system and coupled system, which is conducive to understand the actual discharge properties of realistic neurons. PMID:29209192

  16. Response of Electrical Activity in an Improved Neuron Model under Electromagnetic Radiation and Noise.

    PubMed

    Zhan, Feibiao; Liu, Shenquan

    2017-01-01

    Electrical activities are ubiquitous neuronal bioelectric phenomena, which have many different modes to encode the expression of biological information, and constitute the whole process of signal propagation between neurons. Therefore, we focus on the electrical activities of neurons, which is also causing widespread concern among neuroscientists. In this paper, we mainly investigate the electrical activities of the Morris-Lecar (M-L) model with electromagnetic radiation or Gaussian white noise, which can restore the authenticity of neurons in realistic neural network. First, we explore dynamical response of the whole system with electromagnetic induction (EMI) and Gaussian white noise. We find that there are slight differences in the discharge behaviors via comparing the response of original system with that of improved system, and electromagnetic induction can transform bursting or spiking state to quiescent state and vice versa. Furthermore, we research bursting transition mode and the corresponding periodic solution mechanism for the isolated neuron model with electromagnetic induction by using one-parameter and bi-parameters bifurcation analysis. Finally, we analyze the effects of Gaussian white noise on the original system and coupled system, which is conducive to understand the actual discharge properties of realistic neurons.

  17. Developmentally induced microencephalopathy in guinea pigs--embryonic glial cell activation marks selective neuronal death.

    PubMed

    Rossner, S; Brückner, M K; Bigl, V

    2001-06-01

    We have recently shown that in utero treatment of guinea pigs with the DNA methylating substance methylazoxymethanol acetate (MAM) on gestation day (GD) 24 results in neocortical microencephalopathy, increased protein kinase C activity and altered processing of the amyloid precursor protein in neocortex of the offsprings. In order to identify the primary neuronal lesions produced by MAM-treatment, we mapped the 5-bromo-2'-deoxyuridine (BrdU)-incorporation in dividing neurons on GD 24 and we followed the effects of MAM-treatment on GD 24 on embryonic immediate early gene expression and on glial cell activation. BrdU injected on GD 24 labeled many neurons of the ventricular zone and of the intermediate zone but only scattered neurons of the cortical plate. When time-mated guinea pigs were injected intraperitoneally with MAM on GD 24, we observed the activation of microglial cells in the ventricular/intermediate zone and the appearence of astrocytes between the intermediate zone and the cortical plate, 48 h after intoxification. The activation of glial cells was accompanied by the neuronal expression of c-Fos but not of c-Jun in the ventricular/intermediate zone. Based on our observations on BrdU-incorporation and on the morphological outcome of MAM treatment in the juvenile guinea pig, our data presented here indicate that selective neurodegeneration during development induces the activation of both phagocytotic microglial cells and of astrocytes which might trophically support damaged neurons surviving this lesion procedure.

  18. Causal relationships between neurons of the nucleus incertus and the hippocampal theta activity in the rat.

    PubMed

    Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Luque-García, Aina; Martínez-Ricós, Joana; Valverde-Navarro, Alfonso; Bataller, Manuel; Guerrero, Juan; Teruel-Marti, Vicent

    2017-03-01

    The nucleus incertus is a key node of the brainstem circuitry involved in hippocampal theta rhythmicity. Synchronisation exists between the nucleus incertus and hippocampal activities during theta periods. By the Granger causality analysis, we demonstrated a directional information flow between theta rhythmical neurons in the nucleus incertus and the hippocampus in theta-on states. The electrical stimulation of the nucleus incertus is also able to evoke a phase reset of the hippocampal theta wave. Our data suggest that the nucleus incertus is a key node of theta generation and the modulation network. In recent years, a body of evidence has shown that the nucleus incertus (NI), in the dorsal tegmental pons, is a key node of the brainstem circuitry involved in hippocampal theta rhythmicity. Ascending reticular brainstem system activation evokes hippocampal theta rhythm with coupled neuronal activity in the NI. In a recent paper, we showed three populations of neurons in the NI with differential firing during hippocampal theta activation. The objective of this work was to better evaluate the causal relationship between the activity of NI neurons and the hippocampus during theta activation in order to further understand the role of the NI in the theta network. A Granger causality analysis was run to determine whether hippocampal theta activity with sensory-evoked theta depends on the neuronal activity of the NI, or vice versa. The analysis showed causal interdependence between the NI and the hippocampus during theta activity, whose directional flow depended on the different neuronal assemblies of the NI. Whereas type I and II NI neurons mainly acted as receptors of hippocampal information, type III neuronal activity was the predominant source of flow between the NI and the hippocampus in theta states. We further determined that the electrical activation of the NI was able to reset hippocampal waves with enhanced theta-band power, depending on the septal area

  19. Synchronization in a chaotic neural network with time delay depending on the spatial distance between neurons

    NASA Astrophysics Data System (ADS)

    Tang, Guoning; Xu, Kesheng; Jiang, Luoluo

    2011-10-01

    The synchronization is investigated in a two-dimensional Hindmarsh-Rose neuronal network by introducing a global coupling scheme with time delay, where the length of time delay is proportional to the spatial distance between neurons. We find that the time delay always disturbs synchronization of the neuronal network. When both the coupling strength and length of time delay per unit distance (i.e., enlargement factor) are large enough, the time delay induces the abnormal membrane potential oscillations in neurons. Specifically, the abnormal membrane potential oscillations for the symmetrically placed neurons form an antiphase, so that the large coupling strength and enlargement factor lead to the desynchronization of the neuronal network. The complete and intermittently complete synchronization of the neuronal network are observed for the right choice of parameters. The physical mechanism underlying these phenomena is analyzed.

  20. Brain activity-induced neuronal glucose uptake/glycolysis: Is the lactate shuttle not required?

    PubMed

    Tang, Bor Luen

    2018-03-01

    The astrocyte-neuron lactate shuttle (ANLS) hypothesis posits that during neuronal activation, astrocytic glycolysis consumes glucose and generates lactate, with the latter then imported by neurons as a preferred fuel. The hypothesis has been controversial, with multiple theoretical postulates for and against, and with empirical evidence that were either supportive or otherwise. Recent findings using direct in vivo imaging of lactate and glucose uptake as well as associated metabolic changes in neurons have now placed important constraints on the hypothesis. Here, I review these recent findings and discuss their implications on neuronal energetics. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures.

    PubMed

    Beggiato, Sarah; Borelli, Andrea Celeste; Ferraro, Luca; Tanganelli, Sergio; Antonelli, Tiziana; Tomasini, Maria Cristina

    2018-01-01

    Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease. We firstly evaluated whether astrocytes could participate in regulating the Aβ42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aβ42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters. The presence of astrocytes pre-exposed to Aβ42 (0.5μM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aβ42 pre-exposure induced an increase in the number of neurite aggregations/100μm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1μM), applied 1 h before and maintained during Aβ42 treatment. Astrocytes contribute to Aβ42-induced neurotoxicity and PEA, by blunting Aβ42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures.

  2. Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons

    PubMed Central

    Bradford, Aaron B; McNutt, Patrick M

    2015-01-01

    Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments. PMID:26240679

  3. Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone

    PubMed Central

    Liu, Tiemin; Kong, Dong; Shah, Bhavik P.; Ye, Chianping; Koda, Shuichi; Saunders, Arpiar; Ding, Jun B.; Yang, Zongfang; Sabatini, Bernardo L.; Lowell, Bradford B.

    2012-01-01

    SUMMARY AgRP neuron activity drives feeding and weight gain while that of nearby POMC neurons does the opposite. However, the role of excitatory glutamatergic input in controlling these neurons is unknown. To address this question, we generated mice lacking NMDA receptors (NMDARs) on either AgRP or POMC neurons. Deletion of NMDARs from AgRP neurons markedly reduced weight, body fat and food intake whereas deletion from POMC neurons had no effect. Activation of AgRP neurons by fasting, as assessed by c-Fos, Agrp and Npy mRNA expression, AMPA receptor-mediated EPSCs, depolarization and firing rates, required NMDARs. Furthermore, AgRP but not POMC neurons have dendritic spines and increased glutamatergic input onto AgRP neurons caused by fasting was paralleled by an increase in spines, suggesting fasting induced synaptogenesis and spinogenesis. Thus glutamatergic synaptic transmission and its modulation by NMDARs play key roles in controlling AgRP neurons and determining the cellular and behavioral response to fasting. PMID:22325203

  4. Naphthazarin protects against glutamate-induced neuronal death via activation of the Nrf2/ARE pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Son, Tae Gen; Kawamoto, Elisa M.; Yu, Qian-Sheng

    2013-04-19

    Highlights: •Naphthazarin activates the Nrf2/ARE pathway. •Naphthazarin induces Nrf2-driven genes in neurons and astrocytes. •Naphthazarin protects neurons against excitotoxicity. -- Abstract: Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. We previously screened several natural phytochemicals and identified plumbagin as a novel activator of the Nrf2/ARE pathway that can protect neurons against ischemic injury. Here we extended our studies to natural and synthetic derivatives of plumbagin. We found that 5,8-dimethoxy-1,4-naphthoquinone (naphthazarin) is a potent activator of the Nrf2/ARE pathway, up-regulates the expression of Nrf2-driven genes in primary neuronal andmore » glial cultures, and protects neurons against glutamate-induced excitotoxicity.« less

  5. Using Human iPSC-Derived Neurons to Model TAU Aggregation

    PubMed Central

    Verheyen, An; Diels, Annick; Dijkmans, Joyce; Oyelami, Tutu; Meneghello, Giulia; Mertens, Liesbeth; Versweyveld, Sofie; Borgers, Marianne; Buist, Arjan; Peeters, Pieter; Cik, Miroslav

    2015-01-01

    Alzheimer’s disease and frontotemporal dementia are amongst the most common forms of dementia characterized by the formation and deposition of abnormal TAU in the brain. In order to develop a translational human TAU aggregation model suitable for screening, we transduced TAU harboring the pro-aggregating P301L mutation into control hiPSC-derived neural progenitor cells followed by differentiation into cortical neurons. TAU aggregation and phosphorylation was quantified using AlphaLISA technology. Although no spontaneous aggregation was observed upon expressing TAU-P301L in neurons, seeding with preformed aggregates consisting of the TAU-microtubule binding repeat domain triggered robust TAU aggregation and hyperphosphorylation already after 2 weeks, without affecting general cell health. To validate our model, activity of two autophagy inducers was tested. Both rapamycin and trehalose significantly reduced TAU aggregation levels suggesting that iPSC-derived neurons allow for the generation of a biologically relevant human Tauopathy model, highly suitable to screen for compounds that modulate TAU aggregation. PMID:26720731

  6. ROCK1 in AgRP neurons regulates energy expenditure and locomotor activity in male mice.

    PubMed

    Huang, Hu; Lee, Seung Hwan; Ye, Chianping; Lima, Ines S; Oh, Byung-Chul; Lowell, Bradford B; Zabolotny, Janice M; Kim, Young-Bum

    2013-10-01

    Normal leptin signaling is essential for the maintenance of body weight homeostasis. Proopiomelanocortin- and agouti-related peptide (AgRP)-producing neurons play critical roles in regulating energy metabolism. Our recent work demonstrates that deletion of Rho-kinase 1 (ROCK1) in the AgRP neurons of mice increased body weight and adiposity. Here, we report that selective loss of ROCK1 in AgRP neurons caused a significant decrease in energy expenditure and locomotor activity of mice. These effects were independent of any change in food intake. Furthermore, AgRP neuron-specific ROCK1-deficient mice displayed central leptin resistance, as evidenced by impaired Signal Transducer and Activator of Transcription 3 activation in response to leptin administration. Leptin's ability to hyperpolarize and decrease firing rate of AgRP neurons was also abolished in the absence of ROCK1. Moreover, diet-induced and genetic forms of obesity resulted in reduced ROCK1 activity in murine arcuate nucleus. Of note, high-fat diet also impaired leptin-stimulated ROCK1 activity in arcuate nucleus, suggesting that a defect in hypothalamic ROCK1 activity may contribute to the pathogenesis of central leptin resistance in obesity. Together, these data demonstrate that ROCK1 activation in hypothalamic AgRP neurons is required for the homeostatic regulation of energy expenditure and adiposity. These results further support previous work identifying ROCK1 as a key regulator of energy balance and suggest that targeting ROCK1 in the hypothalamus may lead to development of antiobesity therapeutics.

  7. A transgenic mouse for imaging activity-dependent dynamics of endogenous Arc mRNA in live neurons.

    PubMed

    Das, Sulagna; Moon, Hyungseok C; Singer, Robert H; Park, Hye Yoon

    2018-06-01

    Localized translation plays a crucial role in synaptic plasticity and memory consolidation. However, it has not been possible to follow the dynamics of memory-associated mRNAs in living neurons in response to neuronal activity in real time. We have generated a novel mouse model where the endogenous Arc/Arg3.1 gene is tagged in its 3' untranslated region with stem-loops that bind a bacteriophage PP7 coat protein (PCP), allowing visualization of individual mRNAs in real time. The physiological response of the tagged gene to neuronal activity is identical to endogenous Arc and reports the true dynamics of Arc mRNA from transcription to degradation. The transcription dynamics of Arc in cultured hippocampal neurons revealed two novel results: (i) A robust transcriptional burst with prolonged ON state occurs after stimulation, and (ii) transcription cycles continue even after initial stimulation is removed. The correlation of stimulation with Arc transcription and mRNA transport in individual neurons revealed that stimulus-induced Ca 2+ activity was necessary but not sufficient for triggering Arc transcription and that blocking neuronal activity did not affect the dendritic transport of newly synthesized Arc mRNAs. This mouse will provide an important reagent to investigate how individual neurons transduce activity into spatiotemporal regulation of gene expression at the synapse.

  8. Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.

    PubMed

    Guo, Chuang; Hao, Li-Juan; Yang, Zhao-Hui; Chai, Rui; Zhang, Shuai; Gu, Yu; Gao, Hui-Ling; Zhong, Man-Li; Wang, Tao; Li, Jia-Yi; Wang, Zhan-You

    2016-06-01

    Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator widely used in clinical settings, has been reported to improve motor deficits and dopaminergic neuronal survival in animal models of PD, DFO has poor penetration to cross the blood-brain barrier and elicits side effects. We evaluated whether an intranasal administration of DFO improves the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic neurons in the nigrostriatal axis and investigated the molecular mechanisms of intranasal DFO treatment in preventing MPTP-induced neurodegeneration. Treatment with DFO efficiently alleviated behavioral deficits, increased the survival of tyrosine hydroxylase (TH)-positive neurons, and decreased the action of astrocytes in the SN and striatum in an MPTP-induced PD mouse model. Interestingly, we found that DFO up-regulated the expression of HIF-1α protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of α-synuclein, divalent metal transporter with iron-responsive element (DMT1+IRE), and transferrin receptor (TFR). This was accompanied by a decrease in iron-positive cells in the SN and striatum of the DFO-treated group. We further revealed that DFO treatment significantly inhibited the MPTP-induced phosphorylation of the c-Jun N-terminal kinase (JNK) and differentially enhanced the phosphorylation of extracellular regulated protein kinases (ERK) and mitogen-activated protein kinase (MAPK)/P38 kinase. Additionally, the effects of DFO on increasing the Bcl-2/Bax ratio were further validated in vitro and in vivo. In SH-SY5Y cells, the DFO-mediated up-regulation of HIF-1α occurred via the activation of

  9. Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression?

    PubMed Central

    Bayraktar, Gonca; Kreutz, Michael R.

    2017-01-01

    DNMT3A and 3B are the main de novo DNA methyltransferases (DNMTs) in the brain that introduce new methylation marks to non-methylated DNA in postmitotic neurons. DNA methylation is a key epigenetic mark that is known to regulate important cellular processes in neuronal development and brain plasticity. Accumulating evidence disclosed rapid and dynamic changes in DNA methylation of plasticity-relevant genes that are important for learning and memory formation. To understand how DNMTs contribute to brain function and how they are regulated by neuronal activity is a prerequisite for a deeper appreciation of activity-dependent gene expression in health and disease. This review discusses the functional role of de novo methyltransferases and in particular DNMT3A1 in the adult brain with special emphasis on synaptic plasticity, memory formation, and brain disorders. PMID:28513272

  10. Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity

    NASA Astrophysics Data System (ADS)

    Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

    2016-11-01

    The increasing number of recording electrodes enhances the capability of capturing the network’s cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity.

  11. Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity.

    PubMed

    Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

    2016-11-08

    The increasing number of recording electrodes enhances the capability of capturing the network's cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity.

  12. Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task

    PubMed Central

    Miller, Rikki L.A.

    2017-01-01

    Abstract The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior. PMID:29034318

  13. Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task.

    PubMed

    Miller, Rikki L A; Francoeur, Miranda J; Gibson, Brett M; Mair, Robert G

    2017-01-01

    The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior.

  14. Levetiracetam reduces abnormal network activations in temporal lobe epilepsy.

    PubMed

    Wandschneider, Britta; Stretton, Jason; Sidhu, Meneka; Centeno, Maria; Kozák, Lajos R; Symms, Mark; Thompson, Pamela J; Duncan, John S; Koepp, Matthias J

    2014-10-21

    We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE). In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose. We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left. Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response. This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures. © 2014 American Academy of Neurology.

  15. The synchronous activity of lateral habenular neurons is essential for regulating hippocampal theta oscillation.

    PubMed

    Aizawa, Hidenori; Yanagihara, Shin; Kobayashi, Megumi; Niisato, Kazue; Takekawa, Takashi; Harukuni, Rie; McHugh, Thomas J; Fukai, Tomoki; Isomura, Yoshikazu; Okamoto, Hitoshi

    2013-05-15

    Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase-locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons.

  16. Microglia in Glia-Neuron Co-cultures Exhibit Robust Phagocytic Activity Without Concomitant Inflammation or Cytotoxicity.

    PubMed

    Adams, Alexandra C; Kyle, Michele; Beaman-Hall, Carol M; Monaco, Edward A; Cullen, Matthew; Vallano, Mary Lou

    2015-10-01

    A simple method to co-culture granule neurons and glia from a single brain region is described, and microglia activation profiles are assessed in response to naturally occurring neuronal apoptosis, excitotoxin-induced neuronal death, and lipopolysaccharide (LPS) addition. Using neonatal rat cerebellar cortex as a tissue source, glial proliferation is regulated by omission or addition of the mitotic inhibitor cytosine arabinoside (AraC). After 7-8 days in vitro, microglia in AraC(-) cultures are abundant and activated based on their amoeboid morphology, expressions of ED1 and Iba1, and ability to phagocytose polystyrene beads and the majority of neurons undergoing spontaneous apoptosis. Microglia and phagocytic activities are sparse in AraC(+) cultures. Following exposure to excitotoxic kainate concentrations, microglia in AraC(-) cultures phagocytose most dead neurons within 24 h without exacerbating neuronal loss or mounting a strong or sustained inflammatory response. LPS addition induces a robust inflammatory response, based on microglial expressions of TNF-α, COX-2 and iNOS proteins, and mRNAs, whereas these markers are essentially undetectable in control cultures. Thus, the functional effector state of microglia is primed for phagocytosis but not inflammation or cytotoxicity even after kainate exposure that triggers death in the majority of neurons. This model should prove useful in studying the progressive activation states of microglia and factors that promote their conversion to inflammatory and cytotoxic phenotypes.

  17. Genetic Feedback Regulation of Frontal Cortical Neuronal Ensembles Through Activity-Dependent Arc Expression and Dopaminergic Input.

    PubMed

    Mastwal, Surjeet; Cao, Vania; Wang, Kuan Hong

    2016-01-01

    Mental functions involve coordinated activities of specific neuronal ensembles that are embedded in complex brain circuits. Aberrant neuronal ensemble dynamics is thought to form the neurobiological basis of mental disorders. A major challenge in mental health research is to identify these cellular ensembles and determine what molecular mechanisms constrain their emergence and consolidation during development and learning. Here, we provide a perspective based on recent studies that use activity-dependent gene Arc/Arg3.1 as a cellular marker to identify neuronal ensembles and a molecular probe to modulate circuit functions. These studies have demonstrated that the transcription of Arc is activated in selective groups of frontal cortical neurons in response to specific behavioral tasks. Arc expression regulates the persistent firing of individual neurons and predicts the consolidation of neuronal ensembles during repeated learning. Therefore, the Arc pathway represents a prototypical example of activity-dependent genetic feedback regulation of neuronal ensembles. The activation of this pathway in the frontal cortex starts during early postnatal development and requires dopaminergic (DA) input. Conversely, genetic disruption of Arc leads to a hypoactive mesofrontal dopamine circuit and its related cognitive deficit. This mutual interaction suggests an auto-regulatory mechanism to amplify the impact of neuromodulators and activity-regulated genes during postnatal development. Such a mechanism may contribute to the association of mutations in dopamine and Arc pathways with neurodevelopmental psychiatric disorders. As the mesofrontal dopamine circuit shows extensive activity-dependent developmental plasticity, activity-guided modulation of DA projections or Arc ensembles during development may help to repair circuit deficits related to neuropsychiatric disorders.

  18. Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins.

    PubMed

    Schönhofen, Patrícia; de Medeiros, Liana M; Bristot, Ivi Juliana; Lopes, Fernanda M; De Bastiani, Marco A; Kapczinski, Flávio; Crippa, José Alexandre S; Castro, Mauro Antônio A; Parsons, Richard B; Klamt, Fábio

    2015-08-01

    Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 μM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 μM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 μM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins.

  19. Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats.

    PubMed

    Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir K Roy; Smith, Darrell R; Dobrowsky, Rick T; Fernyhough, Paul

    2011-01-01

    Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to

  20. MND2: A new mouse model of inherited motor neuron disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jones, J.M.; Albin, R.L.; Feldman, E.L.

    1993-06-01

    The autosomal recessive mutation mnd2 results in early onset motor neuron disease with rapidly progressive paralysis, severe muscle wasting, regression of thymus and spleen, and death before 40 days of age. mnd2 has been mapped to mouse chromosome 6 with the gene order: centromere-Tcrb-Ly-2-Sftp-3-D6Mit4-mnd2-D6Mit6, D6Mit9-D6Rck132-Raf-1, D6Mit11-D6Mit12-D6Mit14. mnd2 is located within a conserved linkage group with homologs on human chromosome 2p12-p13. Spinal motor neurons of homozygous affected animals are swollen and stain weakly, and electromyography revealed spontaneous activity characteristic of muscle denervation. Myelin staining was normal throughout the neuraxis. The clinical observations are consistent with a primary abnormality of lower motormore » neuron function. This new animal model will be of value for identification of a genetic defect responsible for motor neuron disease and for evaluation of new therapies. 36 refs., 7 figs., 2 tabs.« less

  1. PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

    PubMed Central

    Cork, Simon C.

    2015-01-01

    Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short- and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. PMID:26290108

  2. PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation.

    PubMed

    Trapp, Stefan; Cork, Simon C

    2015-10-15

    Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short- and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. Copyright © 2015 the American Physiological Society.

  3. elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves

    PubMed Central

    Longhurst, John C.; Tjen-A-Looi, Stephanie C.; Fu, Liang-Wu

    2016-01-01

    The external lateral parabrachial nucleus (elPBN) within the pons and rostral ventrolateral medulla (rVLM) contributes to central processing of excitatory cardiovascular reflexes during stimulation of cardiac sympathetic afferent nerves (CSAN). However, the importance of elPBN cardiovascular neurons in regulation of rVLM activity during CSAN activation remains unclear. We hypothesized that CSAN stimulation excites the elPBN cardiovascular neurons and, in turn, increases rVLM activity through elPBN-rVLM projections. Compared with controls, in rats subjected to microinjection of retrograde tracer into the rVLM, the numbers of elPBN neurons double-labeled with c-Fos (an immediate early gene) and the tracer were increased after CSAN stimulation (P < 0.05). The majority of these elPBN neurons contain vesicular glutamate transporter 3. In cats, epicardial bradykinin and electrical stimulation of CSAN increased the activity of elPBN cardiovascular neurons, which was attenuated (n = 6, P < 0.05) after blockade of glutamate receptors with iontophoresis of kynurenic acid (Kyn, 25 mM). In separate cats, microinjection of Kyn (1.25 nmol/50 nl) into the elPBN reduced rVLM activity evoked by both bradykinin and electrical stimulation (n = 5, P < 0.05). Excitation of the elPBN with microinjection of dl-homocysteic acid (2 nmol/50 nl) significantly increased basal and CSAN-evoked rVLM activity. However, the enhanced rVLM activity induced by dl-homocysteic acid injected into the elPBN was reversed following iontophoresis of Kyn into the rVLM (n = 7, P < 0.05). These data suggest that cardiac sympathetic afferent stimulation activates cardiovascular neurons in the elPBN and rVLM sequentially through a monosynaptic (glutamatergic) excitatory elPBN-rVLM pathway. PMID:27225950

  4. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy.

    PubMed

    Vilchez, David; Ros, Susana; Cifuentes, Daniel; Pujadas, Lluís; Vallès, Jordi; García-Fojeda, Belén; Criado-García, Olga; Fernández-Sánchez, Elena; Medraño-Fernández, Iria; Domínguez, Jorge; García-Rocha, Mar; Soriano, Eduardo; Rodríguez de Córdoba, Santiago; Guinovart, Joan J

    2007-11-01

    Glycogen synthesis is normally absent in neurons. However, inclusion bodies resembling abnormal glycogen accumulate in several neurological diseases, particularly in progressive myoclonus epilepsy or Lafora disease. We show here that mouse neurons have the enzymatic machinery for synthesizing glycogen, but that it is suppressed by retention of muscle glycogen synthase (MGS) in the phosphorylated, inactive state. This suppression was further ensured by a complex of laforin and malin, which are the two proteins whose mutations cause Lafora disease. The laforin-malin complex caused proteasome-dependent degradation both of the adaptor protein targeting to glycogen, PTG, which brings protein phosphatase 1 to MGS for activation, and of MGS itself. Enforced expression of PTG led to glycogen deposition in neurons and caused apoptosis. Therefore, the malin-laforin complex ensures a blockade of neuronal glycogen synthesis even under intense glycogenic conditions. Here we explain the formation of polyglucosan inclusions in Lafora disease by demonstrating a crucial role for laforin and malin in glycogen synthesis.

  5. Antipsychotics Activate mTORC1-Dependent Translation to Enhance Neuronal Morphological Complexity

    PubMed Central

    Bowling, Heather; Zhang, Guoan; Bhattacharya, Aditi; Pérez-Cuesta, Luis M.; Deinhardt, Katrin; Hoeffer, Charles A.; Neubert, Thomas A.; Gan, Wen-biao; Klann, Eric; Chao, Moses V.

    2014-01-01

    Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. Here, we showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D2R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics. PMID:24425786

  6. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons

    PubMed Central

    Linehan, Victoria; Trask, Robert B.; Briggs, Chantalle; Rowe, Todd M.; Hirasawa, Michiru

    2017-01-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID:26036709

  7. Phrenic Long-Term Facilitation Requires PKCθ Activity within Phrenic Motor Neurons

    PubMed Central

    Devinney, Michael J.; Fields, Daryl P.; Huxtable, Adrianne G.; Peterson, Timothy J.; Dale, Erica A.

    2015-01-01

    Acute intermittent hypoxia (AIH) induces a form of spinal motor plasticity known as phrenic long-term facilitation (pLTF); pLTF is a prolonged increase in phrenic motor output after AIH has ended. In anesthetized rats, we demonstrate that pLTF requires activity of the novel PKC isoform, PKCθ, and that the relevant PKCθ is within phrenic motor neurons. Whereas spinal PKCθ inhibitors block pLTF, inhibitors targeting other PKC isoforms do not. PKCθ is highly expressed in phrenic motor neurons, and PKCθ knockdown with intrapleural siRNAs abolishes pLTF. Intrapleural siRNAs targeting PKCζ, an atypical PKC isoform expressed in phrenic motor neurons that underlies a distinct form of phrenic motor plasticity, does not affect pLTF. Thus, PKCθ plays a critical role in spinal AIH-induced respiratory motor plasticity, and the relevant PKCθ is localized within phrenic motor neurons. Intrapleural siRNA delivery has considerable potential as a therapeutic tool to selectively manipulate plasticity in vital respiratory motor neurons. PMID:26019328

  8. Secondary Abnormalities of Neurotransmitters in Infants with Neurological Disorders

    ERIC Educational Resources Information Center

    Garcia-Cazorla, A.; Serrano, M.; Perez-Duenas, B.; Gonzalez, V.; Ormazabal, A.; Pineda, M.; Fernandez-Alvarez, E.; Campistol, J. M. D.; Artuch, R. M. D.

    2007-01-01

    Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants…

  9. Synaptic Activity in Serotonergic Neurons Is Required for Air-Puff Stimulated Flight in Drosophila melanogaster

    PubMed Central

    Sadaf, Sufia; Birman, Serge; Hasan, Gaiti

    2012-01-01

    Background Flight is an integral component of many complex behavioral patterns in insects. The giant fiber circuit has been well studied in several insects including Drosophila. However, components of the insect flight circuit that respond to an air-puff stimulus and comprise the flight central pattern generator are poorly defined. Aminergic neurons have been implicated in locust, moth and Drosophila flight. Here we have investigated the requirement of neuronal activity in serotonergic neurons, during development and in adults, on air-puff induced flight in Drosophila. Methodology/Principal Findings To target serotonergic neurons specifically, a Drosophila strain that contains regulatory regions from the TRH (Tryptophan Hydroxylase) gene linked to the yeast transcription factor GAL4 was used. By blocking synaptic transmission from serotonergic neurons with a tetanus toxin transgene or by hyperpolarisation with Kir2.1, close to 50% adults became flightless. Temporal expression of a temperature sensitive Dynamin mutant transgene (Shits) suggests that synaptic function in serotonergic neurons is required both during development and in adults. Depletion of IP3R in serotonergic neurons via RNAi did not affect flight. Interestingly, at all stages a partial requirement for synaptic activity in serotonergic neurons was observed. The status of serotonergic neurons was investigated in the central nervous system of larvae and adults expressing tetanus toxin. A small but significant reduction was observed in serotonergic cell number in adult second thoracic segments from flightless tetanus toxin expressing animals. Conclusions These studies show that loss of synaptic activity in serotonergic neurons causes a flight deficit. The temporal focus of the flight deficit is during pupal development and in adults. The cause of the flight deficit is likely to be loss of neurons and reduced synaptic function. Based on the partial phenotypes, serotonergic neurons appear to be modulatory

  10. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    NASA Technical Reports Server (NTRS)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  11. Bioluminescence Monitoring of Neuronal Activity in Freely Moving Zebrafish Larvae

    PubMed Central

    Knafo, Steven; Prendergast, Andrew; Thouvenin, Olivier; Figueiredo, Sophie Nunes; Wyart, Claire

    2017-01-01

    The proof of concept for bioluminescence monitoring of neural activity in zebrafish with the genetically encoded calcium indicator GFP-aequorin has been previously described (Naumann et al., 2010) but challenges remain. First, bioluminescence signals originating from a single muscle fiber can constitute a major pitfall. Second, bioluminescence signals emanating from neurons only are very small. To improve signals while verifying specificity, we provide an optimized 4 steps protocol achieving: 1) selective expression of a zebrafish codon-optimized GFP-aequorin, 2) efficient soaking of larvae in GFP-aequorin substrate coelenterazine, 3) bioluminescence monitoring of neural activity from motor neurons in free-tailed moving animals performing acoustic escapes and 4) verification of the absence of muscle expression using immunohistochemistry. PMID:29130058

  12. Activation of ATP-sensitive potassium channels antagonize nociceptive behavior and hyperexcitability of DRG neurons from rats.

    PubMed

    Du, Xiaona; Wang, Chao; Zhang, Hailin

    2011-05-14

    Nociceptive responses to noxious stimuli are initiated at peripheral nociceptor terminals. Ion channels play a vital role in pain signal initiation and conduction. Activation of KATP channels has been implicated in mediating the analgesic effects of agents such as morphine. However, systematic studies regarding the effects of KATP activators on nociception and neuronal excitability are scarce. In this study, we describe the antagonistic effects of KATP activators pinacidil and diazoxide on nocifensive behavior induced by bradykinin (BK), thermo and mechanical stimuli, and the bradykinin-induced hyperexcitability of DRG neurons. We also found that KATP activators can moderately activate KATP in DRG neurons. Because the effects of KATP activators can be reversed by the KATP blocker glyburide, direct activation of KATP is most likely the underlying mechanism. This systematic study clearly demonstrates that activation of KATP could have significant modulatory effects on the excitability of sensory neurons and thus on sensory behaviors, such as nociception. KATP activators can be evaluated clinically for the treatment of pain symptoms.

  13. Influence of spaceflight on succinate dehydrogenase activity and soma size of rat ventral horn neurons

    NASA Technical Reports Server (NTRS)

    Ishihara, A.; Ohira, Y.; Roy, R. R.; Nagaoka, S.; Sekiguchi, C.; Hinds, W. E.; Edgerton, V. R.

    1996-01-01

    Succinate dehydrogenase (SDH) activities and soma cross-sectional areas (CSA) of neurons in the dorsolateral region of the ventral horn at the L5 segmental level of the spinal cord in the rat were determined after 14 days of spaceflight and after 9 days of recovery on earth. The results were compared to those in age-matched ground-based control rats. Spinal cords were quick-frozen, and the SDH activity and CSA of a sample of neurons with a visible nucleus were determined using a digitizer and a computer-assisted image analysis system. An inverse relationship between CSA and SDH activity of neurons was observed in all groups of rats. No change in mean CSA or mean SDH activity or in the size distribution of neurons was observed following spaceflight or recovery. However, there was a selective decrease in the SDH activity of neurons with soma CSA between 500 and 800 microns2 in the flight rats, and this effect persisted for at least 9 days following return to 1 g. It remains to be determined whether the selected population of motoneurons or the specific motor pools affected by spaceflight may be restricted to specific muscles.

  14. Regulation of Na(+)/K(+)-ATPase by neuron-specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons.

    PubMed

    Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T

    2014-02-01

    A major source of energy demand in neurons is the Na(+)/K(+)-ATPase pump that restores the ionic gradient across the plasma membrane subsequent to depolarizing neuronal activity. The energy comes primarily from mitochondrial oxidative metabolism, of which cytochrome c oxidase (COX) is a key enzyme. Recently, we found that all 13 subunits of COX are regulated by specificity (Sp) factors, and that the neuron-specific Sp4, but not Sp1 or Sp3, regulates the expression of key glutamatergic receptor subunits as well. The present study sought to test our hypothesis that Sp4 also regulates Na(+)/K(+)-ATPase subunit genes in neurons. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutational analysis, over-expression, and RNA interference studies, we found that Sp4, with minor contributions from Sp1 and Sp3, functionally regulate the Atp1a1, Atp1a3, and Atp1b1 subunit genes of Na(+)/K(+)-ATPase in neurons. Transcripts of all three genes were up-regulated by depolarizing KCl stimulation and down-regulated by the impulse blocker tetrodotoxin (TTX), indicating that their expression was activity-dependent. Silencing of Sp4 blocked the up-regulation of these genes induced by KCl, whereas over-expression of Sp4 rescued them from TTX-induced suppression. The effect of silencing or over-expressing Sp4 on primary neurons was much greater than those of Sp1 or Sp3. The binding sites of Sp factors on these genes are conserved among mice, rats and humans. Thus, Sp4 plays an important role in the transcriptional coupling of energy generation and energy consumption in neurons. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  15. Neuron activity in rat hippocampus and motor cortex during discrimination reversal.

    PubMed

    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.

  16. Plasticity of Neuron-Glial Transmission: Equipping Glia for Long-Term Integration of Network Activity.

    PubMed

    Croft, Wayne; Dobson, Katharine L; Bellamy, Tomas C

    2015-01-01

    The capacity of synaptic networks to express activity-dependent changes in strength and connectivity is essential for learning and memory processes. In recent years, glial cells (most notably astrocytes) have been recognized as active participants in the modulation of synaptic transmission and synaptic plasticity, implicating these electrically nonexcitable cells in information processing in the brain. While the concept of bidirectional communication between neurons and glia and the mechanisms by which gliotransmission can modulate neuronal function are well established, less attention has been focussed on the computational potential of neuron-glial transmission itself. In particular, whether neuron-glial transmission is itself subject to activity-dependent plasticity and what the computational properties of such plasticity might be has not been explored in detail. In this review, we summarize current examples of plasticity in neuron-glial transmission, in many brain regions and neurotransmitter pathways. We argue that induction of glial plasticity typically requires repetitive neuronal firing over long time periods (minutes-hours) rather than the short-lived, stereotyped trigger typical of canonical long-term potentiation. We speculate that this equips glia with a mechanism for monitoring average firing rates in the synaptic network, which is suited to the longer term roles proposed for astrocytes in neurophysiology.

  17. Energy Homeostasis and Abnormal RNA Metabolism in Amyotrophic Lateral Sclerosis

    PubMed Central

    Liu, Yu-Ju; Tsai, Po-Yi; Chern, Yijuang

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is clinically characterized by progressive muscle weakness and impaired voluntary movement due to the loss of motor neurons in the brain, brain stem and spinal cord. To date, no effective treatment is available. Ample evidence suggests that impaired RNA homeostasis and abnormal energy status are two major pathogenesis pathways in ALS. In the present review article, we focus on recent studies that report molecular insights of both pathways, and discuss the possibility that energy dysfunction might negatively regulate RNA homeostasis via the impairment of cytoplasmic-nuclear shuttling in motor neurons and subsequently contribute to the development of ALS. PMID:28522961

  18. Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias.

    PubMed

    Gibbons, David D; Southerland, E Marie; Hoover, Donald B; Beaumont, Eric; Armour, J Andrew; Ardell, Jeffrey L

    2012-02-01

    Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ∼4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

  19. Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity.

    PubMed

    Weber, Tillmann; Vogt, Miriam A; Gartside, Sarah E; Berger, Stefan M; Lujan, Rafael; Lau, Thorsten; Herrmann, Elke; Sprengel, Rolf; Bartsch, Dusan; Gass, Peter

    2015-05-01

    Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

  20. Simultaneous multi-patch-clamp and extracellular-array recordings: Single neuron reflects network activity

    PubMed Central

    Vardi, Roni; Goldental, Amir; Sardi, Shira; Sheinin, Anton; Kanter, Ido

    2016-01-01

    The increasing number of recording electrodes enhances the capability of capturing the network’s cooperative activity, however, using too many monitors might alter the properties of the measured neural network and induce noise. Using a technique that merges simultaneous multi-patch-clamp and multi-electrode array recordings of neural networks in-vitro, we show that the membrane potential of a single neuron is a reliable and super-sensitive probe for monitoring such cooperative activities and their detailed rhythms. Specifically, the membrane potential and the spiking activity of a single neuron are either highly correlated or highly anti-correlated with the time-dependent macroscopic activity of the entire network. This surprising observation also sheds light on the cooperative origin of neuronal burst in cultured networks. Our findings present an alternative flexible approach to the technique based on a massive tiling of networks by large-scale arrays of electrodes to monitor their activity. PMID:27824075

  1. Intracortical Microstimulation (ICMS) Activates Motor Cortex Layer 5 Pyramidal Neurons Mainly Transsynaptically.

    PubMed

    Hussin, Ahmed T; Boychuk, Jeffery A; Brown, Andrew R; Pittman, Quentin J; Teskey, G Campbell

    2015-01-01

    Intracortical microstimulation (ICMS) is a technique used for a number of purposes including the derivation of cortical movement representations (motor maps). Its application can activate the output layer 5 of motor cortex and can result in the elicitation of body movements depending upon the stimulus parameters used. The extent to which pyramidal tract projection neurons of the motor cortex are activated transsynaptically or directly by ICMS remains an open question. Given this uncertainty in the mode of activation, we used a preparation that combined patch clamp whole-cell recordings from single layer 5 pyramidal neurons and extracellular ICMS in slices of motor cortex as well as a standard in vivo mapping technique to ask how ICMS activated motor cortex pyramidal neurons. We measured changes in synaptic spike threshold and spiking rate to ICMS in vitro and movement threshold in vivo in the presence or absence of specific pharmacological blockers of glutamatergic (AMPA, NMDA and Kainate) receptors and GABAA receptors. With major excitatory and inhibitory synaptic transmission blocked (with DNQX, APV and bicuculline methiodide), we observed a significant increase in the ICMS current intensity required to elicit a movement in vivo as well as to the first spike and an 85% reduction in spiking responses in vitro. Subsets of neurons were still responsive after the synaptic block, especially at higher current intensities, suggesting a modest direct activation. Taken together our data indicate a mainly synaptic mode of activation to ICMS in layer 5 of rat motor cortex. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Decoupled choice-driven and stimulus-related activity in parietal neurons may be misrepresented by choice probabilities.

    PubMed

    Zaidel, Adam; DeAngelis, Gregory C; Angelaki, Dora E

    2017-09-28

    Trial-by-trial correlations between neural responses and choices (choice probabilities) are often interpreted to reflect a causal contribution of neurons to task performance. However, choice probabilities may arise from top-down, rather than bottom-up, signals. We isolated distinct sensory and decision contributions to single-unit activity recorded from the dorsal medial superior temporal (MSTd) and ventral intraparietal (VIP) areas of monkeys during perception of self-motion. Superficially, neurons in both areas show similar tuning curves during task performance. However, tuning in MSTd neurons primarily reflects sensory inputs, whereas choice-related signals dominate tuning in VIP neurons. Importantly, the choice-related activity of VIP neurons is not predictable from their stimulus tuning, and these factors are often confounded in choice probability measurements. This finding was confirmed in a subset of neurons for which stimulus tuning was measured during passive fixation. Our findings reveal decoupled stimulus and choice signals in the VIP area, and challenge our understanding of choice signals in the brain.Choice-related signals in neuronal activity may reflect bottom-up sensory processes, top-down decision-related influences, or a combination of the two. Here the authors report that choice-related activity in VIP neurons is not predictable from their stimulus tuning, and that dominant choice signals can bias the standard metric of choice preference (choice probability).

  3. A transgenic mouse for imaging activity-dependent dynamics of endogenous Arc mRNA in live neurons

    PubMed Central

    2018-01-01

    Localized translation plays a crucial role in synaptic plasticity and memory consolidation. However, it has not been possible to follow the dynamics of memory-associated mRNAs in living neurons in response to neuronal activity in real time. We have generated a novel mouse model where the endogenous Arc/Arg3.1 gene is tagged in its 3′ untranslated region with stem-loops that bind a bacteriophage PP7 coat protein (PCP), allowing visualization of individual mRNAs in real time. The physiological response of the tagged gene to neuronal activity is identical to endogenous Arc and reports the true dynamics of Arc mRNA from transcription to degradation. The transcription dynamics of Arc in cultured hippocampal neurons revealed two novel results: (i) A robust transcriptional burst with prolonged ON state occurs after stimulation, and (ii) transcription cycles continue even after initial stimulation is removed. The correlation of stimulation with Arc transcription and mRNA transport in individual neurons revealed that stimulus-induced Ca2+ activity was necessary but not sufficient for triggering Arc transcription and that blocking neuronal activity did not affect the dendritic transport of newly synthesized Arc mRNAs. This mouse will provide an important reagent to investigate how individual neurons transduce activity into spatiotemporal regulation of gene expression at the synapse.

  4. Cerebral cortical neurons with activity linked to central neurogenic spontaneous and evoked elevations in cerebral blood flow

    NASA Technical Reports Server (NTRS)

    Golanov, E. V.; Reis, D. J.

    1996-01-01

    We recorded neurons in rat cerebral cortex with activity relating to the neurogenic elevations in regional cerebral blood flow (rCBF) coupled to stereotyped bursts of EEG activity, burst-cerebrovascular wave complexes, appearing spontaneously or evoked by electrical stimulation of rostral ventrolateral medulla (RVL) or fastigial nucleus (FN). Of 333 spontaneously active neurons only 15 (5%), in layers 5-6, consistently (P < 0.05, chi-square) increased their activity during the earliest potential of the complex, approximately 1.3 s before the rise of rCBF, and during the minutes-long elevation of rCBF elicited by 10 s of stimulation of RVL or FN. The results indicate the presence of a small population of neurons in deep cortical laminae whose activity correlates with neurogenic elevations of rCBF. These neurons may function to transduce afferent neuronal signals into vasodilation.

  5. Activation of Strychnine-Sensitive Glycine Receptors by Shilajit on Preoptic Hypothalamic Neurons of Juvenile Mice.

    PubMed

    Bhattarai, Janardhan Prasad; Cho, Dong Hyu; Han, Seong Kyu

    2016-02-29

    Shilajit, a mineral pitch, has been used in Ayurveda and Siddha system of medicine to treat many human ailments, and is reported to contain at least 85 minerals in ionic form. This study examined the possible mechanism of Shilajit action on preoptic hypothalamic neurons using juvenile mice. The hypothalamic neurons are the key regulator of many hormonal systems. In voltage clamp mode at a holding potential of -60 mV, and under a high chloride pipette solution, Shilajit induced dose-dependent inward current. Shilajit-induced inward currents were reproducible and persisted in the presence of 0.5 μM tetrodotoxin (TTX) suggesting a postsynaptic action of Shilajit on hypothalamic neurons. The currents induced by Shilajit were almost completely blocked by 2 μM strychnine (Stry), a glycine receptor antagonist. In addition, Shilajit-induced inward currents were partially blocked by bicuculline. Under a gramicidin-perforated patch clamp mode, Shilajit induced membrane depolarization on juvenile neurons. These results show that Shilajit affects hypothalamic neuronal activities by activating the Stry-sensitive glycine receptor with α₂/α₂β subunit. Taken together, these results suggest that Shilajit contains some ingredients with possible glycine mimetic activities and might influence hypothalamic neurophysiology through activation of Stry-sensitive glycine receptor-mediated responses on hypothalamic neurons postsynaptically.

  6. The Influence of Neuronal Density and Maturation on Network Activity of Hippocampal Cell Cultures: A Methodological Study

    PubMed Central

    Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra

    2013-01-01

    It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm2 cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm2 cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm2 are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results are

  7. The influence of neuronal density and maturation on network activity of hippocampal cell cultures: a methodological study.

    PubMed

    Biffi, Emilia; Regalia, Giulia; Menegon, Andrea; Ferrigno, Giancarlo; Pedrocchi, Alessandra

    2013-01-01

    It is known that cell density influences the maturation process of in vitro neuronal networks. Neuronal cultures plated with different cell densities differ in number of synapses per neuron and thus in single neuron synaptic transmission, which results in a density-dependent neuronal network activity. Although many authors provided detailed information about the effects of cell density on neuronal culture activity, a dedicated report of density and age influence on neuronal hippocampal culture activity has not yet been reported. Therefore, this work aims at providing reference data to researchers that set up an experimental study on hippocampal neuronal cultures, helping in planning and decoding the experiments. In this work, we analysed the effects of both neuronal density and culture age on functional attributes of maturing hippocampal cultures. We characterized the electrophysiological activity of neuronal cultures seeded at three different cell densities, recording their spontaneous electrical activity over maturation by means of MicroElectrode Arrays (MEAs). We had gather data from 86 independent hippocampal cultures to achieve solid statistic results, considering the high culture-to-culture variability. Network activity was evaluated in terms of simple spiking, burst and network burst features. We observed that electrical descriptors were characterized by a functional peak during maturation, followed by a stable phase (for sparse and medium density cultures) or by a decrease phase (for high dense neuronal cultures). Moreover, 900 cells/mm(2) cultures showed characteristics suitable for long lasting experiments (e.g. chronic effect of drug treatments) while 1800 cells/mm(2) cultures should be preferred for experiments that require intense electrical activity (e.g. to evaluate the effect of inhibitory molecules). Finally, cell cultures at 3600 cells/mm(2) are more appropriate for experiments in which time saving is relevant (e.g. drug screenings). These results

  8. Photostimulation of Phox2b medullary neurons activates cardiorespiratory function in conscious rats.

    PubMed

    Kanbar, Roy; Stornetta, Ruth L; Cash, Devin R; Lewis, Stephen J; Guyenet, Patrice G

    2010-11-01

    Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing. To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of central chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be central chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans.

  9. Photostimulation of Phox2b Medullary Neurons Activates Cardiorespiratory Function in Conscious Rats

    PubMed Central

    Kanbar, Roy; Stornetta, Ruth L.; Cash, Devin R.; Lewis, Stephen J.; Guyenet, Patrice G.

    2010-01-01

    Rationale: Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing. Objectives: To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. Methods: A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of central chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. Measurements and Main Results: The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Conclusions: Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be central chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans. PMID:20622037

  10. Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons

    PubMed Central

    Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge; Estévez, Álvaro G.; Manfredi, Giovanni

    2012-01-01

    Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Taken together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. PMID:22219285

  11. Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats.

    PubMed

    Schuelert, N; Gorodetskaya, N; Just, S; Doods, H; Corradini, L

    2015-04-16

    Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Silencing of the Drosophila ortholog of SOX5 leads to abnormal neuronal development and behavioral impairment.

    PubMed

    Li, Airong; Hooli, Basavaraj; Mullin, Kristina; Tate, Rebecca E; Bubnys, Adele; Kirchner, Rory; Chapman, Brad; Hofmann, Oliver; Hide, Winston; Tanzi, Rudolph E

    2017-04-15

    SOX5 encodes a transcription factor that is expressed in multiple tissues including heart, lung and brain. Mutations in SOX5 have been previously found in patients with amyotrophic lateral sclerosis (ALS) and developmental delay, intellectual disability and dysmorphic features. To characterize the neuronal role of SOX5, we silenced the Drosophila ortholog of SOX5, Sox102F, by RNAi in various neuronal subtypes in Drosophila. Silencing of Sox102F led to misorientated and disorganized michrochaetes, neurons with shorter dendritic arborization (DA) and reduced complexity, diminished larval peristaltic contractions, loss of neuromuscular junction bouton structures, impaired olfactory perception, and severe neurodegeneration in brain. Silencing of SOX5 in human SH-SY5Y neuroblastoma cells resulted in a significant repression of WNT signaling activity and altered expression of WNT-related genes. Genetic association and meta-analyses of the results in several large family-based and case-control late-onset familial Alzheimer's disease (LOAD) samples of SOX5 variants revealed several variants that show significant association with AD disease status. In addition, analysis for rare and highly penetrate functional variants revealed four novel variants/mutations in SOX5, which taken together with functional prediction analysis, suggests a strong role of SOX5 causing AD in the carrier families. Collectively, these findings indicate that SOX5 is a novel candidate gene for LOAD with an important role in neuronal function. The genetic findings warrant further studies to identify and characterize SOX5 variants that confer risk for AD, ALS and intellectual disability. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Electrical activity controls area-specific expression of neuronal apoptosis in the mouse developing cerebral cortex.

    PubMed

    Blanquie, Oriane; Yang, Jenq-Wei; Kilb, Werner; Sharopov, Salim; Sinning, Anne; Luhmann, Heiko J

    2017-08-21

    Programmed cell death widely but heterogeneously affects the developing brain, causing the loss of up to 50% of neurons in rodents. However, whether this heterogeneity originates from neuronal identity and/or network-dependent processes is unknown. Here, we report that the primary motor cortex (M1) and primary somatosensory cortex (S1), two adjacent but functionally distinct areas, display striking differences in density of apoptotic neurons during the early postnatal period. These differences in rate of apoptosis negatively correlate with region-dependent levels of activity. Disrupting this activity either pharmacologically or by electrical stimulation alters the spatial pattern of apoptosis and sensory deprivation leads to exacerbated amounts of apoptotic neurons in the corresponding functional area of the neocortex. Thus, our data demonstrate that spontaneous and periphery-driven activity patterns are important for the structural and functional maturation of the neocortex by refining the final number of cortical neurons in a region-dependent manner.

  14. Amplitude of low frequency fluctuation abnormalities in adolescents with online gaming addiction.

    PubMed

    Yuan, Kai; Jin, Chenwang; Cheng, Ping; Yang, Xuejuan; Dong, Tao; Bi, Yanzhi; Xing, Lihong; von Deneen, Karen M; Yu, Dahua; Liu, Junyu; Liang, Jun; Cheng, Tingting; Qin, Wei; Tian, Jie

    2013-01-01

    The majority of previous neuroimaging studies have demonstrated both structural and task-related functional abnormalities in adolescents with online gaming addiction (OGA). However, few functional magnetic resonance imaging (fMRI) studies focused on the regional intensity of spontaneous fluctuations in blood oxygen level-dependent (BOLD) during the resting state and fewer studies investigated the relationship between the abnormal resting-state properties and the impaired cognitive control ability. In the present study, we employed the amplitude of low frequency fluctuation (ALFF) method to explore the local features of spontaneous brain activity in adolescents with OGA and healthy controls during resting-state. Eighteen adolescents with OGA and 18 age-, education- and gender-matched healthy volunteers participated in this study. Compared with healthy controls, adolescents with OGA showed a significant increase in ALFF values in the left medial orbitofrontal cortex (OFC), the left precuneus, the left supplementary motor area (SMA), the right parahippocampal gyrus (PHG) and the bilateral middle cingulate cortex (MCC). The abnormalities of these regions were also detected in previous addiction studies. More importantly, we found that ALFF values of the left medial OFC and left precuneus were positively correlated with the duration of OGA in adolescents with OGA. The ALFF values of the left medial OFC were also correlated with the color-word Stroop test performance. Our results suggested that the abnormal spontaneous neuronal activity of these regions may be implicated in the underlying pathophysiology of OGA.

  15. Abnormal Brain Activation During Theory of Mind Tasks in Schizophrenia: A Meta-Analysis.

    PubMed

    Kronbichler, Lisa; Tschernegg, Melanie; Martin, Anna Isabel; Schurz, Matthias; Kronbichler, Martin

    2017-10-21

    Social cognition abilities are severely impaired in schizophrenia (SZ). The current meta-analysis used foci of 21 individual studies on functional abnormalities in the schizophrenic brain in order to identify regions that reveal convergent under- or over-activation during theory of mind (TOM) tasks. Studies were included in the analyses when contrasting tasks that require the processing of mental states with tasks which did not. Only studies that investigated patients with an ICD or DSM diagnosis were included. Quantitative voxel-based meta-analyses were done using Seed-based d Mapping software. Common TOM regions like medial-prefrontal cortex and temporo-parietal junction revealed abnormal activation in schizophrenic patients: Under-activation was identified in the medial prefrontal cortex, left orbito-frontal cortex, and in a small section of the left posterior temporo-parietal junction. Remarkably, robust over-activation was identified in a more dorsal, bilateral section of the temporo-parietal junction. Further abnormal activation was identified in medial occipito-parietal cortex, right premotor areas, left cingulate gyrus, and lingual gyrus. The findings of this study suggest that SZ patients simultaneously show over- and under-activation in TOM-related regions. Especially interesting, temporo-parietal junction reveals diverging activation patterns with an under-activating left posterior and an over-activating bilateral dorsal section. In conclusion, SZ patients show less specialized brain activation in regions linked to TOM and increased activation in attention-related networks suggesting compensatory effects. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  16. Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

    PubMed

    Linehan, Victoria; Trask, Robert B; Briggs, Chantalle; Rowe, Todd M; Hirasawa, Michiru

    2015-08-01

    Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 μM) and high (100 μM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  17. Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Aziz, Gulzeb; Akselsen, Oyvind W.; Hansen, Trond V.

    2010-09-15

    Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibitedmore » both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.« less

  18. Peroxisome proliferator-activated receptor-α agonists protect cortical neurons from inflammatory mediators and improve peroxisomal function.

    PubMed

    Gray, Elizabeth; Ginty, Mark; Kemp, Kevin; Scolding, Neil; Wilkins, Alastair

    2011-04-01

    Inflammation is known to cause significant neuronal damage and axonal injury in many neurological disorders. Among the range of inflammatory mediators, nitric oxide is a potent neurotoxic agent. Recent evidence has suggested that cellular peroxisomes may be important in protecting neurons from inflammatory damage. To assess the influence of peroxisomal activation on nitric oxide-mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator-activated receptor (PPAR)-α agonist fenofibrate on cortical neurons exposed to a nitric oxide donor or co-cultured with activated microglia. Fenofibrate protected neurons and axons against both nitric oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in gene expression of ABCD3 (the gene encoding for peroxisomal membrane protein-70), with a concomitant increase in protein levels of PPAR-α and catalase, which was associated with a functional increase in the activity of this enzyme. Collectively, these observations provide evidence that modulation of PPAR-α activity and peroxisomal function by fenofibrate attenuates nitric oxide-mediated neuronal and axonal damage, suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  19. A frightening thought: Neuronal activity enhances tumor growth.

    PubMed

    Thompson, Emily G; Sontheimer, Harald

    2015-08-01

    Stem cells present in the adult brain are regulated by neuronal activity; malignant gliomas, which most likely originate from this population of cells, could also be regulated in this manner. A recent study by Venkatesh et al. published in Cell has identified Neuroligin-3 (NLGN3) as a mitogen promoting high-grade glioma growth.

  20. Noise focusing and the emergence of coherent activity in neuronal cultures

    NASA Astrophysics Data System (ADS)

    Orlandi, Javier G.; Soriano, Jordi; Alvarez-Lacalle, Enrique; Teller, Sara; Casademunt, Jaume

    2013-09-01

    At early stages of development, neuronal cultures in vitro spontaneously reach a coherent state of collective firing in a pattern of nearly periodic global bursts. Although understanding the spontaneous activity of neuronal networks is of chief importance in neuroscience, the origin and nature of that pulsation has remained elusive. By combining high-resolution calcium imaging with modelling in silico, we show that this behaviour is controlled by the propagation of waves that nucleate randomly in a set of points that is specific to each culture and is selected by a non-trivial interplay between dynamics and topology. The phenomenon is explained by the noise focusing effect--a strong spatio-temporal localization of the noise dynamics that originates in the complex structure of avalanches of spontaneous activity. Results are relevant to neuronal tissues and to complex networks with integrate-and-fire dynamics and metric correlations, for instance, in rumour spreading on social networks.

  1. The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons

    PubMed Central

    Davidson, Steve; Zhang, Xijing; Yoon, Chul H.; Khasabov, Sergey G.; Simone, Donald A.; Giesler, Glenn J.

    2010-01-01

    Itch is an everyday sensation, but when associated with disease or infection it can be chronic and debilitating. Several forms of itch can be blocked using antihistamines, but others cannot and these constitute an important clinical problem. Little information is available on the mechanisms underlying itch that is produced by nonhistaminergic mechanisms. We examined the responses of spinothalamic tract neurons to histaminergic and, for the first time, nonhistaminergic forms of itch stimuli. Fifty-seven primate spinothalamic tract (STT) neurons were identified using antidromic activation techniques and examined for their responses to histamine and cowhage, the nonhistaminergic itch-producing spicules covering the pod of the legume Mucuna pruriens. Each examined neuron had a receptive field on the hairy skin of the hindlimb and responded to noxious mechanical stimulation. STT neurons were tested with both pruritogens applied in a random order and we found 12 that responded to histamine and seven to cowhage. Each pruritogen-responsive STT neuron was activated by the chemical algogen capsaicin and two-thirds responded to noxious heat stimuli, demonstrating that these neurons convey chemical, thermal, and mechanical nociceptive information as well. Histamine or cowhage responsive STT neurons were found in both the marginal zone and the deep dorsal horn and were classified as high threshold and wide dynamic range. Unexpectedly, histamine and cowhage never activated the same cell. Our results demonstrate that the spinothalamic tract contains mutually exclusive populations of neurons responsive to histamine or the nonhistaminergic itch-producing agent cowhage. PMID:17855615

  2. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS.

    PubMed

    Silva, Mauro Sb; Prescott, Melanie; Campbell, Rebecca E

    2018-04-05

    Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

  3. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

    PubMed Central

    Silva, Mauro S.B.; Prescott, Melanie; Campbell, Rebecca E.

    2018-01-01

    Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP–transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype. PMID:29618656

  4. Parathyroid hormone-related peptide activates and modulates TRPV1 channel in human DRG neurons.

    PubMed

    Shepherd, A J; Mickle, A D; McIlvried, L A; Gereau, R W; Mohapatra, D P

    2018-05-24

    Parathyroid hormone-related peptide (PTHrP) is associated with advanced tumor growth and metastasis, especially in breast, prostate and myeloma cancers that metastasize to bones, resulting in debilitating chronic pain conditions. Our recent studies revealed that the receptor for PTHrP, PTH1R, is expressed in mouse DRG sensory neurons, and its activation leads to flow-activation and modulation of TRPV1 channel function, resulting in peripheral heat and mechanical hypersensitivity. In order to verify the translatability of our findings in rodents to humans, we explored whether this signalling axis operates in primary human DRG sensory neurons. Analysis of gene expression data from recently reported RNA deep sequencing experiments performed on mouse and human DRGs reveals that PTH1R is expressed in DRG and tibial nerve. Furthermore, exposure of cultured human DRG neurons to PTHrP leads to slow-sustained activation of TRPV1 and modulation of capsaicin-induced channel activation. Both activation and modulation of TRPV1 by PTHrP were dependent on PKC activity. Our findings suggest that functional PTHrP/PTH1R-TRPV1 signalling exists in human DRG neurons, which could contribute to local nociceptor excitation in the vicinity of metastatic bone tumor microenvironment. © 2018 European Pain Federation - EFIC®.

  5. Zebrafish embryos exposed to alcohol undergo abnormal development of motor neurons and muscle fibers.

    PubMed

    Sylvain, Nicole J; Brewster, Daniel L; Ali, Declan W

    2010-01-01

    Children exposed to alcohol in utero have significantly delayed gross and fine motor skills, as well as deficiencies in reflex development. The reasons that underlie the motor deficits caused by ethanol (EtOH) exposure remain to be fully elucidated. The present study was undertaken to investigate the effects of embryonic alcohol exposure (1.5%, 2% and 2.5% EtOH) on motor neuron and muscle fiber morphology in 3 days post fertilization (dpf) larval zebrafish. EtOH treated fish exhibited morphological deformities and fewer bouts of swimming in response to touch, compared with untreated fish. Immunolabelling with anti-acetylated tubulin indicated that fish exposed to 2.5% EtOH had significantly higher rates of motor neuron axon defects. Immunolabelling of primary and secondary motor neurons, using znp-1 and zn-8, revealed that fish exposed to 2% and 2.5% EtOH exhibited significantly higher rates of primary and secondary motor neuron axon defects compared to controls. Examination of red and white muscle fibers revealed that fish exposed to EtOH had significantly smaller fibers compared with controls. These findings indicate that motor neuron and muscle fiber morphology is affected by early alcohol exposure in zebrafish embryos, and that this may be related to deficits in locomotion. Copyright 2010 Elsevier Inc. All rights reserved.

  6. Activity-dependent sensitivity of proprioceptive sensory neurons in the stick insect femoral chordotonal organ.

    PubMed

    DiCaprio, Ralph A; Wolf, Harald; Büschges, Ansgar

    2002-11-01

    Mechanosensory neurons exhibit a wide range of dynamic changes in response, including rapid and slow adaptation. In addition to mechanical factors, electrical processes may also contribute to sensory adaptation. We have investigated adaptation of afferent neurons in the stick insect femoral chordotonal organ (fCO). The fCO contains sensory neurons that respond to position, velocity, and acceleration of the tibia. We describe the influence of random mechanical stimulation of the fCO on the response of fCO afferent neurons. The activity of individual sensory neurons was recorded intracellularly from their axons in the main leg nerve. Most fCO afferents (93%) exhibited a marked decrease in response to trapezoidal stimuli following sustained white noise stimulation (bandwidth = 60 Hz, amplitudes from +/-5 to +/-30 degrees ). Concurrent decreases in the synaptic drive to leg motoneurons and interneurons were also observed. Electrical stimulation of spike activity in individual fCO afferents in the absence of mechanical stimulation also led to a dramatic decrease in response in 15 of 19 afferents tested. This indicated that electrical processes are involved in the regulation of the generator potential or encoding of action potentials and partially responsible for the decreased response of the afferents. Replacing Ca(2+) with Ba(2+) in the saline surrounding the fCO greatly reduced or blocked the decrease in response elicited by electrically induced activity or mechanical stimulation when compared with control responses. Our results indicate that activity of fCO sensory neurons strongly affects their sensitivity, most likely via Ca(2+)-dependent processes.

  7. Monosodium glutamate-sensitive hypothalamic neurons contribute to the control of bone mass

    NASA Technical Reports Server (NTRS)

    Elefteriou, Florent; Takeda, Shu; Liu, Xiuyun; Armstrong, Dawna; Karsenty, Gerard

    2003-01-01

    Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.

  8. Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure.

    PubMed

    Hervig, Mona El-Sayed; Jensen, Nadja Cecilie Hvid; Rasmussen, Nadja Bredo; Rydbirk, Rasmus; Olesen, Mikkel Vestergaard; Hay-Schmidt, Anders; Pakkenberg, Bente; Aznar, Susana

    2017-05-30

    The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT 2A receptor (5-HT 2A R) dependent. Here, we further investigated how blockade of 5-HT 2A Rs in mice exposed to a novel open-field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantification for obtaining the total number of c-Fos-IR neurons as a measure of regional activation. We further examined the impact of 5-HT 2A R blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin-treated animals, upholding its involvement in modulating averseness. Ketanserin did not affect the number of activated striatal-projecting BLA neurons (measured by number of Cholera Toxin b (CTb) retrograde labelled neurons also being c-Fos-IR) following CTb injection in the ventral striatum. These results support a role of 5-HT 2A R activation in modulating mPFC and BLA activation during exposure to a novel environment, which may be interrelated. Conversely, 5-HT 2A R blockade does not seem to affect the amygdala-striatal projection. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Unique gene alterations are induced in FACS-purified Fos-positive neurons activated during cue-induced relapse to heroin seeking.

    PubMed

    Fanous, Sanya; Guez-Barber, Danielle H; Goldart, Evan M; Schrama, Regina; Theberge, Florence R M; Shaham, Yavin; Hope, Bruce T

    2013-01-01

    Cue-induced heroin seeking after prolonged withdrawal is associated with neuronal activation and altered gene expression in prefrontal cortex (PFC). However, these previous studies assessed gene expression in all neurons regardless of their activity state during heroin seeking. Using Fos as a marker of neural activity, we describe distinct molecular alterations induced in activated versus non-activated neurons during cue-induced heroin seeking after prolonged withdrawal. We trained rats to self-administer heroin for 10 days (6 h/day) and assessed cue-induced heroin seeking in extinction tests after 14 or 30 days. We used fluorescent-activated cell sorting (FACS) to purify Fos-positive and Fos-negative neurons from PFC 90 min after extinction testing. Flow cytometry showed that Fos-immunoreactivity was increased in less than 10% of sparsely distributed PFC neurons. mRNA levels of the immediate early genes fosB, arc, egr1, and egr2, as well as npy and map2k6, were increased in Fos-positive, but not Fos-negative, neurons. In support of these findings, double-label immunohistochemistry indicated substantial coexpression of neuropeptide Y (NPY)- and Arc-immunoreactivity in Fos-positive neurons. Our data indicate that cue-induced relapse to heroin seeking after prolonged withdrawal induces unique molecular alterations within activated PFC neurons that are distinct from those observed in the surrounding majority of non-activated neurons. Published 2012. This article is a US Government work and is in the public domain in the USA.

  10. Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease

    PubMed Central

    Mosaheb, Sabrina; Thorpe, Julian R.; Hashemzadeh-Bonehi, Lida; Bigio, Eileen H.; Gearing, Marla; Cairns, Nigel J.

    2006-01-01

    Abnormal neuronal cytoplasmic inclusions (NCIs) containing aggregates of α-internexin and the neurofilament (NF) subunits, NF-H, NF-M, and NF-L, are the signature lesions of neuronal intermediate filament (IF) inclusion disease (NIFID). The disease has a clinically heterogeneous phenotype, including fronto-temporal dementia, pyramidal and extrapyramidal signs presenting at a young age. NCIs are variably ubiquitinated and about half of cases also have neuronal intranuclear inclusions (NIIs), which are also ubiquitinated. NIIs have been described in polyglutamine-repeat expansion diseases, where they are strongly ubiquitin immunoreactive. The fine structure of NIIs of NIFID has not previously been described. Therefore, to determine the ultrastructure of NIIs, immunoelectron microscopy was undertaken on NIFID cases and normal aged control brains. Our results indicate that the NIIs of NIFID are strongly ubiquitin immunoreactive. However, unlike NCIs which contain ubiquitin, α-internexin and NF epitopes, NIIs contain neither epitopes of α-internexin nor NF subunits. Neither NIIs nor NCIs were recognised by antibodies to expanded polyglutamine repeats. The NII of NIFID lacks a limiting membrane and contains straight filaments of 20 nm mean width (range 11–35 nm), while NCIs contain filaments with a mean width of 10 nm (range 5–18 nm; t-test, P<0.001). Biochemistry revealed no differences in neuronal IF protein mobilities between NIFID and normal brain tissue. Therefore, NIIs of NIFID contain filaments morphologically and immunologically distinct from those of NCIs, and both types of inclusion lack expanded polyglutamine tracts of the triplet-repeat expansion diseases. These observations indicate that abnormal protein aggregation follows separate pathways in different neuronal compartments of NIFID. PMID:16025283

  11. Crosstalk between Activated Microglia and Neurons in the Spinal Dorsal Horn Contributes to Stress-induced Hyperalgesia

    PubMed Central

    Qi, Jian; Chen, Chen; Meng, Qing-Xi; Wu, Yan; Wu, Haitao; Zhao, Ting-Bao

    2016-01-01

    Stress has been shown to enhance pain sensitivity resulting in stress-induced hyperalgesia. However, the underlying mechanisms have yet to be elucidated. Using single-prolonged stress combined with Complete Freund’s Adjuvant injection model, we explored the reciprocal regulatory relationship between neurons and microglia, which is critical for the maintenance of posttraumatic stress disorder (PTSD)-induced hyperalgesia. In our assay, significant mechanical allodynia was observed. Additionally, activated neurons in spinal dorsal horn were observed by analysis of Fos expression. And, microglia were also significantly activated with the presence of increased Iba-1 expression. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or minocycline (a specific microglia inhibitor) attenuated mechanical allodynia. Moreover, intrathecal administration of c-fos ASO significantly suppressed the activation of neurons and microglia. Interestingly, inhibition of microglia activation by minocycline significantly suppressed the activation of both neurons and microglia in spinal dorsal horn. P38 inhibitor SB203580 suppressed IL-6 production, and inhibition of IL-6 receptor (IL-6R) activation by tocilizumab suppressed Fos expression. Together, our data suggest that the presence of a “crosstalk” between activated microglia and neurons in the spinal dorsal horn, which might contribute to the stress-induced hyperactivated state, leading to an increased pain sensitivity. PMID:27995982

  12. RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation.

    PubMed

    Wu, Xiangbing; Walker, Chandler L; Lu, Qingbo; Wu, Wei; Eddelman, Daniel B; Parish, Jonathan M; Xu, Xiao-Ming

    2017-11-01

    Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10th thoracic (T10) vertebral level. We found that co-administration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33, 52 and 43 %, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly downregulated cPLA 2 activation by 66 and 60 %, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2 , two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression and reduced injury-induced apoptosis at and close to the lesion site. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

  13. Endoplasmic reticulum stress in wake-active neurons progresses with aging.

    PubMed

    Naidoo, Nirinjini; Zhu, Jingxu; Zhu, Yan; Fenik, Polina; Lian, Jie; Galante, Ray; Veasey, Sigrid

    2011-08-01

    Fragmentation of wakefulness and sleep are expected outcomes of advanced aging. We hypothesize that wake neurons develop endoplasmic reticulum dyshomeostasis with aging, in parallel with impaired wakefulness. In this series of experiments, we sought to more fully characterize age-related changes in wakefulness and then, in relevant wake neuronal populations, explore functionality and endoplasmic reticulum homeostasis. We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c-fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age-related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  14. Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets

    PubMed Central

    Humphries, Edward S. A.

    2015-01-01

    Potassium (K+) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K+ (KATP) channels, very few selective K+ channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K+ channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K+ channel modulators. PMID:26303307

  15. Comparative Analysis of Human and Rodent Brain Primary Neuronal Culture Spontaneous Activity Using Micro-Electrode Array Technology.

    PubMed

    Napoli, Alessandro; Obeid, Iyad

    2016-03-01

    Electrical activity in embryonic brain tissue has typically been studied using Micro Electrode Array (MEA) technology to make dozens of simultaneous recordings from dissociated neuronal cultures, brain stem cell progenitors, or brain slices from fetal rodents. Although these rodent neuronal primary culture electrical properties are mostly investigated, it has not been yet established to what extent the electrical characteristics of rodent brain neuronal cultures can be generalized to those of humans. A direct comparison of spontaneous spiking activity between rodent and human primary neurons grown under the same in vitro conditions using MEA technology has never been carried out before and will be described in the present study. Human and rodent dissociated fetal brain neuronal cultures were established in-vitro by culturing on a glass grid of 60 planar microelectrodes neurons under identical conditions. Three different cultures of human neurons were produced from tissue sourced from a single aborted fetus (at 16-18 gestational weeks) and these were compared with seven different cultures of embryonic rat neurons (at 18 gestational days) originally isolated from a single rat. The results show that the human and rodent cultures behaved significantly differently. Whereas the rodent cultures demonstrated robust spontaneous activation and network activity after only 10 days, the human cultures required nearly 40 days to achieve a substantially weaker level of electrical function. These results suggest that rat neuron preparations may yield inferences that do not necessarily transfer to humans. © 2015 Wiley Periodicals, Inc.

  16. Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex

    PubMed Central

    Corcoran, Andrea E.; Brust, Rachael D.; Chang, YoonJeung; Nattie, Eugene E.

    2017-01-01

    Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 (Tac1) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1, referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine-N-oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO2. Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei. SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using genetic

  17. Activity of Tachykinin1-Expressing Pet1 Raphe Neurons Modulates the Respiratory Chemoreflex.

    PubMed

    Hennessy, Morgan L; Corcoran, Andrea E; Brust, Rachael D; Chang, YoonJeung; Nattie, Eugene E; Dymecki, Susan M

    2017-02-15

    Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the Tachykinin-1 ( Tac1 ) gene. Here, we characterize in mice a 5-HT neuron subtype identified by expression of Tac1 and the serotonergic transcription factor gene Pet1 , referred to as the Tac1-Pet1 neuron subtype. Transgenic cell labeling showed Tac1-Pet1 soma resident largely in the caudal medulla. Chemogenetic [clozapine -N- oxide (CNO)-hM4Di] perturbation of Tac1-Pet1 neuron activity blunted the ventilatory response of the respiratory CO 2 chemoreflex, which normally augments ventilation in response to hypercapnic acidosis to restore normal pH and PCO 2 Tac1-Pet1 axonal boutons were found localized to brainstem areas implicated in respiratory modulation, with highest density in motor regions. These findings demonstrate that the activity of a Pet1 neuron subtype with the potential to release both 5-HT and substance P is necessary for normal respiratory dynamics, perhaps via motor outputs that engage muscles of respiration and maintain airway patency. These Tac1-Pet1 neurons may act downstream of Egr2-Pet1 serotonergic neurons, which were previously established in respiratory chemoreception, but do not innervate respiratory motor nuclei. SIGNIFICANCE STATEMENT Serotonin (5-HT) neurons modulate physiological processes and behaviors as diverse as body temperature, respiration, aggression, and mood. Using

  18. Differential regulation of the Rac1 GTPase-activating protein (GAP) BCR during oxygen/glucose deprivation in hippocampal and cortical neurons.

    PubMed

    Smith, Katharine R; Rajgor, Dipen; Hanley, Jonathan G

    2017-12-08

    Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signaling via Rho-family small GTPases, their upstream guanine nucleotide exchange factors, and GTPase-activating proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 guanine nucleotide exchange factor Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons; however, the identity of an antagonistic GAP remains elusive. Here we show that the Rac1 GAP breakpoint cluster region (BCR) associates with NMDA receptors (NMDARs) along with Tiam1 and that this protein complex is more abundant in hippocampal compared with cortical neurons. Although total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared with cortical neurons. OGD causes an NMDAR- and Ca 2+ -permeable AMPAR-dependent deactivation of BCR in hippocampal but not cortical neurons. BCR knockdown occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1-NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Dopamine Attenuates Ketamine-Induced Neuronal Apoptosis in the Developing Rat Retina Independent of Early Synchronized Spontaneous Network Activity.

    PubMed

    Dong, Jing; Gao, Lingqi; Han, Junde; Zhang, Junjie; Zheng, Jijian

    2017-07-01

    Deprivation of spontaneous rhythmic electrical activity in early development by anesthesia administration, among other interventions, induces neuronal apoptosis. However, it is unclear whether enhancement of neuronal electrical activity attenuates neuronal apoptosis in either normal development or after anesthesia exposure. The present study investigated the effects of dopamine, an enhancer of spontaneous rhythmic electrical activity, on ketamine-induced neuronal apoptosis in the developing rat retina. TUNEL and immunohistochemical assays indicated that ketamine time- and dose-dependently aggravated physiological and ketamine-induced apoptosis and inhibited early-synchronized spontaneous network activity. Dopamine administration reversed ketamine-induced neuronal apoptosis, but did not reverse the inhibitory effects of ketamine on early synchronized spontaneous network activity despite enhancing it in controls. Blockade of D1, D2, and A2A receptors and inhibition of cAMP/PKA signaling partially antagonized the protective effect of dopamine against ketamine-induced apoptosis. Together, these data indicate that dopamine attenuates ketamine-induced neuronal apoptosis in the developing rat retina by activating the D1, D2, and A2A receptors, and upregulating cAMP/PKA signaling, rather than through modulation of early synchronized spontaneous network activity.

  20. A Discrete Population of Neurons in the Lateral Amygdala Is Specifically Activated by Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Wilson, Yvette M.; Murphy, Mark

    2009-01-01

    There is no clear identification of the neurons involved in fear conditioning in the amygdala. To search for these neurons, we have used a genetic approach, the "fos-tau-lacZ" (FTL) mouse, to map functionally activated expression in neurons following contextual fear conditioning. We have identified a discrete population of neurons in the lateral…

  1. ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Han, Jeong-Ho; Yu, Tae-Hoon; Ryu, Hyun-Hee

    2013-08-01

    Tar-DNA binding protein of 43 kDa (TDP-43) has been characterized as a major component of protein aggregates in brains with neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, physiological roles of TDP-43 and early cellular pathogenic effects caused by disease associated mutations in differentiated neurons are still largely unknown. Here, we investigated the physiological roles of TDP-43 and the effects of missense mutations associated with diseases in differentiated cortical neurons. The reduction of TDP-43 by siRNA increased abnormal neurites and decreased cell viability. ALS/FTLD-associated missense mutant proteins (A315T, Q331K, and M337V) were partially mislocalizedmore » to the cytosol and neurites when compared to wild-type and showed abnormal neurites similar to those observed in cases of loss of TDP-43. Interestingly, cytosolic expression of wild-type TDP-43 with mutated nuclear localization signals also induced abnormal neurtie morphology and reduction of cell viability. However, there was no significant difference in the effects of cytosolic expression in neuronal morphology and cell toxicity between wild-type and missense mutant proteins. Thus, our results suggest that mislocalization of missense mutant TDP-43 may contribute to loss of TDP-43 function and affect neuronal morphology, probably via dominant negative action before severe neurodegeneration in differentiated cortical neurons. Highlights: • The function of nuclear TDP-43 in neurite morphology in mature neurons. • Partial mislocalization of TDP-43 missense mutants into cytosol from nucleus. • Abnormal neurite morphology caused by missense mutants of TDP-43. • The effect of cytosolic expression of TDP-43 in neurite morphology and in cell survival.« less

  2. Modelling the Effects of Electrical Coupling between Unmyelinated Axons of Brainstem Neurons Controlling Rhythmic Activity

    PubMed Central

    Hull, Michael J.; Soffe, Stephen R.; Willshaw, David J.; Roberts, Alan

    2015-01-01

    Gap junctions between fine unmyelinated axons can electrically couple groups of brain neurons to synchronise firing and contribute to rhythmic activity. To explore the distribution and significance of electrical coupling, we modelled a well analysed, small population of brainstem neurons which drive swimming in young frog tadpoles. A passive network of 30 multicompartmental neurons with unmyelinated axons was used to infer that: axon-axon gap junctions close to the soma gave the best match to experimentally measured coupling coefficients; axon diameter had a strong influence on coupling; most neurons were coupled indirectly via the axons of other neurons. When active channels were added, gap junctions could make action potential propagation along the thin axons unreliable. Increased sodium and decreased potassium channel densities in the initial axon segment improved action potential propagation. Modelling suggested that the single spike firing to step current injection observed in whole-cell recordings is not a cellular property but a dynamic consequence of shunting resulting from electrical coupling. Without electrical coupling, firing of the population during depolarising current was unsynchronised; with coupling, the population showed synchronous recruitment and rhythmic firing. When activated instead by increasing levels of modelled sensory pathway input, the population without electrical coupling was recruited incrementally to unpatterned activity. However, when coupled, the population was recruited all-or-none at threshold into a rhythmic swimming pattern: the tadpole “decided” to swim. Modelling emphasises uncertainties about fine unmyelinated axon physiology but, when informed by biological data, makes general predictions about gap junctions: locations close to the soma; relatively small numbers; many indirect connections between neurons; cause of action potential propagation failure in fine axons; misleading alteration of intrinsic firing

  3. Excitotoxicity-induced prostaglandin D2 production induces sustained microglial activation and delayed neuronal death.

    PubMed

    Iwasa, Kensuke; Yamamoto, Shinji; Yagishita, Sosuke; Maruyama, Kei; Yoshikawa, Keisuke

    2017-04-01

    Excitotoxicity is the pivotal mechanism of neuronal death. Prostaglandins (PGs) produced during excitotoxicity play important roles in neurodegenerative conditions. Previously, we demonstrated that initial burst productions of PGD 2 , PGE 2 , and PGF 2α are produced by cyclooxygenase-2 (COX-2) in the hippocampus following a single systemic kainic acid (KA) administration. In addition, we showed that blocking of all PG productions ameliorated hippocampal delayed neuronal death at 30 days after KA administration. To investigate the role of individual PGs in the delayed neuronal death, we performed intracerebroventricular injection of PGD 2 , PGE 2 , or PGF 2α in rats whose hippocampal PG productions were entirely blocked by pretreatment of NS398, a COX-2 selective inhibitor. Administration of PGD 2 and PGF 2α had a latent contribution to the delayed neuronal death, sustained over 30 days after a single KA treatment. Furthermore, PGD 2 enhanced microglial activation, which may be involved in the delayed neuronal death in the hippocampus. These findings suggest that excitotoxic delayed neuronal death is mediated through microglia activated by PGD 2 . Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  4. Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus

    USDA-ARS?s Scientific Manuscript database

    Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However the mechanisms underlying its anorexigenic effects remain to be identified. We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and ne...

  5. Effects of Two Commonly Found Strains of Influenza A Virus on Developing Dopaminergic Neurons, in Relation to the Pathophysiology of Schizophrenia

    PubMed Central

    Landreau, Fernando; Galeano, Pablo; Caltana, Laura R.; Masciotra, Luis; Chertcoff, Agustín; Pontoriero, A.; Baumeister, Elsa; Amoroso, Marcela; Brusco, Herminia A.; Tous, Mónica I.; Savy, Vilma L.; Lores Arnaiz, María del Rosario; de Erausquin, Gabriel A.

    2012-01-01

    Influenza virus (InfV) infection during pregnancy is a known risk factor for neurodevelopment abnormalities in the offspring, including the risk of schizophrenia, and has been shown to result in an abnormal behavioral phenotype in mice. However, previous reports have concentrated on neuroadapted influenza strains, whereas increased schizophrenia risk is associated with common respiratory InfV. In addition, no specific mechanism has been proposed for the actions of maternal infection on the developing brain that could account for schizophrenia risk. We identified two common isolates from the community with antigenic configurations H3N2 and H1N1 and compared their effects on developing brain with a mouse modified-strain A/WSN/33 specifically on the developing of dopaminergic neurons. We found that H1N1 InfV have high affinity for dopaminergic neurons in vitro, leading to nuclear factor kappa B activation and apoptosis. Furthermore, prenatal infection of mothers with the same strains results in loss of dopaminergic neurons in the offspring, and in an abnormal behavioral phenotype. We propose that the well-known contribution of InfV to risk of schizophrenia during development may involve a similar specific mechanism and discuss evidence from the literature in relation to this hypothesis. PMID:23251423

  6. Two-photon imaging of neuronal activity in motor cortex of marmosets during upper-limb movement tasks.

    PubMed

    Ebina, Teppei; Masamizu, Yoshito; Tanaka, Yasuhiro R; Watakabe, Akiya; Hirakawa, Reiko; Hirayama, Yuka; Hira, Riichiro; Terada, Shin-Ichiro; Koketsu, Daisuke; Hikosaka, Kazuo; Mizukami, Hiroaki; Nambu, Atsushi; Sasaki, Erika; Yamamori, Tetsuo; Matsuzaki, Masanori

    2018-05-14

    Two-photon imaging in behaving animals has revealed neuronal activities related to behavioral and cognitive function at single-cell resolution. However, marmosets have posed a challenge due to limited success in training on motor tasks. Here we report the development of protocols to train head-fixed common marmosets to perform upper-limb movement tasks and simultaneously perform two-photon imaging. After 2-5 months of training sessions, head-fixed marmosets can control a manipulandum to move a cursor to a target on a screen. We conduct two-photon calcium imaging of layer 2/3 neurons in the motor cortex during this motor task performance, and detect task-relevant activity from multiple neurons at cellular and subcellular resolutions. In a two-target reaching task, some neurons show direction-selective activity over the training days. In a short-term force-field adaptation task, some neurons change their activity when the force field is on. Two-photon calcium imaging in behaving marmosets may become a fundamental technique for determining the spatial organization of the cortical dynamics underlying action and cognition.

  7. Expression of ESR1 in Glutamatergic and GABAergic Neurons Is Essential for Normal Puberty Onset, Estrogen Feedback, and Fertility in Female Mice.

    PubMed

    Cheong, Rachel Y; Czieselsky, Katja; Porteous, Robert; Herbison, Allan E

    2015-10-28

    Circulating estradiol exerts a profound influence on the activity of the gonadotropin-releasing hormone (GnRH) neuronal network controlling fertility. Using genetic strategies enabling neuron-specific deletion of estrogen receptor α (Esr1), we examine here whether estradiol-modulated GABA and glutamate transmission are critical for the functioning of the GnRH neuron network in the female mouse. Using Vgat- and Vglut2-ires-Cre knock-in mice and ESR1 immunohistochemistry, we demonstrate that subpopulations of GABA and glutamate neurons throughout the limbic forebrain express ESR1, with ESR1-GABAergic neurons being more widespread and numerous than ESR1-glutamatergic neurons. We crossed Vgat- and Vglut2-ires-Cre mice with an Esr1(lox/lox) line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat-ires-Cre;Esr1(lox/lox) mice were infertile, with abnormal estrous cycles, and exhibited a complete failure of the estrogen positive feedback mechanism responsible for the preovulatory GnRH surge. However, puberty onset and estrogen negative feedback were normal. Vglut2-ires-Cre;Esr1(lox/lox) mice were also infertile but displayed a wider range of deficits, including advanced puberty onset, abnormal negative feedback, and abolished positive feedback. Whereas <25% of preoptic kisspeptin neurons expressed Cre in Vgat- and Vglut2-ires-Cre lines, ∼70% of arcuate kisspeptin neurons were targeted in Vglut2-ires-Cre;Esr1(lox/lox) mice, possibly contributing to their advanced puberty phenotype. These observations show that, unexpectedly, ESR1-GABA neurons are only essential for the positive feedback mechanism. In contrast, we reveal the key importance of ESR1 in glutamatergic neurons for multiple estrogen feedback loops within the GnRH neuronal network required for fertility in the female mouse. Copyright © 2015 the authors 0270-6474/15/3514533-11$15.00/0.

  8. Melatonin-mediated β-catenin activation protects neuron cells against prion protein-induced neurotoxicity.

    PubMed

    Jeong, Jae-Kyo; Lee, Ju-Hee; Moon, Ji-Hong; Lee, You-Jin; Park, Sang-Youel

    2014-11-01

    Activation of β-catenin in neurons regulates mitochondrial function and protects against protein misfolding disorders, including Alzheimer's disease and Huntington's disease. Melatonin, a natural secretory product of the pineal gland, exerts neuroprotective effects through the activation of β-catenin. In this study, melatonin increased β-catenin protein expression and activation in human neuroblastoma cell lines SH-SY5Y cells. Melatonin also inhibited PrP (106-126)-induced neurotoxicity and the inhibition attenuated by treatment of β-catenin inhibitor ICG-001. Activation of β-catenin blocked PrP (106-126)-mediated downregulation of anti-apoptotic protein survivin and Bcl-2. Reduction of mitochondrial membrane potential, translocation of Bax, and cytochrome c release which induced by PrP (106-126) treatment were inhibited by β-catenin activation, which contributed to prevented PrP (106-126)-induced neuronal cell death. In conclusion, β-catenin activation by melatonin prevented PrP (106-126)-induced neuronal cell death through regulating anti-apoptotic proteins and mitochondrial pathways. These results also suggest the therapeutic value of Wnt/β-catenin signaling in prion-related disorders as influenced by melatonin. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage.

    PubMed

    Thomas, David M; Francescutti-Verbeem, Dina M; Kuhn, Donald M

    2006-03-01

    Microglia are the resident antigen-presenting cells within the central nervous system (CNS), and they serve immune-like functions in protecting the brain against injury and invading pathogens. By contrast, activated microglia can secrete numerous reactants that damage neurons. The pathogenesis of various neurodegenerative diseases has been associated with microglial activation, but the signaling pathways that program a neuronally protective or destructive phenotype in microglia are not known. To increase the understanding of microglial activation, microarray analysis was used to profile the transcriptome of BV-2 microglial cells after activation. Microglia were activated by lipopolysaccharide, the HIV neurotoxic protein TAT, and dopamine quinone, each of which has been linked to dopamine neuronal damage. We identified 210 of 9882 genes whose expression was differentially regulated by all activators (116 increased and 94 decreased in expression). Gene ontology analysis assigned up-regulated genes to a number of specific biological processes and molecular functions, including immune response, inflammation, and cytokine/chemokine activity. Genes down-regulated in expression contribute to conditions that are permissive of microglial migration, lowered adhesion to matrix, lessened phagocytosis, and reduction in receptors that oppose chemotaxis and inflammation. These results elaborate a broad profile of microglial genes whose expression is altered by conditions associated with both neurodegenerative diseases and microglial activation.

  10. Mirror neuron activity during contagious yawning--an fMRI study.

    PubMed

    Haker, Helene; Kawohl, Wolfram; Herwig, Uwe; Rössler, Wulf

    2013-03-01

    Yawning is contagious. However, little research has been done to elucidate the neuronal representation of this phenomenon. Our study objective was to test the hypothesis that the human mirror neuron system (MNS) is activated by visually perceived yawning. We used functional magnetic resonance imaging to assess brain activity during contagious yawning (CY). Signal-dependent changes in blood oxygen levels were compared when subjects viewed videotapes of yawning faces as opposed to faces with a neutral expression. In response to yawning, subjects showed unilateral activation of their Brodmann's area 9 (BA 9) portion of the right inferior frontal gyrus, a region of the MNS. In this way, two individuals could share physiological and associated emotional states based on perceived motor patterns. This is one component of empathy (motor empathy) that underlies the development of cognitive empathy. The BA 9 is reportedly active in tasks requiring mentalizing abilities. Our results emphasize the connection between the MNS and higher cognitive empathic functions, including mentalizing. We conclude that CY is based on a functional substrate of empathy.

  11. Engineering a light-activated caspase-3 for precise ablation of neurons in vivo

    PubMed Central

    Smart, Ashley D.; Pache, Roland A.; Thomsen, Nathan D.; Kortemme, Tanja; Davis, Graeme W.; Wells, James A.

    2017-01-01

    The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light-activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila. Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV–induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms. PMID:28893998

  12. Engineering a light-activated caspase-3 for precise ablation of neurons in vivo.

    PubMed

    Smart, Ashley D; Pache, Roland A; Thomsen, Nathan D; Kortemme, Tanja; Davis, Graeme W; Wells, James A

    2017-09-26

    The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light-activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV-induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms.

  13. Early Correlated Network Activity in the Hippocampus: Its Putative Role in Shaping Neuronal Circuits.

    PubMed

    Griguoli, Marilena; Cherubini, Enrico

    2017-01-01

    Synchronized neuronal activity occurring at different developmental stages in various brain structures represents a hallmark of developmental circuits. This activity, which differs in its specific patterns among animal species may play a crucial role in de novo formation and in shaping neuronal networks. In the rodent hippocampus in vitro , the so-called giant depolarizing potentials (GDPs) constitute a primordial form of neuronal synchrony preceding more organized forms of activity such as oscillations in the theta and gamma frequency range. GDPs are generated at the network level by the interaction of the neurotransmitters glutamate and GABA which, immediately after birth, exert both a depolarizing and excitatory action on their targets. GDPs are triggered by GABAergic interneurons, which in virtue of their extensive axonal branching operate as functional hubs to synchronize large ensembles of cells. Intrinsic bursting activity, driven by a persistent sodium conductance and facilitated by the low expression of Kv7.2 and Kv7.3 channel subunits, responsible for I M , exerts a permissive role in GDP generation. Here, we discuss how GDPs are generated in a probabilistic way when neuronal excitability within a local circuit reaches a certain threshold and how GDP-associated calcium transients act as coincident detectors for enhancing synaptic strength at emerging GABAergic and glutamatergic synapses. We discuss the possible in vivo correlate of this activity. Finally, we debate recent data showing how, in several animal models of neuropsychiatric disorders including autism, a GDPs dysfunction is associated to morphological alterations of neuronal circuits and behavioral deficits reminiscent of those observed in patients.

  14. EFFECTS OF CHRONIC ANTIDEPRESSANT DRUG ADMINISTRATION AND ELECTROCONVULSIVE SHOCK ON ACTIVITY OF DOPAMINERGIC NEURONS IN THE VENTRAL TEGMENTUM

    PubMed Central

    West, Charles Hutchison Keesor; Weiss, Jay Michael

    2010-01-01

    Increasing attention is now focused on reduced dopaminergic neurotransmission in the forebrain as participating in depression. The present paper assessed whether effective antidepressant (AD) treatments might counteract, or compensate for, such a change by altering the neuronal activity of dopaminergic neurons in the ventral tegmental area (VTA-DA neurons), the cell bodies of the mesocorticolimbic dopaminergic system. Eight AD drugs or vehicle were administered to rats for 14 days via subcutaneously-implanted minipumps, at which time single-unit electrophysiological activity of VTA-DA neurons was recorded under anesthesia. Also, animals received a series of five electroconvulsive shocks (ECS) or control procedures, after which VTA-DA activity was measured either three or five days after the last ECS. Results showed that the chronic administration of all AD drugs tested except for the monoamine oxidase inhibitor increased the spontaneous firing rate of VTA-DA neurons, while effects on “burst” firing activity were found to be considerably less notable or consistent. ECS increased both spontaneous firing rate and burst firing of VTA-DA neurons. It is suggested that the effects observed are consistent with reports of increased dopamine release in regions to which VTA neurons project after effective AD treatment. However, it is further suggested that changes in VTA-DA neuronal activity in response to AD treatment should be most appropriately assessed under conditions associated with depression, such as stressful conditions. PMID:20482941

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

    PubMed

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

    2017-03-01

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

  16. Beadex Function in the Motor Neurons Is Essential for Female Reproduction in Drosophila melanogaster

    PubMed Central

    Kairamkonda, Subhash; Nongthomba, Upendra

    2014-01-01

    Drosophila melanogaster has served as an excellent model system for understanding the neuronal circuits and molecular mechanisms regulating complex behaviors. The Drosophila female reproductive circuits, in particular, are well studied and can be used as a tool to understand the role of novel genes in neuronal function in general and female reproduction in particular. In the present study, the role of Beadex, a transcription co-activator, in Drosophila female reproduction was assessed by generation of mutant and knock down studies. Null allele of Beadex was generated by transposase induced excision of P-element present within an intron of Beadex gene. The mutant showed highly compromised reproductive abilities as evaluated by reduced fecundity and fertility, abnormal oviposition and more importantly, the failure of sperm release from storage organs. However, no defect was found in the overall ovariole development. Tissue specific, targeted knock down of Beadex indicated that its function in neurons is important for efficient female reproduction, since its neuronal knock down led to compromised female reproductive abilities, similar to Beadex null females. Further, different neuronal class specific knock down studies revealed that Beadex function is required in motor neurons for normal fecundity and fertility of females. Thus, the present study attributes a novel and essential role for Beadex in female reproduction through neurons. PMID:25396431

  17. Male mice ultrasonic vocalizations enhance female sexual approach and hypothalamic kisspeptin neuron activity.

    PubMed

    Asaba, Akari; Osakada, Takuya; Touhara, Kazushige; Kato, Masahiro; Mogi, Kazutaka; Kikusui, Takefumi

    2017-08-01

    Vocal communication in animals is important for ensuring reproductive success. Male mice emit song-like "ultrasonic vocalizations (USVs)" when they encounter female mice, and females show approach to the USVs. However, it is unclear whether USVs of male mice trigger female behavioral and endocrine responses in reproduction. In this study, we first investigated the relationship between the number of deliveries in breeding pairs for 4months and USVs syllables emitted from those paired males during 3min of sexual encounter with unfamiliar female mice. There was a positive correlation between these two indices, which suggests that breeding pairs in which males could emit USVs more frequently had more offspring. Further, we examined the effect of USVs of male mice on female sexual behavior. Female mice showed more approach behavior towards vocalizing males than devocalized males. Finally, to determine whether USVs of male mice could activate the neural system governing reproductive function in female mice, the activation of kisspeptin neurons, key neurons to drive gonadotropin-releasing hormone neurons in the hypothalamus, was examined using dual-label immunocytochemistry with cAMP response element-binding protein phosphorylation (pCREB). In the arcuate nucleus (Arc), the number of kisspeptin neurons expressing pCREB significantly increased after exposure to USVs of male as compared with noise exposure group. In conclusion, our results suggest that USVs of male mice promote fertility in female mice by activating both their approaching behavior and central kisspeptin neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons.

    PubMed

    Han, P; Lucero, M T

    2005-01-01

    Pituitary adenylate cyclase activating polypeptide has been shown to reduce apoptosis in neonatal cerebellar and olfactory receptor neurons, however the underlying mechanisms have not been elucidated. In addition, the neuroprotective effects of pituitary adenylate cyclase activating polypeptide have not been examined in adult tissues. To study the effects of pituitary adenylate cyclase activating polypeptide on neurons in apoptosis, we measured caspase activation in adult olfactory receptor neurons in vitro. Interestingly, we found that the protective effects of pituitary adenylate cyclase activating polypeptide were related to the absence of a 4-aminopyridine (IC50=144 microM) sensitive rapidly inactivating potassium current often referred to as A-type current. In the presence of 40 nM pituitary adenylate cyclase activating polypeptide 38, both A-type current and activated caspases were significantly reduced. A-type current reduction by pituitary adenylate cyclase activating polypeptide was blocked by inhibiting the phospholipase C pathway, but not the adenylyl cyclase pathway. Our observation that 5 mM 4-aminopyridine mimicked the caspase inhibiting effects of pituitary adenylate cyclase activating polypeptide indicates that A-type current is involved in apoptosis. This work contributes to our growing understanding that potassium currents are involved with the activation of caspases to affect the balance between cell life and death.

  19. Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

    PubMed

    Phumsatitpong, Chayarndorn; Moenter, Suzanne M

    2018-01-01

    Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

  20. The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus.

    PubMed

    Suntsova, Natalia; Guzman-Marin, Ruben; Kumar, Sunil; Alam, Md Noor; Szymusiak, Ronald; McGinty, Dennis

    2007-02-14

    The perifornical-lateral hypothalamic area (PF/LH) contains neuronal groups playing an important role in control of waking and sleep. Among the brain regions that regulate behavioral states, one of the strongest sources of projections to the PF/LH is the median preoptic nucleus (MnPN) containing a sleep-active neuronal population. To evaluate the role of MnPN afferents in the control of PF/LH neuronal activity, we studied the responses of PF/LH cells to electrical stimulation or local chemical manipulation of the MnPN in freely moving rats. Single-pulse electrical stimulation evoked responses in 79% of recorded PF/LH neurons. No cells were activated antidromically. Direct and indirect transsynaptic effects depended on sleep-wake discharge pattern of PF/LH cells. The majority of arousal-related neurons, that is, cells discharging at maximal rates during active waking (AW) or during AW and rapid eye movement (REM) sleep, exhibited exclusively or initially inhibitory responses to stimulation. Sleep-related neurons, the cells with elevated discharge during non-REM and REM sleep or selectively active in REM sleep, exhibited exclusively or initially excitatory responses. Activation of the MnPN via microdialytic application of L-glutamate or bicuculline resulted in reduced discharge of arousal-related and in excitation of sleep-related PF/LH neurons. Deactivation of the MnPN with muscimol caused opposite effects. The results indicate that the MnPN contains subset(s) of neurons, which exert inhibitory control over arousal-related and excitatory control over sleep-related PF/LH neurons. We hypothesize that MnPN sleep-active neuronal group has both inhibitory and excitatory outputs that participate in the inhibitory control of arousal-promoting PF/LH mechanisms.

  1. M- and T-tropic HIVs Promote Apoptosis in Rat Neurons

    PubMed Central

    Bachis, Alessia; Biggio, Francesca; Major, Eugene O.; Mocchetti, Italo

    2009-01-01

    Neuronal loss, reactive astrocytes, and other abnormalities are seen in the brain of individuals with acquired immune deficiency syndrome-associated Dementia Complex (ADC). Human immunodeficiency virus-1 (HIV-1) is believed to be the main agent causing ADC. However, little is known about the molecular and cellular mechanisms of HIV-1 neurotoxicity considering that HIV-1 does not infect post-mitotic neurons and that viral load does not necessarily correlate with ADC. Various viral proteins, such as the envelope protein gp120 and the transcription activator Tat, have been shown to induce neuronal apoptosis through direct and indirect mechanisms both in vitro and in vivo. Progeny HIV-1 virions can also cause neuronal death. However, it has not been fully established yet whether HIV-1 promotes neuronal apoptosis by a direct mechanism. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-1, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCR5 coreceptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in cell lysates. Instead, neurons were gp 120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCR5 receptor inhibitor D-Ala-peptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the N-methyl-D-aspartate receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp 120 binding to neuronal chemokine receptors. PMID:19034668

  2. Organizational and activational effects of sex steroids on kisspeptin neuron development

    PubMed Central

    Poling, Matthew C.; Kauffman, Alexander S.

    2012-01-01

    Kisspeptin, encoded by the Kiss1 gene, is a neuropeptide required for puberty and adult reproductive function. Understanding the regulation and development of the kisspeptin system provides valuable knowledge about the physiology of puberty and adult fertility, and may provide insights into human pubertal or reproductive disorders. Recent studies, particularly in rodent models, have assessed how kisspeptin neurons develop and how hormonal and non-hormonal factors regulate this developmental process. Exposure to sex steroids (testosterone and estradiol) during critical periods of development can induce organizational (permanent) effects on kisspeptin neuron development, with respect to both sexually dimorphic and non-sexually dimorphic aspects of kisspeptin biology. In addition, sex steroids can also impart activational (temporary) effects on kisspeptin neurons and Kiss1 gene expression at various times during neonatal and peripubertal development, as they do in adulthood. Here, we discuss the current knowledge—and in some cases, lack thereof—of the influence of hormones and other factors on kisspeptin neuronal development. PMID:22728025

  3. Dynamical state of the network determines the efficacy of single neuron properties in shaping the network activity

    PubMed Central

    Sahasranamam, Ajith; Vlachos, Ioannis; Aertsen, Ad; Kumar, Arvind

    2016-01-01

    Spike patterns are among the most common electrophysiological descriptors of neuron types. Surprisingly, it is not clear how the diversity in firing patterns of the neurons in a network affects its activity dynamics. Here, we introduce the state-dependent stochastic bursting neuron model allowing for a change in its firing patterns independent of changes in its input-output firing rate relationship. Using this model, we show that the effect of single neuron spiking on the network dynamics is contingent on the network activity state. While spike bursting can both generate and disrupt oscillations, these patterns are ineffective in large regions of the network state space in changing the network activity qualitatively. Finally, we show that when single-neuron properties are made dependent on the population activity, a hysteresis like dynamics emerges. This novel phenomenon has important implications for determining the network response to time-varying inputs and for the network sensitivity at different operating points. PMID:27212008

  4. Dynamical state of the network determines the efficacy of single neuron properties in shaping the network activity.

    PubMed

    Sahasranamam, Ajith; Vlachos, Ioannis; Aertsen, Ad; Kumar, Arvind

    2016-05-23

    Spike patterns are among the most common electrophysiological descriptors of neuron types. Surprisingly, it is not clear how the diversity in firing patterns of the neurons in a network affects its activity dynamics. Here, we introduce the state-dependent stochastic bursting neuron model allowing for a change in its firing patterns independent of changes in its input-output firing rate relationship. Using this model, we show that the effect of single neuron spiking on the network dynamics is contingent on the network activity state. While spike bursting can both generate and disrupt oscillations, these patterns are ineffective in large regions of the network state space in changing the network activity qualitatively. Finally, we show that when single-neuron properties are made dependent on the population activity, a hysteresis like dynamics emerges. This novel phenomenon has important implications for determining the network response to time-varying inputs and for the network sensitivity at different operating points.

  5. Tissue Plasminogen Activator Induction in Purkinje Neurons After Cerebellar Motor Learning

    NASA Astrophysics Data System (ADS)

    Seeds, Nicholas W.; Williams, Brian L.; Bickford, Paula C.

    1995-12-01

    The cerebellar cortex is implicated in the learning of complex motor skills. This learning may require synaptic remodeling of Purkinje cell inputs. An extracellular serine protease, tissue plasminogen activator (tPA), is involved in remodeling various nonneural tissues and is associated with developing and regenerating neurons. In situ hybridization showed that expression of tPA messenger RNA was increased in the Purkinje neurons of rats within an hour of their being trained for a complex motor task. Antibody to tPA also showed the induction of tPA protein associated with cerebellar Purkinje cells. Thus, the induction of tPA during motor learning may play a role in activity-dependent synaptic plasticity.

  6. Characteristics of hyperpolarization-activated cyclic nucleotide-gated channels in dorsal root ganglion neurons at different ages and sizes.

    PubMed

    Hou, Baohua; Chen, Hengling; Qu, Xiangwei; Lin, Xianguang; Luo, Fang; Li, Chenhong

    2015-11-11

    In rat's sensory neurons, hyperpolarization-activated inward currents (Ih) play an essential role in mediating action potentials and contributing to neuronal excitability. Classified by the size of neurons and ages, we studied the Ih and transcription levels of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels using electrophysiology and the single-cell RT-PCR. In voltage-clamp studies, Ih and half-maximal activation voltage (V1/2) changed with age and size. An analysis of all HCN subtypes in dorsal root ganglion (DRG) neurons by single-cell RT-PCR was carried out. HCN1 and HCN3 in medium-small elderly neurons had a weak expression. HCN2 in newborns and HCN4 in elderly rats also had a weak expression. The aim of this study is to examine the age-related Ih and HCN channels subunits in different ages and sizes of DRG neurons. The results would be significant in understanding the physiological and pathophysiological function of different sizes of DRG neurons in different age periods.

  7. Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury.

    PubMed

    Huang, Tingqin; Zhao, Junjie; Guo, Dan; Pang, Honggang; Zhao, Yonglin; Song, Jinning

    2018-05-23

    Diffuse axonal injury (DAI) accounts for more than 50% of all traumatic brain injury. In response to the mechanical damage associated with DAI, the abnormal proteins produced in the neurons and axons, namely, β-APP and p-tau, induce endoplasmic reticulum (ER) stress. Curcumin, a major component extracted from the rhizome of Curcuma longa, has shown potent anti-inflammatory, antioxidant, anti-infection, and antitumor activity in previous studies. Moreover, curcumin is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2) and promotes its nuclear translocation. In this study, we evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and β-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2.

  8. Acquired granulocyte abnormality during drug allergic reactions: possible role of complement activation.

    PubMed

    Bowers, T K; Craddock, P R; Jacob, H S

    1977-01-01

    A profound defect in granulocyte chemotaxis was documented in an otherwise healthy 21-yr-old man who failed to localize granulocytes to an area of cellulitis during an allergic reaction to cephalothin. During the period of drug allergy, characterized by urticaria, eosinophilia, and profound hypocomplementemia, in vitro migration of the patient's granulocytes in the Boyden chamber was markedly impaired. Although devoid of hemolytic complement activity, the patient's serum possessed supranormal chemotactic activity, even following heat inactivation, suggesting the presence of chemotactically active complement split products. Chemotactic function improved concomitantly with steroid therapy and normalization of serum complement levels, and was entirely normal following clinical recovery and cessation of steroid therapy. The chemotactic abnormality noted in the patient's cells was reproduced in normal granulocytes by preincubation either with patient serum or with cobra venom-activated fresh (but not heated) normal serum, suggesting that in vivo exposure of granulocytes to activated complement was responsible for the patient's abnormal chemotactic response. This mechanism may contribute to the increased infection propensity noted in other conditions characterized by in vivo complement activation, such as rheumatoid arthritis and systemic lupus erythematosis.

  9. Pseudorabies Virus Infection Alters Neuronal Activity and Connectivity In Vitro

    PubMed Central

    McCarthy, Kelly M.; Tank, David W.; Enquist, Lynn W.

    2009-01-01

    Alpha-herpesviruses, including human herpes simplex virus 1 & 2, varicella zoster virus and the swine pseudorabies virus (PRV), infect the peripheral nervous system of their hosts. Symptoms of infection often include itching, numbness, or pain indicative of altered neurological function. To determine if there is an in vitro electrophysiological correlate to these characteristic in vivo symptoms, we infected cultured rat sympathetic neurons with well-characterized strains of PRV known to produce virulent or attenuated symptoms in animals. Whole-cell patch clamp recordings were made at various times after infection. By 8 hours of infection with virulent PRV, action potential (AP) firing rates increased substantially and were accompanied by hyperpolarized resting membrane potentials and spikelet-like events. Coincident with the increase in AP firing rate, adjacent neurons exhibited coupled firing events, first with AP-spikelets and later with near identical resting membrane potentials and AP firing. Small fusion pores between adjacent cell bodies formed early after infection as demonstrated by transfer of the low molecular weight dye, Lucifer Yellow. Later, larger pores formed as demonstrated by transfer of high molecular weight Texas red-dextran conjugates between infected cells. Further evidence for viral-induced fusion pores was obtained by infecting neurons with a viral mutant defective for glycoprotein B, a component of the viral membrane fusion complex. These infected neurons were essentially identical to mock infected neurons: no increased AP firing, no spikelet-like events, and no electrical or dye transfer. Infection with PRV Bartha, an attenuated circuit-tracing strain delayed, but did not eliminate the increased neuronal activity and coupling events. We suggest that formation of fusion pores between infected neurons results in electrical coupling and elevated firing rates, and that these processes may contribute to the altered neural function seen in PRV

  10. Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult

    PubMed Central

    Larhammar, Martin; Huntwork-Rodriguez, Sarah; Jiang, Zhiyu; Solanoy, Hilda; Sengupta Ghosh, Arundhati; Wang, Bei; Kaminker, Joshua S; Huang, Kevin; Eastham-Anderson, Jeffrey; Siu, Michael; Modrusan, Zora; Farley, Madeline M; Tessier-Lavigne, Marc; Lewcock, Joseph W; Watkins, Trent A

    2017-01-01

    The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4). Disruption of PERK signaling delays neurodegeneration without reducing JNK signaling. Furthermore, DLK is both sufficient for PERK activation and necessary for engaging the ISR subsequent to JNK-mediated retrograde injury signaling. These findings identify DLK as a central regulator of not only JNK but also PERK stress signaling in neurons, with both pathways contributing to neurodegeneration. DOI: http://dx.doi.org/10.7554/eLife.20725.001 PMID:28440222

  11. Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability

    PubMed Central

    Tompkins, John D.; Clason, Todd A.; Hardwick, Jean C.; Girard, Beatrice M.; Merriam, Laura A.; May, Victor

    2016-01-01

    Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participate in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, and as these neurons are readily accessible, this neuronal system is particularly amenable to study of PACAP modulation of ionic conductances. The present study investigated how PACAP activation of MEK/ERK signaling contributed to the peptide-induced increase in cardiac neuron excitability. Treatment with the MEK inhibitor PD 98059 blocked PACAP-stimulated phosphorylated ERK and, in parallel, suppressed the increase in cardiac neuron excitability. However, PD 98059 did not blunt the ability of PACAP to enhance two inward ionic currents, one flowing through hyperpolarization-activated nonselective cationic channels (Ih) and another flowing through low-voltage-activated calcium channels (IT), which support the peptide-induced increase in excitability. Thus a PACAP- and MEK/ERK-sensitive, voltage-dependent conductance(s), in addition to Ih and IT, modulates neuronal excitability. Despite prior work implicating PACAP downregulation of the KV4.2 potassium channel in modulation of excitability in other cells, treatment with the KV4.2 current blocker 4-aminopyridine did not replicate the PACAP-induced increase in excitability in cardiac neurons. However, cardiac neurons express the ERK target, the NaV1.7 sodium channel, and treatment with the selective NaV1.7 channel inhibitor PF-04856264 decreased the PACAP modulation of excitability. From these results, PACAP/PAC1 activation of MEK/ERK signaling may phosphorylate the NaV1.7 channel, enhancing sodium currents near the threshold, an action contributing to repetitive firing of the cardiac neurons exposed to PACAP. PMID:27488668

  12. Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation

    PubMed Central

    Chua, Yansong; Morrison, Abigail

    2016-01-01

    The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be

  13. Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation.

    PubMed

    Chua, Yansong; Morrison, Abigail

    2016-01-01

    The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be

  14. Relationships between selective neuronal loss and microglial activation after ischaemic stroke in man.

    PubMed

    Morris, Rhiannon S; Simon Jones, P; Alawneh, Josef A; Hong, Young T; Fryer, Tim D; Aigbirhio, Franklin I; Warburton, Elizabeth A; Baron, Jean-Claude

    2018-05-09

    Modern ischaemic stroke management involves intravenous thrombolysis followed by mechanical thrombectomy, which allows markedly higher rates of recanalization and penumbral salvage than thrombolysis alone. However, <50% of treated patients eventually enjoy independent life. It is therefore important to identify complementary therapeutic targets. In rodent models, the salvaged penumbra is consistently affected by selective neuronal loss, which may hinder recovery by interfering with plastic processes, as well as by microglial activation, which may exacerbate neuronal death. However, whether the salvaged penumbra in man is similarly affected is still unclear. Here we determined whether these two processes affect the non-infarcted penumbra in man and, if so, whether they are inter-related. We prospectively recruited patients with (i) acute middle-cerebral artery stroke; (ii) penumbra present on CT perfusion obtained <4.5 h of stroke onset; and (iii) early neurological recovery as a marker of penumbral salvage. PET with 11C-flumazenil and 11C-PK11195, as well as MRI to map the final infarct, were obtained at predefined follow-up times. The presence of selective neuronal loss and microglial activation was determined voxel-wise within the MRI normal-appearing ipsilateral non-infarcted zone and surviving penumbra masks, and their inter-relationship was assessed both across and within patients. Dilated infarct contours were consistently excluded to control for partial volume effects. Across the 16 recruited patients, there was reduced 11C-flumazenil and increased 11C-PK11195 binding in the whole ipsilateral non-infarcted zone (P = 0.04 and 0.02, respectively). Within the non-infarcted penumbra, 11C-flumazenil was also reduced (P = 0.001), but without clear increase in 11C-PK11195 (P = 0.18). There was no significant correlation between 11C-flumazenil and 11C-PK11195 in either compartment. This mechanistic study provides direct evidence for the presence of both neuronal

  15. Neurochemical abnormalities in premanifest and early spinocerebellar ataxias.

    PubMed

    Joers, James M; Deelchand, Dinesh K; Lyu, Tianmeng; Emir, Uzay E; Hutter, Diane; Gomez, Christopher M; Bushara, Khalaf O; Eberly, Lynn E; Öz, Gülin

    2018-04-01

    To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829. © 2018 American Neurological Association.

  16. SNARE-dependent upregulation of KCC2 activity following metabotropic zinc receptor (mZnR/GPR39) activation in rat cortical neurons in vitro

    PubMed Central

    Saadi, Robert A.; He, Kai; Hartnett, Karen A.; Kandler, Karl; Hershfinkel, Michal; Aizenman, Elias

    2012-01-01

    The major outward chloride transporter in neurons is the potassium chloride co-transporter 2 (KCC2), critical for maintaining an inhibitory reversal potential for GABAA receptor channels. In a recent study, we showed that Zn2+ regulates GABAA reversal potentials in the hippocampus by enhancing the activity of KCC2 via an increase in its surface expression. Zn2+ initiates this process by activating the Gq-coupled metabotropic Zn2+ receptor mZnR/GPR39. Here, we first demonstrated that mZnR/GPR39 is functional in cortical neurons in culture and then tested the hypothesis that the increase in KCC2 activity is mediated through a SNARE-dependent process. We established the presence of functional mZnR in rat cultured cortical neurons by loading cells with a Ca2+ indicator and exposing cells to Zn2+, which triggered consistent Ca2+ responses that were blocked by the Gq antagonist YM-254890, but not by the metabotropic glutamate receptor antagonist MCPG. Importantly, Zn2+ treatment under these conditions did not increase the intracellular concentrations of Zn2+ itself. We then measured KCC2 activity by monitoring both the rate and relative amount of furosemide-sensitive NH4+ influx via the co-transporter using an intracellular pH sensitive fluorescent indicator. We observed that Zn2+ pretreatment induced a Ca2+-dependent increase in KCC2 activity. The effects of Zn2+ on KCC2 activity were also observed in wild-type mouse cortical neurons in culture, but not in neurons obtained from mZnR/GPR39−/− mice, suggesting that Zn2+ acts via mZnR/GPR39 activation to upregulate KCC2 activity. We next transfected rat cortical neurons with a plasmid encoding botulinum toxin C1 (Botox C1), which cleaves the SNARE proteins syntaxin 1 and SNAP-25. Basal KCC2 activity was similar in both transfected and non-transfected neurons. Non-transfected cells, or cells transfected with marker vector alone, showed a Zn2+-dependent increase in KCC2 activity. In contrast, KCC2 activity in neurons

  17. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells

    NASA Astrophysics Data System (ADS)

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-01

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  18. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells.

    PubMed

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-09-14

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5.

  19. Redox/methylation mediated abnormal DNA methylation as regulators of ambient fine particulate matter-induced neurodevelopment related impairment in human neuronal cells

    PubMed Central

    Wei, Hongying; Liang, Fan; Meng, Ge; Nie, Zhiqing; Zhou, Ren; Cheng, Wei; Wu, Xiaomeng; Feng, Yan; Wang, Yan

    2016-01-01

    Fine particulate matter (PM2.5) has been implicated as a risk factor for neurodevelopmental disorders including autism in children. However, the underlying biological mechanism remains unclear. DNA methylation is suggested to be a fundamental mechanism for the neuronal responses to environmental cues. We prepared whole particle of PM2.5 (PM2.5), water-soluble extracts (Pw), organic extracts (Po) and carbon core component (Pc) and characterized their chemical constitutes. We found that PM2.5 induced significant redox imbalance, decreased the levels of intercellular methyl donor S-adenosylmethionine and caused global DNA hypomethylation. Furthermore, PM2.5 exposure triggered gene-specific promoter DNA hypo- or hypermethylation and abnormal mRNA expression of autism candidate genes. PM2.5-induced DNA hypermethylation in promoter regions of synapse related genes were associated with the decreases in their mRNA and protein expression. The inhibiting effects of antioxidative reagents, a methylation-supporting agent and a DNA methyltransferase inhibitor demonstrated the involvement of redox/methylation mechanism in PM2.5-induced abnormal DNA methylation patterns and synaptic protein expression. The biological effects above generally followed a sequence of PM2.5 ≥ Pwo > Po > Pw > Pc. Our results implicated a novel epigenetic mechanism for the neurodevelopmental toxicity of particulate air pollution, and that eliminating the chemical components could mitigate the neurotoxicity of PM2.5. PMID:27624276

  20. [P21-activated kinases and their role in the nervous system].

    PubMed

    Qin, Yuan; Ding, Yue-Min; Xia, Qiang

    2012-12-25

    P21-activated kinases (PAK) participate in a variety of important cellular activities, such as cytoskeleton remodeling, cell migration, cell cycle regulation, and apoptosis or survival. PAK also has an important impact on brain development, neuronal differentiation, and regulation of synaptic plasticity in the nervous system. PAK abnormalities result in diseases including cancer, Parkinson's disease (PD), Alzheimer's disease (AD) and neural retardation. Therefore, it is of vital physiological significance to investigate the neuronal function of PAK. In this paper we review the advancement of research on the neuronal biological function and the underlying mechanisms of PAK.