Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in pathophysiology of depression. However, the contribution of inhibitory transmission remains elusive. Here, we dissect an inhibitory projection from sensory thalamic reticular nucleus (sTRN) to LHb, which is activated by acute aversive stimuli. Repeated activation of the LHb-projecting sTRN neurons prevents CRS-induced depression onset and hyperexcitability of LHb neurons. Moreover, acute inhibition of sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, both neuropathic pain and comorbid pain in chronic stress are unaffected by this pathway. Finally, we dissected sTRN upstream brain regions associated with stress. Together, our study demonstrates an inhibitory sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

中文翻译：

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丘脑网状核外侧缰核回路调节慢性应激和慢性疼痛中的抑郁样行为

慢性压力和慢性疼痛是引发抑郁症的两个主要诱发因素。外侧缰核 (LHb) 的兴奋性输入增强与抑郁症的病理生理学有关。然而，抑制性传播的贡献仍然难以捉摸。在这里，我们剖析了从感觉丘脑网状核 (sTRN) 到 LHb 的抑制投射，该投射由急性厌恶刺激激活。重复激活投射 LHb 的 sTRN 神经元可防止 CRS 诱导的抑郁发作和 LHb 神经元的过度兴奋。此外，急性抑制 sTRN-LHb 回路会在健康小鼠中诱发抑郁样行为，而增强该回路可缓解由慢性压力和慢性疼痛引起的抑郁。有趣的是，慢性压力下的神经性疼痛和合并症疼痛均不受该通路的影响。最后，我们解剖了与压力相关的 sTRN 上游大脑区域。总之，我们的研究证明了抑制性 sTRN-LHb 回路在建立和调节抑郁症方面的作用，从而揭示了预防或控制抑郁症的潜在治疗靶点。