Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neu...Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain 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 synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.展开更多
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
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
To understand the structure of GABAergic neurons in the VMP and ＂barrel＂, the distribution of GABAergic neurons in the two areas were studied through immunohistochemistry and Laser Scanning Confocal Microscope. The ...To understand the structure of GABAergic neurons in the VMP and ＂barrel＂, the distribution of GABAergic neurons in the two areas were studied through immunohistochemistry and Laser Scanning Confocal Microscope. The results show that the distribution of GABAergic neurons in VMP and barrel are different, and the coding of information transmission in the two areas are also dissimilar; GABAergic neurons mainly distribute among the lines asymmetrically in VMP, the somata, dendrite and axon of GABAergic neurons are restricted in the ＂barrel＂, rarely having synaptic connections with other ＂barrel＂ around. Therefore, VMP and barrel may have different roles in transmission and on processing of informatiton.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 the...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
The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive un...The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.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
GABAergic neurons are the major inhibitory interneurons that powerfully control the function of spinal neuronal networks.In recent years,tremendous progresses have been made in understanding the transcriptional contro...GABAergic neurons are the major inhibitory interneurons that powerfully control the function of spinal neuronal networks.In recent years,tremendous progresses have been made in understanding the transcriptional control of GABAergic neuron development in the dorsal spinal cord.New experimental approaches provide a relatively high throughput way to study the molecular regulation of subgroup fate determination.Our understanding of the molecular mechanisms on GABAergic neuron development in the dorsal spinal cord is rapidly expanding.Recent studies have defined several transcription factors that play essential roles in GABAergic neuron development in the spinal dorsal horn.Here,we review results of very recent analyses of the mechanisms that specify the GABAergic neuron development in the dorsal spinal cord,especially the progresses in the homeodomain(HD) and basic-helix-loop-helix(bHLH) containing transcription factors.展开更多
Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized acti...Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized activities. Gamma-aminobutyric acid-ergic(GABAergic) pathway is an important inhibitory pathway in retina.In the present study, the effects of GABAergic pathway on the contrast adaptation process of bullfrog RGCs were studied using multi-electrode recording technique. It was found that the application of bicuculline(BIC), a gamma-aminobutyric acid A(GABAA) receptor antagonist, caused a number of changes in the RGCs' response characteristics, including attenuation in adaptation-dependent firing rate decrease and the adaptation-dependent weakening in synchronized activities between adjacent neuron-pairs, whereas intensified the adaptation-dependent RF size shrinkage. These results suggest that GABAAreceptors are involved in the modulation of the firing activity and synchronized activities in contrast adaptation process of the RGCs, whereas the adaptation-related RF property changes involve more complicated mechanisms.展开更多
Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracel...Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracellular fluid volume. Gamma-aminobutyric acid (GABA) and Angiotensin (Ang) receptors in the brain are involved with thirst, water intake and balance of body liquid. The present study investigated the interaction between Angiotensinergic and GABAergic systems on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24 h deprivation of water intake. After deprivation the volume of consumed water was measured for 1 h. Administration of Losartan (45 μg/rat), Muscimol (0.1 μg/rat) significantly decreased water intake while, i.c.v. microinjection of Bicuculline (1 μg/rat) significantly increased it as compared to Saline-treated controls. I.C.V. microinjection of Muscimol 15 min after Losartan administration decreased water intake significantly, while, i.c.v. microinjection of Bicuculline 15min after Losartan administration could attenuate increasing effect of Bicuculline on water intake. It is concluded that Angiotensinergic system have interaction with GABAergic system on water intake.展开更多
As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the lea...As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the least controversial therapeutic benefits of acupuncture treatment. To date, the mechanism underlying acupuncture analgesia remains poorly understood. In this review, roles of members of GABAergic neurotransmission system which has long been related to pain perception and modulation, in acupuncture analgesia are discussed.展开更多
It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024)....It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.展开更多
Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapi...Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.展开更多
The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory ...The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory fibers.While the reticulospinal tract has been shown to be particularly prone to axonal growth and plasticity following injuries of the spinal cord,the differential capacities of excitatory and inhibitory fibers for plasticity remain unclear.As adaptive axonal plasticity involves a sophisticated interplay between excitatory and inhibitory input,we investigated in this study the plastic potential of glutamatergic(vGlut2)and GABAergic(vGat)fibers originating from the gigantocellular nucleus and the lateral paragigantocellular nucleus,two nuclei important for locomotor function.Using a combination of viral tracing,chemogenetic silencing,and AI-based kinematic analysis,we investigated plasticity and its impact on functional recovery within the first 3 weeks following injury,a period prone to neuronal remodeling.We demonstrate that,in this time frame,while vGlut2-positive fibers within the gigantocellular and lateral paragigantocellular nuclei rewire significantly following cervical spinal cord injury,vGat-positive fibers are rather unresponsive to injury.We also show that the acute silencing of excitatory axonal fibers which rewire in response to lesions of the spinal cord triggers a worsening of the functional recovery.Using kinematic analysis,we also pinpoint the locomotion features associated with the gigantocellular nucleus or lateral paragigantocellular nucleus during functional recovery.Overall,our study increases the understanding of the role of the gigantocellular and lateral paragigantocellular nuclei during functional recovery following spinal cord injury.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
Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry und...Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.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
文摘Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain 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 synapse function in neurological disorders,including Alzheimer's disease and Alzheimer's diseaserelated dementia.
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Supported by National Natural Science Fund(30670230)~~
文摘To understand the structure of GABAergic neurons in the VMP and ＂barrel＂, the distribution of GABAergic neurons in the two areas were studied through immunohistochemistry and Laser Scanning Confocal Microscope. The results show that the distribution of GABAergic neurons in VMP and barrel are different, and the coding of information transmission in the two areas are also dissimilar; GABAergic neurons mainly distribute among the lines asymmetrically in VMP, the somata, dendrite and axon of GABAergic neurons are restricted in the ＂barrel＂, rarely having synaptic connections with other ＂barrel＂ around. Therefore, VMP and barrel may have different roles in transmission and on processing of informatiton.
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This work was supported by the National Natural Science Foundation of China(32271056,81671081,and 81701095)University Science and Technology Fund Planning Projects(2022XC002 and 2019XB006).
文摘The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
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the National Natural Science Foundation of China (30470556)the Program for New Century Excellent Talents in University
文摘GABAergic neurons are the major inhibitory interneurons that powerfully control the function of spinal neuronal networks.In recent years,tremendous progresses have been made in understanding the transcriptional control of GABAergic neuron development in the dorsal spinal cord.New experimental approaches provide a relatively high throughput way to study the molecular regulation of subgroup fate determination.Our understanding of the molecular mechanisms on GABAergic neuron development in the dorsal spinal cord is rapidly expanding.Recent studies have defined several transcription factors that play essential roles in GABAergic neuron development in the spinal dorsal horn.Here,we review results of very recent analyses of the mechanisms that specify the GABAergic neuron development in the dorsal spinal cord,especially the progresses in the homeodomain(HD) and basic-helix-loop-helix(bHLH) containing transcription factors.
基金the National Natural Science Foundation of China(No.61375114)
文摘Retinal ganglion cells(RGCs) exhibit adaptive changes in response to sustained light stimulation,which include decrease in firing rate, tendency to shrink in receptive field(RF) size and reduction in synchronized activities. Gamma-aminobutyric acid-ergic(GABAergic) pathway is an important inhibitory pathway in retina.In the present study, the effects of GABAergic pathway on the contrast adaptation process of bullfrog RGCs were studied using multi-electrode recording technique. It was found that the application of bicuculline(BIC), a gamma-aminobutyric acid A(GABAA) receptor antagonist, caused a number of changes in the RGCs' response characteristics, including attenuation in adaptation-dependent firing rate decrease and the adaptation-dependent weakening in synchronized activities between adjacent neuron-pairs, whereas intensified the adaptation-dependent RF size shrinkage. These results suggest that GABAAreceptors are involved in the modulation of the firing activity and synchronized activities in contrast adaptation process of the RGCs, whereas the adaptation-related RF property changes involve more complicated mechanisms.
文摘Thirst is a subjective perception that provides the urge for human and animals to drink fluids and it is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracellular fluid volume. Gamma-aminobutyric acid (GABA) and Angiotensin (Ang) receptors in the brain are involved with thirst, water intake and balance of body liquid. The present study investigated the interaction between Angiotensinergic and GABAergic systems on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24 h deprivation of water intake. After deprivation the volume of consumed water was measured for 1 h. Administration of Losartan (45 μg/rat), Muscimol (0.1 μg/rat) significantly decreased water intake while, i.c.v. microinjection of Bicuculline (1 μg/rat) significantly increased it as compared to Saline-treated controls. I.C.V. microinjection of Muscimol 15 min after Losartan administration decreased water intake significantly, while, i.c.v. microinjection of Bicuculline 15min after Losartan administration could attenuate increasing effect of Bicuculline on water intake. It is concluded that Angiotensinergic system have interaction with GABAergic system on water intake.
文摘As one of the essential components of traditional Chinese medicine, acupuncture has been accepted world-widely for its effectiveness in treating various disease and health conditions. Pain management is one of the least controversial therapeutic benefits of acupuncture treatment. To date, the mechanism underlying acupuncture analgesia remains poorly understood. In this review, roles of members of GABAergic neurotransmission system which has long been related to pain perception and modulation, in acupuncture analgesia are discussed.
文摘It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.
基金supported by the National Key Research and Development Program of China(2021YFA1101800,2022YFA1104800,2023YFF1203600)National Natural Science Foundation of China(82325015,82171528,U23A20429,82371260,21904069,22274079,82401794)+2 种基金Jiangsu Provincial Natural Science Fund for Excellent Young Scholars(BK20240131)Natural Science Foundation of Jiangsu Province(BK20200677)Joint Project of the Yangtze River Delta Science and Technology Innovation Community(2024CSJZN0600)。
文摘Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.
基金supported by the Deutsche Forschungsgemeinschaft(DFG),TRR274(Project ID 408885537,Sy Nergy,EXC 2145/ID 390857198,to FMB)。
文摘The remodeling of axonal connections following injury is an important feature driving functional recovery.The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory fibers.While the reticulospinal tract has been shown to be particularly prone to axonal growth and plasticity following injuries of the spinal cord,the differential capacities of excitatory and inhibitory fibers for plasticity remain unclear.As adaptive axonal plasticity involves a sophisticated interplay between excitatory and inhibitory input,we investigated in this study the plastic potential of glutamatergic(vGlut2)and GABAergic(vGat)fibers originating from the gigantocellular nucleus and the lateral paragigantocellular nucleus,two nuclei important for locomotor function.Using a combination of viral tracing,chemogenetic silencing,and AI-based kinematic analysis,we investigated plasticity and its impact on functional recovery within the first 3 weeks following injury,a period prone to neuronal remodeling.We demonstrate that,in this time frame,while vGlut2-positive fibers within the gigantocellular and lateral paragigantocellular nuclei rewire significantly following cervical spinal cord injury,vGat-positive fibers are rather unresponsive to injury.We also show that the acute silencing of excitatory axonal fibers which rewire in response to lesions of the spinal cord triggers a worsening of the functional recovery.Using kinematic analysis,we also pinpoint the locomotion features associated with the gigantocellular nucleus or lateral paragigantocellular nucleus during functional recovery.Overall,our study increases the understanding of the role of the gigantocellular and lateral paragigantocellular nuclei during functional recovery following spinal cord injury.
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.
文摘Striatal interneurons play a key role in modulating striatal-dependent behaviors,including motor activity and reward and emotional processing.Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson's or Huntington's disease.This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions.In addition to direct circuit modulation,striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood.We discuss this interesting and novel role of striatal interneurons,with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.
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.
