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

慢性应激对外侧缰核回路影响的多层次研究

• 批准号: 9900592
• 负责人: Stephan Lammel
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-16 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900592
• 关键词: Acute; Address; Affect; Afferent Pathways; Anatomy; Anhedonia; Animal Model; Architecture; Axon; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cells; Chronic stress; Data; Deep Brain Stimulation; Depressed mood; Disease; Economic Burden; Efferent Pathways; Electrophysiology (science); Emotional; Excitatory Synapse; Exposure to; Feeling hopeless; Functional disorder; Glutamates; Goals; Habenula; Health; Human; Hyperactive behavior; Hypothalamic structure; Individual; Intervention; Investigation; Lateral; Learned Helplessness; Life; Link; Major Depressive Disorder; Maps; Mediating; Membrane; Mental Depression; Methods; Midbrain structure; Modernization; Molecular Genetics; Moods; Morphology; Motivation; Mus; Neuraxis; Neurons; Neurosciences; Neurotransmitters; Pathway interactions; Pattern; Persons; Physiological; Prevalence; Prevention; Process; Property; Rabies virus; Research; Rewards; Slice; Societies; Stress Tests; Symptoms; Synapses; Synaptic Transmission; System; Testing; Time; Ventral Tegmental Area; base; behavioral response; depression model; dopaminergic neuron; dorsal raphe nucleus; effective therapy; endopeduncular nucleus; experience; experimental study; innovation; insight; neural circuit; novel; novel therapeutic intervention; optogenetics; patch clamp; pleasure; postsynaptic; relating to nervous system; response; tool; transmission process; treatment strategy

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.

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。遭受痛苦的人 从抑郁症经历延长的悲伤，绝望，动力减少和绝望的时期， 一旦发现令人愉快，他们通常无法享受活动。目前，有效的治疗方法 抑郁症和其他功能失调的情绪状态仍然难以捉摸。传统的治疗观点有 概念化抑郁是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 特定大脑网络的功能障碍，介导情绪和奖励反应。外侧Habenula（LHB）， 奖励电路的一部分，为腹侧中脑多巴胺神经元提供“负值” 对抑郁症病理生理学的关键大脑区域已出现，对损伤区域（VTA）。 LHB 投射到VTA的神经元在抑郁的动物模型中过度活跃，并减少突触 通过深脑刺激向LHB神经元传播可以改善与抑郁症相关的行为。 但是，驱动这些神经元多动的传入途径的身份在很大程度上未知。 在这里，我们提出了一种创新的实验策略，该策略采用了最先进的结合 方法，包括新型分子和遗传工具，电生理学，光遗传学和行为 调查慢性压力的范例，这是人类抑郁的重要原因，改变了突触 特定LHB传入途径的传输。我们的目标是（1）确切确定哪种LHB途径 在慢性应激暴露后会改变，（2）描述基本的合成机制和（3） 制定特定电路的策略来逆转慢性应激引起的行为变化。连接慢性 压力引起的突触适应相关的LHB途径将提供重要的见解 大脑过程慢性压力以产生适应不良的行为反应，这可能会激发 新的治疗策略涉及重新编程以治疗抑郁症的特定脑回路。