Abstract Background Takeda G-protein-coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression. Methods In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, using fiber photometry, optogenetic, chemogenetic, pharmacological, molecular profiling techniques and behavioral tests, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5-10). Results Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyNs activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in TGR5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNs→somatostatin (SST)-GABAergic neurons of dorsolateral septum (DLS) circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs. Conclusions These findings indicate that TGR5 can regulate depression via CA3 PyNs→SST-GABAergic neurons of DLS transmission, suggesting that TGR5 could be a novel target for developing antidepressants.

中文翻译：

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武田 G 蛋白偶联受体 5 通过传入背外侧隔膜的海马 CA3 锥体神经元调节抑郁样行为

摘要背景武田G蛋白偶联受体5（TGR5）被认为是2型糖尿病和代谢综合征的有希望的靶点。它的表达已在大脑中得到证实，并被认为具有神经保护作用。在这里，我们假设中枢 TGR5 的功能障碍可能导致抑郁症的发病机制。方法 在成熟的慢性社交失败压力 (CSDS) 和慢性约束压力 (CRS) 抑郁症模型中，我们使用纤维光度法、光遗传学、化学遗传学、药理学、分子谱分析技术和行为测试，研究了 TGR5 在 CA3 锥体中的功能作用神经元 (PyN) 和抑郁症神经元回路的潜在机制（体内研究，n = 10；体外研究，n = 5-10）。结果 CSDS 和 CRS 都最显着地降低了海马 CA3 PyNs 的 TGR5 表达。CA3 PyNs 中 TGR5 的遗传过表达或 INT-777 的 CA3 内输注，一种特定的激动剂，可防止 CSDS 和 CRS，发挥通过 CA3 PyNs 激活介导的显着抗抑郁样作用。相反，CA3 中的基因敲除或 TGR5 敲除促进了压力诱导的抑郁样行为。CA3 PyNs 中 TGR5 的重新表达而不是 INT-777 的输注显着改善了暴露于 CSDS 或 CRS 的 TGR5 敲除小鼠的抑郁样行为。CA3 PyNs 的沉默和刺激→背外侧隔膜 (DLS) 回路的生长抑素 (SST)-GABA 能神经元双向调节抑郁样行为，阻断该回路消除了 TGR5 激活 CA3 PyNs 的抗抑郁样作用。