A multi-level investigation into the effects of chronic stress on lateral habenula circuitry

抑郁症是一种使人衰弱的疾病，可以极大地影响一个人的健康和生活。人患 抑郁症患者会经历长时间的悲伤、绝望、动力减少和绝望， 而且他们常常无法享受曾经觉得愉快的活动。目前，有效的治疗 抑郁症和其他功能失调的情绪状态仍然难以捉摸。传统的治疗方法 将抑郁症概念化为特定单胺能神经递质系统的功能障碍。最近， 由于努力将疾病症状与 调节情绪和奖励反应的特定大脑网络功能障碍。外侧缰核（LHb）， 奖励回路的一部分，为腹侧的中脑多巴胺神经元提供“负值” 被盖区（VTA），已成为抑郁症的病理生理学的关键脑区。LHB 投射到腹侧被盖区的神经元在抑郁症的动物模型中过度活跃， 通过脑深部刺激传递到LHb神经元可以改善抑郁相关行为。 然而，驱动这些神经元过度活跃的传入通路的身份在很大程度上是未知的。 在这里，我们提出了一个创新的实验策略，采用了最先进的组合 方法，包括新的分子和遗传工具，电生理学，光遗传学和行为 范式来研究慢性压力，人类抑郁症的重要原因，如何改变突触 在特定的LHb传入通路中传递。我们的目标是（1）准确识别哪些LHb通路 在慢性应激暴露后发生改变，（2）描述潜在的突触机制和（3） 制定特定于回路的策略，以逆转慢性压力引起的行为变化。链接慢性 应激诱导的突触适应相关的LHb途径将提供重要的见解， 大脑处理慢性压力，以产生适应不良的行为反应，这可能会激发 新的治疗策略，包括重新编程特定的大脑回路来治疗抑郁症。

Depression is a debilitating disease that can dramatically affect a person's health and life. People suffering from depression experience extended periods of sadness, despair, reduced motivation and hopelessness, and they are often unable to enjoy activities once found pleasurable. At present, effective treatments for depression and other dysfunctional emotional states remain elusive. Traditional treatment perspectives have conceptualized depression as a dysfunction of specific monoaminergic neurotransmitter systems. Recently, more nuanced conceptual frameworks have arisen as a result of efforts to correlate disease symptoms with dysfunction of specific brain networks mediating mood and reward responses. The lateral habenula (LHb), a part of the reward circuit that provides ‘negative value’ to midbrain dopamine neurons in the ventral tegmental area (VTA), has emerged as a key brain region for the pathophysiology of depression. LHb neurons projecting to the VTA are hyperactive in an animal model of depression, and reducing synaptic transmission onto LHb neurons through deep brain stimulation can ameliorate depression-related behaviors. However, the identities of afferent pathways that drive hyperactivity of these neurons are largely unknown. Here, we propose an innovative experimental strategy that employs a combination of state-of-the-art methods, including novel molecular and genetic tools, electrophysiology, optogenetics and behavioral paradigms to investigate how chronic stress, an important cause for depression in humans, alters synaptic transmission in specific LHb afferent pathways. Our goals are to (1) identify precisely which LHb pathways are altered following chronic stress exposure, (2) describe the underlying synaptic mechanisms and (3) develop circuit-specific strategies to reverse chronic stress-induced behavioral changes. Linking chronic stress-induced synaptic adaptations to relevant LHb pathways will provide important insights into how the brain processes chronic stress in order to generate maladaptive behavioral responses, which may inspire novel treatment strategies that involve reprogramming of specific brain circuits for treating depression.