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

基本信息

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
项目类别：
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

项目摘要

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。由于抑郁症经历了长时间的悲伤、绝望、动力减弱和绝望，他们常常无法享受曾经令人愉快的活动。抑郁症和其他功能失调的情绪状态仍然难以捉摸。最近，将抑郁症概念化为特定单胺能神经递质系统的功能障碍。由于努力将疾病症状与疾病相关联，出现了更细致的概念框架。调节情绪和奖励反应的特定大脑网络功能障碍。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）已成为抑郁症病理生理学的关键大脑区域。在抑郁症动物模型中，投射到 VTA 的神经元过度活跃，突触减少通过深部脑刺激传输到 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尚不清楚。在这里，我们提出了一种创新的实验策略，该策略结合了最先进的技术方法，包括新颖的分子和遗传工具、电生理学、光遗传学和行为学研究慢性压力（人类抑郁症的一个重要原因）如何改变突触的范例我们的目标是 (1) 准确识别哪些 LHb 传入途径。慢性压力暴露后发生改变，(2) 描述潜在的突触机制，(3) 制定针对慢性压力引起的行为变化的特定回路策略。应激诱导的突触对相关 LHb 通路的适应将为了解大脑处理慢性压力以产生适应不良的行为反应，这可能会激发新颖的治疗策略涉及重新编程特定的大脑回路来治疗抑郁症。