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%的重度抑郁症患者。对于这些患者，传统的药物治疗往往是无效的，而脑深部刺激分离脑区域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），它是上皮体的一个组成部分，接收来自情绪和运动系统的融合输入，强烈影响中脑多巴胺（DA）神经元的活动，并且越来越多地与厌恶刺激处理、学习和临床抑郁有关。然而，这个系统的电路和新发现的元件在系统中的关键作用仍然不完全了解。例如，新发现的rostromedial tetemental nucleus (RMTg)，一个gaba能的中脑区域，接收LHb输入并强烈地投射到DA神经元，其作用在很大程度上尚未被探索，尽管它的已知特性表明可能在抑郁现象中起核心作用。我们的建议使用一系列行为学和电生理学技术来解决关于这些habenulo-中脑回路的几个基本的突出问题，这些技术分为三个相关的目标。在目的1中，我们将检验与LHb的急性和慢性激活相关的生理和行为效应是通过LHb到RMTg的投射介导的假设。目的2将验证LHb和RMTg在两种不同的动物制剂中对人类抑郁症内表型模型的适应不良行为起关键作用的假设。本研究目的是利用损伤和刺激研究来描述这一通路在对厌恶和奖励刺激（绝望、快感缺乏）的抑郁相关反应中的重要性。最后，在目标3中，我们将验证抑郁症引起的LHb和RMTg放电模式的变化是抑郁症中行为和认知缺陷的基础。总的来说，这些研究调查了一个基本回路LHb-RMTg-VTA的失调，参与了对不良事件的不适应反应。从这些实验中获得的结果将强调NIMH研究领域标准（RDoC）的一个主要焦点，即基于跨诊断界限的神经生物学测量来定义精神障碍。大脑奖励系统的功能障碍对抑郁症、精神分裂症、双相情感障碍和药物滥用有明显的影响。鉴于越来越多的临床前和临床数据，这些研究具有明确的翻译相关性。

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.