Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.
压力是抑郁障碍的主要风险因素，通过在特定的脑区和神经环路产生持久的功能异常，进而导致抑郁发作。在压力积累的动态过程中，外侧缰核是大脑众多区域中处理负性情绪信息的关键枢纽，因此被认为参与抑郁症发病。外侧缰核的神经元整合了不同上游脑区输入的负性情绪效价，其中有多个上游脑区选择性支配外侧缰核内侧部或外侧部。与此同时，外侧缰核的亚区通过投射到下游不同的中脑靶区，进行负性情绪效价的分配，并且形成反馈神经环路。尽管已有这些进展，但是在压力诱发抑郁样状态的发病过程中，以外侧缰核为核心的神经环路时空动态机制依然是一个未解之谜。本综述试图提出一个理论框架，描述外侧缰核通过“输入-输出”特异性的神经元架构进行负性情绪效价的整合。值得注意的是，最近的研究揭示了外侧缰核具有一种在生理情况下响应多种压力刺激的“赫伯可塑性”，能够通过特定的上游输入促进神经元的过度兴奋，进而因果性地编码慢性压力的经历和驱动抑郁的发生。综上所述，外侧缰核神经环路的最新进展和未来展望将为抑郁症的早期干预和神经环路特异的抗抑郁疗法带来曙光。.
压力是抑郁障碍的主要风险因素，通过在特定的脑区和神经环路产生持久的功能异常，进而导致抑郁发作。在压力积累的动态过程中，外侧缰核是大脑众多区域中处理负性情绪信息的关键枢纽，因此被认为参与抑郁症发病。外侧缰核的神经元整合了不同上游脑区输入的负性情绪效价，其中有多个上游脑区选择性支配外侧缰核内侧部或外侧部。与此同时，外侧缰核的亚区通过投射到下游不同的中脑靶区，进行负性情绪效价的分配，并且形成反馈神经环路。尽管已有这些进展，但是在压力诱发抑郁样状态的发病过程中，以外侧缰核为核心的神经环路时空动态机制依然是一个未解之谜。本综述试图提出一个理论框架，描述外侧缰核通过“输入-输出”特异性的神经元架构进行负性情绪效价的整合。值得注意的是，最近的研究揭示了外侧缰核具有一种在生理情况下响应多种压力刺激的“赫伯可塑性”，能够通过特定的上游输入促进神经元的过度兴奋，进而因果性地编码慢性压力的经历和驱动抑郁的发生。综上所述，外侧缰核神经环路的最新进展和未来展望将为抑郁症的早期干预和神经环路特异的抗抑郁疗法带来曙光。
Keywords: Aversion; Depression-like state; Head-to-head comparison; Lateral habenula; Neural circuits; Stress dynamics.