Habenulomesencephalic pathway in aversion, reward and depression

描述(申请人提供)：难治性抑郁症是一种慢性、致残性和危及生命的疾病，影响多达30%被诊断为严重抑郁障碍的个人。对于这些患者，传统的药物治疗往往是无效的，脑深部刺激离散的大脑区域已经成为唯一可行的治疗选择之一。这类治疗的靶区之一是外侧缰核(LHb)，它是上皮层的一个组成部分，接受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部件在系统中的关键作用仍然没有完全被了解。例如，新发现的旋转内侧被盖核(RMTg)是GABA能的中脑区域，接受LHb输入并强烈投射到DA神经元，其作用在很大程度上尚未被探索，尽管已知的特性表明它可能在抑郁现象中发挥核心作用。我们的提案使用一系列行为和电生理技术解决了有关缰核-中脑回路的几个基本悬而未决的问题，这些技术被归类为三个相关的目标。在目标1中，我们将检验这一假设，即与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。目的2将检验这一假设，即LHb和RMTg在模拟人类抑郁症内表型的两种不同动物制剂中对不良适应行为起关键作用。这个目的是利用损伤和刺激研究来表征这一通路在抑郁症相关反应中的重要性，这些反应既包括厌恶刺激，也包括奖励刺激(绝望、快感丧失)。最后，在目标3中，我们将测试这一假设，即抑郁症引起的LHb和RMTG放电模式的变化是抑郁症行为和认知缺陷的基础。总体而言，这些研究调查了一个命题，即基础回路LHb-RMTg-VTA的失调与不良事件的适应反应有关。从这些实验中获得的结果将突出NIMH研究领域标准(RDoC)的一个主要重点，该标准基于跨越诊断边界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对抑郁症、精神分裂症、双相情感障碍和药物滥用也有明显的意义。鉴于临床前和临床数据日益趋同，这些研究具有明显的翻译相关性。

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.