Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.

中文翻译：

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TGR5介导的下丘脑外侧-dCA3-背外侧隔膜回路调节雄性小鼠的抑郁样行为


尽管胆汁酸在抑郁症中发挥着显着作用，但胆汁酸 TGR5 膜型受体在这种疾病中的病理意义仍然难以捉摸。使用雄性小鼠慢性社交失败压力和慢性束缚压力的抑郁模型，我们发现下丘脑外侧区（LHA）中的TGR5主要在GABA能神经元中减少，而在抑郁样小鼠中其兴奋性增加。 LHA 中 TGR5 的上调或 GABA 能兴奋性的抑制显着减轻了抑郁样行为，而 TGR5 的下调或 GABA 能兴奋性的增强则促进了应激诱发的抑郁样行为。 TGR5 还通过细胞外调节蛋白激酶依赖性 Kv4.2 通道双向调节 LHA GABA 能神经元的兴奋性。值得注意的是，LHA GABA 能神经元特异性支配背侧 CA3 (dCA3) CaMKIIα 神经元，以介导抑郁样行为。 LHA GABAergic TGR5 通过抑制投射到背外侧隔膜 (DLS) 的 dCA3 CaMKIIα 神经元发挥抗抑郁样作用。这些发现增进了我们对 TGR5 和 LHAGABA→dCA3CaMKIIα→DLSGABA 回路的理解，以开发抑郁症的潜在治疗策略。