Habenulomesencephalic pathway in aversion, reward and depression

描述（由申请人提供）：难治性抑郁症是一种慢性、致残和危及生命的疾病，影响多达30%的被诊断患有重度抑郁症的个体。对于这些患者，传统的药物治疗通常无效，离散脑区域的深部脑刺激已成为唯一可行的治疗选择之一。这种治疗的一个目标区域是外侧缰（LHb），其是上丘脑的一个组成部分，其接收来自情绪和运动系统的汇合输入，强烈影响中脑多巴胺（DA）神经元的活动，并且越来越多地涉及厌恶刺激处理、学习和临床抑郁症。然而，这个系统的电路和系统中新发现的组件的关键作用仍然不完全清楚。例如，新发现的头内侧被盖核（RMTg），一个GABA能中脑区域，接收LHb输入并强烈投射到DA神经元，其作用在很大程度上尚未探索，尽管它的已知特性表明可能在抑郁现象中起中心作用。我们的建议解决了几个基本的悬而未决的问题，这些缰-中脑电路使用一系列的行为和电生理技术，分为三个相关的目标。在目标1中，我们将测试的假设，即与急性和慢性激活的LHb介导的生理和行为的影响，通过从LHb的RMTg的投影。目的2将测试的假设，即LHb和RMTg关键有助于适应不良的行为，在两个不同的动物制剂，模型人类抑郁症内表型。这一目标使用损伤和刺激的研究，以表征这一途径的重要性，在抑郁相关的反应，厌恶和奖励刺激（绝望，快感缺失）。最后，在目标3中，我们将检验抑郁诱导的LHb和RMTg放电模式变化是抑郁症中观察到的行为和认知缺陷的基础这一假设。总体而言，这些研究调查的命题，失调的基本电路，LHb-RMTg-VTA，参与不良事件的适应不良反应。从这些实验中获得的结果将说明NIMH研究领域标准（RDoC）的主要重点，即基于跨越诊断界限的神经生物学测量来定义精神障碍。大脑奖赏系统的功能障碍与抑郁症、精神分裂症、双相情感障碍和药物滥用有明显的关系。鉴于临床前和临床数据日益趋同，这些研究具有明显的转化相关性。 公共卫生相关性：缰核和中脑多巴胺神经元之间的连接是参与从环境线索中学习的回路的一部分，这些环境线索预测了不期望的结果，如厌恶的刺激或预期奖励的遗漏。在这个应用程序中，我们提出的实验设计，以确定在这条通路中缺失的组件和测试的假设，重复激活这个电路有助于抑郁行为的发展。除了提供新的见解到潜在的病理生理学的疾病，每年影响1500万美国成年人，这项研究计划将解决NIMH研究领域标准（RDoC）的主要重点，努力定义精神障碍的基础上，跨越诊断界限的神经生物学措施，并推进我们的认知和情感的变化，发生在重度抑郁症患者的理解。

DESCRIPTION (provided by applicant): Treatment resistant depression is a chronic, disabling and life-threatening disease that affects as many as 30% of individuals diagnosed with major depressive disorder. For these patients, traditional pharmacological treat- ments are often not effective, and deep brain stimulation of discrete brain regions has emerged as one of the only viable treatment options. One target area for such treatment is the lateral habenula (LHb), a component of the epithalamus that receives confluent input from emotional and motor systems, strongly influences activity of midbrain dopamine (DA) neurons, and is increasingly implicated in aversive stimulus processing, learning, and clinical depression. However, the circuitry of this system and the critical role of newly discovered components within the system remain incompletely understood. For example, the role of the newly identified rostromedial tegmental nucleus (RMTg), a GABAergic midbrain region which receives LHb input and projects intensely to DA neurons, is largely unexplored, although it's known properties suggest possibly central roles in depressive phenomena. Our proposal addresses several fundamental outstanding questions regarding these habenulo- mesencephalic circuits using a range of behavioral and electrophysiological techniques that are grouped into three related aims. In Aim 1, we will test the hypothesis that the physiological and behavioral effects associated with acute and chronic activation of the LHb are mediated via a projection from the LHb to the RMTg. Aim 2 will test the hypothesis that the LHb and RMTg critically contribute to maladaptive behaviors in two distinct animal preparations that model human depression endophenotypes. This aim uses lesion and stimulation studies to characterize the importance of this pathway in depression-related responses to both aversive and rewarding stimuli (despair, anhedonia). Finally, in Aim 3, we will test the hypothesis that depression-induced changes in LHb and RMTg patterns of firing underlie the behavioral and cognitive deficits seen in depressive disorders. Overall, these studies investigate the proposition that dysregulation of a fundamental circuit, LHb-RMTg-VTA, is involved in the maladaptive response to adverse events. Results obtained from these experiments will ad- dress a major focus of the NIMH Research Domain Criteria (RDoC) efforts to define mental disorders based on neurobiological measures that cross diagnostic boundaries. Dysfunction of brain reward systems has clear im- plications for depression, and also schizophrenia, bipolar disorder, and drug abuse. Given growing convergent preclinical and clinical data, these studies have clear translational relevance. PUBLIC HEALTH RELEVANCE: Connections between the habenula and midbrain dopamine neurons are part of a circuit involved in learning from environmental cues that predict undesirable outcomes such as aversive stimuli or the omission of an expected reward. In this application, we propose experiments designed to identify a missing component in this pathway and test the hypothesis that repeated activation of this circuit contributes to the development of depressed behavior. In addition to providing new insights into the underlying pathophysiology of an illness that affects 15 million American adults annually, this program of research will address a major focus of the NIMH Research Domain Criteria (RDoC) efforts to define mental disorders based on neurobiological measures that cross diagnostic boundaries and advance our understanding of the cognitive and emotional changes that occur in patients with major depressive disorder.