The GABAergic neurons in the parafacial zone（PZ） play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediatin...The GABAergic neurons in the parafacial zone（PZ） play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediating this function remain poorly characterized. Here, we performed whole-brain mapping of both the inputs and outputs of the GABAergic neurons in the PZ of the mouse brain. We used the modified rabies virus Env A-DG-Ds Red combined with a Cre/lox P gene-expression strategy to map the direct monosynaptic inputs to the GABAergic neurons in the PZ, and found that they receive inputs mainly from the hypothalamic area, zona incerta, and parasubthalamic nucleus in the hypothalamus; the substantia nigra, pars reticulata and deep mesencephalic nucleus in the midbrain;and the intermediate reticular nucleus and medial vestibular nucleus（parvocellular part） in the pons and medulla.We also mapped the axonal projections of the PZ GABAergic neurons with adeno-associated virus, and defined the reciprocal connections of the PZ GABAergic neurons with their input and output nuclei. The newlyfound inputs and outputs of the PZ were also listed compared with the literature. This cell-type-specific neuronal whole-brain mapping of the PZ GABAergic neurons may reveal the circuits underlying various functions such as sleep-wake regulation.展开更多
Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrate...Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.展开更多
Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's dis...Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic s展开更多
Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role ...Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.展开更多
Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induc...Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induced polarization affects the interneuron response as the interneuron receives NMDA synaptic inputs.Considering the key role of NMDA receptor-mediated supralinear dendritic integration in neuronal computations,we suppose that the applied EFs could functionally modulate interneurons’response via regulating dendritic integration.At first,we build a simplified multi-dendritic circuit model with inhomogeneous extracellular potentials,which characterizes the relationship among EF-induced spatial polarizations,dendritic integration,and somatic output.By performing model-based singular perturbation analysis,it is found that the equilibrium point of fast subsystem can be used to asymptotically depict the subthreshold input–output(sI/O)relationship of dendritic integration.It predicted that EF-induced strong depolarizations on the distal dendrites reduce the dendritic saturation output by reducing driving force of synaptic input,and it shifts the steep change of sI/O curve left by reducing stimulation threshold of triggering NMDA spike.Also,the EF modulation prefers the global dendritic integration with asymmetric scatter distribution of NMDA synapses.Furthermore,we identify the respective contribution of EF-regulated dendritic integration and EF-induced somatic polarization to an action potential generation and find that they have an antagonistic effect on AP generation due to the varied NMDA spike threshold under EF stimulation.展开更多
Neuronal progenitor cells cultured on gold-coated glass surfaces modified by different chemical functional groups, including hydroxyl （-OH）, carboxyl （COOH）, amino （-NH2）, bromo （-Br）, mercapto （-SH）, - Phen...Neuronal progenitor cells cultured on gold-coated glass surfaces modified by different chemical functional groups, including hydroxyl （-OH）, carboxyl （COOH）, amino （-NH2）, bromo （-Br）, mercapto （-SH）, - Phenyl and methyl （-CH3）, were studied here to investigate the influence of surface chemistry on the cells＇ adhesion, morphology, proliferation and functional gene expression. Focal adhesion staining indicated in the initial culture stage cells exhibited morphological changes in response to different chemical functional groups. Cells cultured on -NH2 grafted surface displayed focal adhesion plaque and flattened morphology and had the largest contact area. However, their counter parts on -CH3 grafted surface displayed no focal adhesion and rounded morphology and had the smallest contact area. After 6 days culture, the proliferation trend was as follows： NH2〉 SH〉-COOH〉 Phenyl〉 Br〉 OH〉-CH3. To deter- mine the neural functional properties of the cells affected by surface chemistry, the expression of glutamate decarboxylase （GAD67）, nerve growth factor （NGF） and brain- derived neurotrophic factor （BDNF） were characterized. An increase of GAD67 expression was observed on - NH2, -COOH and -SH grafted surfaces, while no increase in NGF and BDNF expression was observed on any chemical surfaces. These results highlight the importance of surface chemistry in the fate determination of neuronal progenitor cells, and suggest that surface chemistry must be considered in the design of biomaterials for neural tissue engineering.展开更多
Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitiv...Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-βand tau in patients with Alzheimer’s disease.At present,sleep disorders are considered as a risk factor for,and may be a predictor of,Alzheimer’s disease development.Given that sleep disorders are encountered in other types of dementia and psychiatric conditions,sleep-related biomarkers to predict Alzheimer’s disease need to have high specificity and sensitivity.Here,we summarize the major Alzheimer’s disease-specific sleep changes,including abnormal non-rapid eye movement sleep,sleep fragmentation,and sleep-disordered breathing,and describe their ability to predict the onset of Alzheimer’s disease at its earliest stages.Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer’s disease.This paper therefore explores some potential mechanisms that may contribute to sleep disorders,including dysregulation of the orexinergic,glutamatergic,andγ-aminobutyric acid systems and the circadian rhythm,together with amyloid-βaccumulation.This review could provide a theoretical basis for the development of drugs to treat Alzheimer’s disease based on sleep disorders in future work.展开更多
Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective ser...Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.展开更多
The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has n...The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.展开更多
The amygdala,which is involved in various behaviors and emotions,is reported to connect with the whole brain.However,the long-range inputs of distinct cell types have not yet been defined.Here,we used a retrograde tra...The amygdala,which is involved in various behaviors and emotions,is reported to connect with the whole brain.However,the long-range inputs of distinct cell types have not yet been defined.Here,we used a retrograde trans-synaptic rabies virus to generate a whole-brain map of inputs to the main cell types in the mouse amygdala.We identified 37 individual regions that projected to neurons expressing vesicular glutamate transporter 2,78 regions to parvalbumin-expressing neurons,104 regions to neurons expressing protein kinase C-δ,and 89 regions to somatostatin-expressing neurons.The amygdala received massive projections from the isocortex and striatum.Several nuclei,such as the caudate-putamen and the CA1 field of the hippocampus,exhibited input preferences to different cell types in the amygdala.Notably,we identified several novel input areas,including the substantia innominata and zona incerta.These findings provide anatomical evidence to help understand the precise connections and diverse functions of the amygdala.展开更多
Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availab...Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.展开更多
The γ-aminobutyric acid neurons（GABAergic neurons） in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this class...The γ-aminobutyric acid neurons（GABAergic neurons） in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this classification is associated with physiological function, the exact role for neurons with various firing patterns in acoustic processing remains poorly understood. In the present study, we analyzed characteristics of inferior colliculus neurons in vitro, and recorded responses to stimulation of the dorsal nucleus of the lateral lemniscus using the wholecell patch clamp technique. Seven inferior colliculus neurons were tested and were classified into two firing patterns： sustained-regular（n = 4） and sustained-adapting firing patterns（n = 3）. The majority of inferior colliculus neurons exhibited slight changes in response to stimulation and bicuculline. The responses of one neuron with a sustained-adapting firing pattern were suppressed after stimulation, but recovered to normal levels following application of the γ-aminobutyric acid receptor antagonist. One neuron with a sustained-regular pattern showed suppressed stimulation responses, which were not affected by bicuculline. Results suggest that GABAergic neurons in the inferior colliculus exhibit sustained-regular or sustained-adapting firing patterns. Additionally, GABAergic projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus are associated with sound localization. The different neuronal responses of various firing patterns suggest a role in sound localization. A better understanding of these mechanisms and functions will provide better clinical treatment paradigms for hearing deficiencies.展开更多
The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across ...The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across vertebrate evolution.Moreover,cell-type-specific SC neurons integrate afferent signals within local networks to generate defined output related to innate and cognitive behaviors.This review focuses on the recent progress in understanding of phenotypic diversity amongst SC neurons and their intrinsic circuits and long-projection targets.We further describe relevant neural circuits and specific cell types in relation to behavioral outputs and cognitive functions.The systematic delineation of SC organization,cell types,and neural connections is further put into context across species as these depend upon laminar architecture.Moreover,we focus on SC neural circuitry involving saccadic eye movement,and cognitive and innate behaviors.Overall,the review provides insight into SC functioning and represents a basis for further understanding of the pathology associated with SC dysfunction.展开更多
Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the de...Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory glutamatergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+channels on summed synaptic excitation when they precede glutamatergic inputs by>15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.展开更多
Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neuroge...Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.展开更多
Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:...Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.展开更多
OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are th...OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d) were posted to 43℃ hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.展开更多
Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right media...Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 k Da, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson＇s disease.展开更多
BACKGROUND： Neurons expressing gamma-aminobutyric acid （GABA） play an important role in the regulation of wakefulness to sleep, as well as the maintenance of sleep. However, the role of GABAergic neurons in the tub...BACKGROUND： Neurons expressing gamma-aminobutyric acid （GABA） play an important role in the regulation of wakefulness to sleep, as well as the maintenance of sleep. However, the role of GABAergic neurons in the tuberomammillary nucleus （TMn）, with regard to the sleep-wakefulness cycle, is poorly understood. OBJECTIVE： To investigate the effects of GABAergic neurons in the TMn on the sleep-wakefulness cycle. DESIGN, TIME AND SETTING： Randomized controlled study, performed at the Laboratory of Neurobiology, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University from July 2007 to February 2008. MATERIALS： Fifteen healthy, adult, male, Sprague Dawley rats were randomly divided into three groups（n = 5）： control, ventrolateral preoptic area （VLPO） lesion, and VLPO lesion plus GABAA receptor antagonist-treated. Ibotenic acid and bicuculline were provided by Sigma （St. Louis, USA）. METHODS： Four electroencephalogram screw electrodes were implanted into the skull at a frontal region （two） and parietal bones （two） on each side. Three flexible electromyogram wire electrodes were placed into the nuchal muscles. On day 8, a fine glass micropipette （10–20 mm tip diameter） containing ibotenic acid solution （10 nmol/L） was injected into the VLPO in both hemispheres following bone wax removal under anesthesia. One week after the second surgery, sleep-wakefulness states were recorded in rats from the VLPO lesion group. On day 10 after VLPO lesion, bicuculline （10 nmol/L）, a GABAA-receptor antagonist, was microinjected into the TMn and sleep-wakefulness states were recorded for 24 hours. MAIN OUTCOME MEASURES： Duration of the sleep-wakefulness cycle in each group using a Data acquisition unit （Micro1 401 mk2） and Data collection software （Spike Ⅱ）. RESULTS： VLPO lesion induced an increased duration of wakefulness （W, 13.17%） and light slow-wave sleep （SWS1, 28.9%）, respectively. Deep slow-wave sleep （SWS2, 43展开更多
基金supported by the National Natural Science Foundation of China (31571090 and 31771167)the National Key Research and Development Program (2016YFC1306700)+1 种基金the National High Technology Research and Development Program (863 Program) of China (2015AA020512)the Fundamental Research Funds for the Central Universities of China (2017FZA7003)
文摘The GABAergic neurons in the parafacial zone（PZ） play an important role in sleep-wake regulation and have been identified as part of a sleep-promoting center in the brainstem, but the long-range connections mediating this function remain poorly characterized. Here, we performed whole-brain mapping of both the inputs and outputs of the GABAergic neurons in the PZ of the mouse brain. We used the modified rabies virus Env A-DG-Ds Red combined with a Cre/lox P gene-expression strategy to map the direct monosynaptic inputs to the GABAergic neurons in the PZ, and found that they receive inputs mainly from the hypothalamic area, zona incerta, and parasubthalamic nucleus in the hypothalamus; the substantia nigra, pars reticulata and deep mesencephalic nucleus in the midbrain;and the intermediate reticular nucleus and medial vestibular nucleus（parvocellular part） in the pons and medulla.We also mapped the axonal projections of the PZ GABAergic neurons with adeno-associated virus, and defined the reciprocal connections of the PZ GABAergic neurons with their input and output nuclei. The newlyfound inputs and outputs of the PZ were also listed compared with the literature. This cell-type-specific neuronal whole-brain mapping of the PZ GABAergic neurons may reveal the circuits underlying various functions such as sleep-wake regulation.
基金supported by the Chongqing Science and Technology CommitteeNatural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。
文摘Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.
基金supported by the National Institute on Aging (NIA)National Institutes of Health (NIH)+3 种基金Nos.K99AG065645,R00AG065645R00AG065645-04S1 (to SK)NIH research grants,NINDS,No.R01 NS115834NINDS/NIA,No.R01 NS115834-02S1 (to LG)。
文摘Gamma-aminobutyric acid(GABA)ergic neurons,the most abundant inhibitory neurons in the human brain,have been found to be reduced in many neurological disorders,including Alzheimer's disease and Alzheimer's disease-related dementia.Our previous study identified the upregulation of microRNA-502-3p(miR-502-3p)and downregulation of GABA type A receptor subunitα-1 in Alzheimer's disease synapses.This study investigated a new molecular relationship between miR-502-3p and GABAergic synapse function.In vitro studies were perfo rmed using the mouse hippocampal neuronal cell line HT22 and miR-502-3p agomiRs and antagomiRs.In silico analysis identified multiple binding sites of miR-502-3p at GABA type A receptor subunitα-1 mRNA.Luciferase assay confirmed that miR-502-3p targets the GABA type A receptor subunitα-1 gene and suppresses the luciferase activity.Furthermore,quantitative reve rse transcription-polymerase chain reaction,miRNA in situ hybridization,immunoblotting,and immunostaining analysis confirmed that overexpression of miR-502-3p reduced the GABA type A receptor subunitα-1 level,while suppression of miR-502-3p increased the level of GABA type A receptor subunitα-1 protein.Notably,as a result of the overexpression of miR-502-3p,cell viability was found to be reduced,and the population of necrotic cells was found to be increased.The whole cell patch-clamp analysis of human-GABA receptor A-α1/β3/γ2L human embryonic kidney(HEK)recombinant cell line also showed that overexpression of miR-502-3p reduced the GABA current and overall GABA function,suggesting a negative correlation between miR-502-3p levels and GABAergic synapse function.Additionally,the levels of proteins associated with Alzheimer s disease were high with miR-502-3p overexpression and reduced with miR-502-3p suppression.The present study provides insight into the molecular mechanism of regulation of GABAergic synapses by miR-502-3p.We propose that micro-RNA,in particular miR-502-3p,could be a potential therapeutic to rget to modulate GABAergic s
基金supported by the National Natural Science Foundation of China,No.82171521(to CL)the Special Funds ofTaishan Scholars Project of Shandong Province,No.tsqn202211368(to CL)+2 种基金the Natural Science Foundation of Shandong Province,Nos.ZR2022YQ65(to CL),ZR2021MH073(to CL),ZR2019PH109(to WW)the Projects of Medical and Health Technology Development Program in Shandong Province,China,Nos.202003090720(to DZ),202003070728(to JL),2019 WS329(to DW)the Scientific Research Foundation of Binzhou Medical University,No.BY2018KJ21(to DW)。
文摘Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.
基金Project supported by the National Natural Science Foundation of China(Grant No.62171312)the Tianjin Municipal Education Commission Scientific Research Project,China(Grant No.2020KJ114).
文摘Evidences show that electric fields(EFs)induced by the magnetic stimulation could modulates brain activities by regulating the excitability of GABAergic interneuron.However,it is still unclear how and why the EF-induced polarization affects the interneuron response as the interneuron receives NMDA synaptic inputs.Considering the key role of NMDA receptor-mediated supralinear dendritic integration in neuronal computations,we suppose that the applied EFs could functionally modulate interneurons’response via regulating dendritic integration.At first,we build a simplified multi-dendritic circuit model with inhomogeneous extracellular potentials,which characterizes the relationship among EF-induced spatial polarizations,dendritic integration,and somatic output.By performing model-based singular perturbation analysis,it is found that the equilibrium point of fast subsystem can be used to asymptotically depict the subthreshold input–output(sI/O)relationship of dendritic integration.It predicted that EF-induced strong depolarizations on the distal dendrites reduce the dendritic saturation output by reducing driving force of synaptic input,and it shifts the steep change of sI/O curve left by reducing stimulation threshold of triggering NMDA spike.Also,the EF modulation prefers the global dendritic integration with asymmetric scatter distribution of NMDA synapses.Furthermore,we identify the respective contribution of EF-regulated dendritic integration and EF-induced somatic polarization to an action potential generation and find that they have an antagonistic effect on AP generation due to the varied NMDA spike threshold under EF stimulation.
基金Acknowledgements We thank Xing-Yu Jiang at National Center for Nanoscience and Technology for providing some of the alkanethiols. This work was supported by National Basic Research Program of China （Grant No. 2011 CB606205）, National Natural Science Foundation of China （Grant Nos. 50830102 and 50973052） and Analysis Foundation of Tsinghua University.
文摘Neuronal progenitor cells cultured on gold-coated glass surfaces modified by different chemical functional groups, including hydroxyl （-OH）, carboxyl （COOH）, amino （-NH2）, bromo （-Br）, mercapto （-SH）, - Phenyl and methyl （-CH3）, were studied here to investigate the influence of surface chemistry on the cells＇ adhesion, morphology, proliferation and functional gene expression. Focal adhesion staining indicated in the initial culture stage cells exhibited morphological changes in response to different chemical functional groups. Cells cultured on -NH2 grafted surface displayed focal adhesion plaque and flattened morphology and had the largest contact area. However, their counter parts on -CH3 grafted surface displayed no focal adhesion and rounded morphology and had the smallest contact area. After 6 days culture, the proliferation trend was as follows： NH2〉 SH〉-COOH〉 Phenyl〉 Br〉 OH〉-CH3. To deter- mine the neural functional properties of the cells affected by surface chemistry, the expression of glutamate decarboxylase （GAD67）, nerve growth factor （NGF） and brain- derived neurotrophic factor （BDNF） were characterized. An increase of GAD67 expression was observed on - NH2, -COOH and -SH grafted surfaces, while no increase in NGF and BDNF expression was observed on any chemical surfaces. These results highlight the importance of surface chemistry in the fate determination of neuronal progenitor cells, and suggest that surface chemistry must be considered in the design of biomaterials for neural tissue engineering.
基金This work was funded by the National Natural Science Foundation of China, Nos. 81660151 (to FFH), 81660751 (to SLY).
文摘Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-βand tau in patients with Alzheimer’s disease.At present,sleep disorders are considered as a risk factor for,and may be a predictor of,Alzheimer’s disease development.Given that sleep disorders are encountered in other types of dementia and psychiatric conditions,sleep-related biomarkers to predict Alzheimer’s disease need to have high specificity and sensitivity.Here,we summarize the major Alzheimer’s disease-specific sleep changes,including abnormal non-rapid eye movement sleep,sleep fragmentation,and sleep-disordered breathing,and describe their ability to predict the onset of Alzheimer’s disease at its earliest stages.Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer’s disease.This paper therefore explores some potential mechanisms that may contribute to sleep disorders,including dysregulation of the orexinergic,glutamatergic,andγ-aminobutyric acid systems and the circadian rhythm,together with amyloid-βaccumulation.This review could provide a theoretical basis for the development of drugs to treat Alzheimer’s disease based on sleep disorders in future work.
基金supported by the Max Planck Society to C.W.T.and National Institutes of Health USDHHS(R01-HD065826to M.G.,OD011107 to Harris Lewin)。
文摘Fluoxetine(Prozac^(TM))is the only antidepressant approved by the US Food and Drug Administration(FDA)for the treatment of major depressive disorder(MDD)in children.Despite its considerable efficacy as a selective serotonin reuptake inhibitor,the possible long-term effects of fluoxetine on brain development in children are poorly understood.In the current study,we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques(Macaca mulatta)one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex(DLPFC)and cingulate cortex(CC)that correlated with impulsivity in animals,suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment.Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.
基金National Natural ScienceFoundation of China(61890953 and 31871088)the Chinese Academy of Medical Sciences Innovation Fund forMedical Sciences(2019-12M-5-014)the Director Fund of Wuhan National Laboratory for Optoelectronics.
文摘The zona incerta(ZI)is involved in various functions and may serve as an integrative node of the circuits for global behavioral modulation.However,the long-range connectivity of different sectors in the mouse ZI has not been comprehensively mapped.Here,we obtained whole-brain images of the input and output connections via fluorescence micro-optical sectioning tomography and viral tracing.The principal regions in the input-output circuits of ZI GABAergic neurons were topologically organized.The 3D distribution of cortical inputs showed rostro-caudal correspondence with different ZI sectors,while the projection fibers from ZI sectors were longitudinally organized in the superior colliculus.Clustering results show that the medial and lateral ZI are two different major functional compartments,and they can be further divided into more subdomains based on projection and input connectivity.This study provides a comprehensive anatomical foundation for understanding how the ZI is involved in integrating different information,conveying motivational states,and modulating global behaviors.
基金the Key Project of the National Natural Science Foundation of China(31430034)the National Key Research and Development Project of the Ministry of Science and Technology of China(2016YF051000)+3 种基金the Science and Technology Program of Guangdong Province,China(2018B030334001)the Key Realm R&D Program of Guangdong Province,China(2019B030335001)Funds for Creative Research Groups of China from the National Natural Science Foundation of China(81521062)the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2019PT310023)。
文摘The amygdala,which is involved in various behaviors and emotions,is reported to connect with the whole brain.However,the long-range inputs of distinct cell types have not yet been defined.Here,we used a retrograde trans-synaptic rabies virus to generate a whole-brain map of inputs to the main cell types in the mouse amygdala.We identified 37 individual regions that projected to neurons expressing vesicular glutamate transporter 2,78 regions to parvalbumin-expressing neurons,104 regions to neurons expressing protein kinase C-δ,and 89 regions to somatostatin-expressing neurons.The amygdala received massive projections from the isocortex and striatum.Several nuclei,such as the caudate-putamen and the CA1 field of the hippocampus,exhibited input preferences to different cell types in the amygdala.Notably,we identified several novel input areas,including the substantia innominata and zona incerta.These findings provide anatomical evidence to help understand the precise connections and diverse functions of the amygdala.
基金Supported by funding from the Ophthalmic Research Institute of Australia,the University of Melbourne De Brettville Trustthe Kel and Rosie Day Foundationthe Centre for Eye Research Australia
文摘Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.
基金supported by the National Natural Science Foundation of China,No.81271090
文摘The γ-aminobutyric acid neurons（GABAergic neurons） in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this classification is associated with physiological function, the exact role for neurons with various firing patterns in acoustic processing remains poorly understood. In the present study, we analyzed characteristics of inferior colliculus neurons in vitro, and recorded responses to stimulation of the dorsal nucleus of the lateral lemniscus using the wholecell patch clamp technique. Seven inferior colliculus neurons were tested and were classified into two firing patterns： sustained-regular（n = 4） and sustained-adapting firing patterns（n = 3）. The majority of inferior colliculus neurons exhibited slight changes in response to stimulation and bicuculline. The responses of one neuron with a sustained-adapting firing pattern were suppressed after stimulation, but recovered to normal levels following application of the γ-aminobutyric acid receptor antagonist. One neuron with a sustained-regular pattern showed suppressed stimulation responses, which were not affected by bicuculline. Results suggest that GABAergic neurons in the inferior colliculus exhibit sustained-regular or sustained-adapting firing patterns. Additionally, GABAergic projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus are associated with sound localization. The different neuronal responses of various firing patterns suggest a role in sound localization. A better understanding of these mechanisms and functions will provide better clinical treatment paradigms for hearing deficiencies.
基金This review was supported by the Key-Area Research and Development Program of Guangdong Province(2018B030331001)the National Natural Science Foundation of China(31630031 and 31930047)+3 种基金the Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Fund(2019025),the Guangdong Provincial Key Laboratory of Brain Connectome and Behavior(2017B030301017)the Chinese Academy of Sciences International Partnership Program(172644KYSB20170004)the CAS President’s International Fellowship for Distinguished Scientists(2021DB0003)the Canadian Institutes of Health Research(#10677).
文摘The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across vertebrate evolution.Moreover,cell-type-specific SC neurons integrate afferent signals within local networks to generate defined output related to innate and cognitive behaviors.This review focuses on the recent progress in understanding of phenotypic diversity amongst SC neurons and their intrinsic circuits and long-projection targets.We further describe relevant neural circuits and specific cell types in relation to behavioral outputs and cognitive functions.The systematic delineation of SC organization,cell types,and neural connections is further put into context across species as these depend upon laminar architecture.Moreover,we focus on SC neural circuitry involving saccadic eye movement,and cognitive and innate behaviors.Overall,the review provides insight into SC functioning and represents a basis for further understanding of the pathology associated with SC dysfunction.
基金supported by the National Natural Science Foundation of China(32130043 and 32071025)the Interdisciplinary Research Fund of Beijing Normal University,China.
文摘Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory glutamatergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+channels on summed synaptic excitation when they precede glutamatergic inputs by>15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.
基金FAPESP-Fundacao de Amparoa Pesquisa do Estado de Sao Paulo,No.2013/12056-0(to GL) and No.2015/02154-0(to CMB)
文摘Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.
基金CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2021-I2M-1-034National Natural Science Foundation of China,Grant/Award Number:31970510Young Elite Scientist Sponsorship Program by CAST,Grant/Award Number:2019QNRC001。
文摘Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.
基金National Natural Science Foundation of China(8163000388).
文摘OBJECTIVE Microglia-mediated dis-placement of synapses has been reported in the setting of experimental neuroinflammation,but its role in neurological disorders is poorly understood.Complex febrile seizures(FS) are the most common infantile seizures,yet its pathological progress is largely unknown.METHODS Mice pups(postnatal 8-10 d) were posted to 43℃ hyperthermia condition to develop FS,and then the latency and threshold of seizures were determined.The displacement of synapses was observed through immunofluorescence staining.We researched whether microglial displacement of GABAergic synapses will influence complex FS-induced increase in GABAergic neurotransmission and neuronal excitability with patch-clamp electrophysiology.Moreover,we used the CD11 bD TR mice to selective ablation of microglia or pharmacological inhibition of microglia to observe their effects on susceptibility to FS and synaptic stripping.RESULTS GABAergic presynaptic terminals surrounding neuronal soma and GABAergic transmissions were increased in complex FS.Meanwhile,the activated microglia ensheathe glutamatergic neuronal soma to displace,but do not phagocytize,GABAergic presynaptic terminals.Patch-clamp electrophysiology established that the microglial displacement of GABAergic synapses reduced complex FS-induced increase in GABAergic neurotransmission and neuronal excitability,while GABA exerts excitatory action in this immature stage.Moreover,pharmacological inhibition of microglial displacement of GABAergic synapses or selective ablation of microglia in CD11 bDTR mice promoted the generation of complex FS.CONCLUSION Displacement of GABAergic synapses by microglia is a protective event in the pathological progress of complex FS.
基金supported by the National Natural Science Foundation of China,No.81471288
文摘Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 k Da, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson＇s disease.
基金the National Natural Science Foundation of China, No. 30670677
文摘BACKGROUND： Neurons expressing gamma-aminobutyric acid （GABA） play an important role in the regulation of wakefulness to sleep, as well as the maintenance of sleep. However, the role of GABAergic neurons in the tuberomammillary nucleus （TMn）, with regard to the sleep-wakefulness cycle, is poorly understood. OBJECTIVE： To investigate the effects of GABAergic neurons in the TMn on the sleep-wakefulness cycle. DESIGN, TIME AND SETTING： Randomized controlled study, performed at the Laboratory of Neurobiology, Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Lanzhou University from July 2007 to February 2008. MATERIALS： Fifteen healthy, adult, male, Sprague Dawley rats were randomly divided into three groups（n = 5）： control, ventrolateral preoptic area （VLPO） lesion, and VLPO lesion plus GABAA receptor antagonist-treated. Ibotenic acid and bicuculline were provided by Sigma （St. Louis, USA）. METHODS： Four electroencephalogram screw electrodes were implanted into the skull at a frontal region （two） and parietal bones （two） on each side. Three flexible electromyogram wire electrodes were placed into the nuchal muscles. On day 8, a fine glass micropipette （10–20 mm tip diameter） containing ibotenic acid solution （10 nmol/L） was injected into the VLPO in both hemispheres following bone wax removal under anesthesia. One week after the second surgery, sleep-wakefulness states were recorded in rats from the VLPO lesion group. On day 10 after VLPO lesion, bicuculline （10 nmol/L）, a GABAA-receptor antagonist, was microinjected into the TMn and sleep-wakefulness states were recorded for 24 hours. MAIN OUTCOME MEASURES： Duration of the sleep-wakefulness cycle in each group using a Data acquisition unit （Micro1 401 mk2） and Data collection software （Spike Ⅱ）. RESULTS： VLPO lesion induced an increased duration of wakefulness （W, 13.17%） and light slow-wave sleep （SWS1, 28.9%）, respectively. Deep slow-wave sleep （SWS2, 43
