Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Cell Rep. 2023 Oct 31;42(10):113170. doi: 10.1016/j.celrep.2023.113170. Epub 2023 Sep 21.
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 the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the 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, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.
慢性应激和慢性疼痛是引发抑郁的两个主要诱发因素。外侧缰核（LHb）中兴奋性输入的增强与抑郁的病理生理学有关。然而，抑制性传递的贡献仍不清楚。在这里，我们解析了一个来自感觉丘脑网状核（sTRN）到 LHb 的抑制性投射，该投射被急性厌恶刺激激活。然而，慢性束缚应激（CRS）削弱了 sTRN-LHb 的突触强度，而这种突触衰减对于 CRS 诱导的 LHb 神经活动过度和抑郁发作是必不可少的。此外，人为抑制 sTRN-LHb 回路会在健康小鼠中引起抑郁样行为，而增强该回路则可以缓解慢性应激和慢性疼痛引起的抑郁。有趣的是，慢性应激引起的神经病理性疼痛或合并的机械性超敏反应都不受该途径的影响。总的来说，我们的研究表明了 sTRN-LHb 回路在建立和调节抑郁中的作用，为预防或管理抑郁提供了潜在的治疗靶点。
