Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by ...Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by using a mouse model of chronic social defeat stress(CSDS),we observed that the dysregulation varied drastically across individual projection neurons(PNs)in the basolateral amygdala(BLA),one of the kernel amygdala subregions critical for stress coping.While persistently reducing the extrasynaptic GABAAreceptor(GABA_(A)R)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus(BLA→v HPC PNs),CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis(BLA→adBNST PNs),suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS.Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss-and gain-of-function ofδ-containing GABA_(A)Rs(GABA_(A)(δ)Rs)in BLA→vHPC and BLA→adBNST PNs,respectively.Importantly,it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice.Virally mediated maintenance of GABA_(A)(δ)R currents in BLA→vHPC PNs occluded CSDS-induced anxiety-like behavior.These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.展开更多
Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral sub...Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference （CPP） and conditioning place aversion （CPA） models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease （approximately 11%） of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase （approximately 230%） of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.展开更多
基金supported by National Natural Science Foundation of China(82125010,81930032,31970953,81741759,31700916,and 81601179)Natural Science Foundation of Jiangxi Province(20172BCB22005,20192ACB20023,and 20192ACB21024)。
文摘Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders.However,the molecular and circuit mechanisms underlying the dysregulation remain elusive.Here,by using a mouse model of chronic social defeat stress(CSDS),we observed that the dysregulation varied drastically across individual projection neurons(PNs)in the basolateral amygdala(BLA),one of the kernel amygdala subregions critical for stress coping.While persistently reducing the extrasynaptic GABAAreceptor(GABA_(A)R)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus(BLA→v HPC PNs),CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis(BLA→adBNST PNs),suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS.Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss-and gain-of-function ofδ-containing GABA_(A)Rs(GABA_(A)(δ)Rs)in BLA→vHPC and BLA→adBNST PNs,respectively.Importantly,it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice.Virally mediated maintenance of GABA_(A)(δ)R currents in BLA→vHPC PNs occluded CSDS-induced anxiety-like behavior.These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.
基金supported by the National Natural Science Foundation of China(No.30230130 and No.30400129)the Ministry of Science and Technology of China(No.2003CB515405,No.2005CB522406)+1 种基金the Program for Changjiang Scholars and Innovative Research Team of Ministry of Education of ChinaShanghai Municipal Commission for Science and Technology(No.06JC14008).
文摘Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference （CPP） and conditioning place aversion （CPA） models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease （approximately 11%） of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase （approximately 230%） of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.
