急性社交挫败通过大麻素1型受体依赖的突触抑制驱动雄性小鼠社交回避：从前腹侧下托到前下丘脑核的通路
Acute social defeat induces cannabinoid type 1 receptor-dependent synaptic depression in the anterior ventral subiculum to anterior hypothalamic nucleus pathway to drive social avoidance in male mice
背景：社交回避是一种保护性反应，可限制对有害社交刺激的暴露。尽管回避是一种特征性的应激表型，但其环路层面的调控机制仍不清楚。腹侧下托（vSUB）是海马的主要输出区域，投射至前下丘脑核（AHN），后者是应激反应的关键区域。方法：雄性小鼠接受急性社交挫败应激（ASDS）或阈下社交挫败应激。我们结合社交互动、旷场和高架十字迷宫测试，以及光遗传学辅助脑片记录、药理学、通路特异性化学遗传学和光遗传学、逆行和顺行跨突触示踪以及原位杂交。结果：ASDS通过糖皮质激素和大麻素1型受体（CB1R）依赖机制，诱导前部vSUB（avSUB）[->] AHN突触的前突触抑制，而后部vSUB（pvSUB）[->] AHN突触未受影响。在ASDS前向AHN输注CB1R拮抗剂，可减弱突触抑制和社交回避。在ASDS期间化学遗传学激活avSUB [->] AHN通路可减弱社交回避，而抑制该通路则在阈下应激下诱导回避。光遗传学激活avSUB [->] AHN通路可立即增加社交趋近。顺行示踪显示，前部和后部vSUB神经元投射至 largely 分离的AHN群体。pvSUB [->] AHN通路调节焦虑样行为，但不改变社交趋近。结论：这些发现揭示了vSUB亚区在社交和情绪反应中的专门作用，并确定avSUB [->] AHN突触的前突触门控是应激诱导社交退缩的控制点。
把腹侧下托前后两段到前下丘脑的通路分开处理，为应激性社交回避找到一条突触前门控通路。
BACKGROUND: Social avoidance is a protective response that limits exposure to harmful social stimuli. Although avoidance is a characteristic stress phenotype, its circuit-level regulation remains unclear. The ventral subiculum (vSUB), a major hippocampal output, projects to the anterior hypothalamic nucleus (AHN), a key region for stress responses. METHODS: Male mice underwent acute social defeat stress (ASDS) or subthreshold social defeat stress. We combined social interaction, open field, and elevated plus maze testing with optogenetic-assisted slice recording, pharmacology, pathway-specific chemogenetics and optogenetics, retrograde and anterograde transsynaptic tracing, and in situ hybridization. RESULTS: ASDS induced presynaptic depression at anterior vSUB (avSUB) [->] AHN synapses through a glucocorticoid- and cannabinoid type 1 receptor (CB1R)-dependent mechanism, while posterior vSUB (pvSUB) [->] AHN synapses were unaffected. Infusing a CB1R antagonist into the AHN before ASDS attenuated both the synaptic depression and the social avoidance. Chemogenetic activation of the avSUB [->] AHN pathway during ASDS attenuated social avoidance, whereas its inhibition induced avoidance under subthreshold stress. Optogenetic activation of the avSUB [->] AHN pathway produced an immediate increase in social approach. Anterograde tracing revealed that anterior and posterior vSUB neurons project to largely separate AHN populations. The pvSUB [->] AHN pathway modulates anxiety-like behavior without altering social approach. CONCLUSIONS: These findings reveal specialized roles for vSUB subregions in social and emotional responses, and identify presynaptic gating of the avSUB [->] AHN synapse as a control point for stress-induced social withdrawal.
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来源：bioRxiv · Neuroscience · biorxiv.org