Habenulomesencephalic pathway in aversion, reward and depression

缰核中脑通路在厌恶、奖赏和抑郁中的作用

• 批准号: 8617302
• 负责人: Gregory I Elmer
• 金额: $ 40.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617302
• 关键词: Acute; Address; Adult; Adverse event; Affect; Affective; American; Anhedonia; Animal Model; Animals; Area; Aversive Stimulus; Behavior; Behavioral; Bipolar Disorder; Brain; Brain region; Cell Nucleus; Cells; Chronic; Clinical Data; Cognitive; Cognitive deficits; Cues; Cutaneous; Deep Brain Stimulation; Depressed mood; Depressive disorder; Development; Diagnosis; Diagnostic; Disease; Dopamine; Drug abuse; Emotional; Endogenous depression; Epithalamic structure; Event; Frequencies; Functional disorder; Habenula; Human; Human Development; Incentives; Individual; Lateral; Learned Helplessness; Learning; Lesion; Life; Link; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mental disorders; Metabolism; Midbrain structure; Modeling; Motor; National Institute of Mental Health; Neurobiology; Neurons; Nociception; Nociceptive Stimulus; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Pharmacological Treatment; Physiological; Preparation; Process; Property; Psyche structure; Rattus; Research; Research Domain Criteria; Resistance; Rewards; Role; Schizophrenia; Source; Specific qualifier value; Sterile coverings; Stimulus; Stress; Sucrose; System; Techniques; Tegmentum Mesencephali; Testing; Time; base; depressive symptoms; design; dopaminergic neuron; endophenotype; in vivo; insight; pre-clinical; preference; programs; remediation; research study; response; sensory discrimination; stimulus processing; stressor

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.

描述（由申请人提供）：抗治疗抑郁症是一种慢性，残疾和威胁生命的疾病，影响了多达30％的被诊断患有重度抑郁症的人。对于这些患者而言，传统的药理治疗通常无效，并且对离散大脑区域的深度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Habenula（LHB），这是上皮的一个成分，它从情绪和运动系统中接收汇合的输入，强烈影响中脑多巴胺（DA）神经元的活动，并且越来越多地参与了厌恶性刺激处理，学习，学习，以及临床抑郁症。但是，该系统的电路以及系统中新发现的组件的关键作用尚未完全理解。例如，新近鉴定的鼻膜细胞核（RMTG）的作用是一种GABA能中脑区域，它在很大程度上尚未探索LHB输入和深入DA神经元的项目，尽管它已知的特性可能是抑郁现象中的主要核心作用。我们的建议使用一系列行为和电生理技术，解决了有关这些脑脑回路的几个基本问​​题，这些问题分为三个相关目标。在AIM 1中，我们将检验以下假设：LHB与LHB的急性和慢性激活相关的生理和行为效应是通过从LHB到RMTG的投影介导的。 AIM 2将检验以下假设：LHB和RMTG在两种截然不同的动物制剂中批判性地适应不良行为，以模拟人类抑郁型内表型。该目标使用病变和刺激研究来表征该途径在抑郁症相关的反应中对厌恶和有益的刺激的重要性（绝望，Anhedonia）。最后，在AIM 3中，我们将检验以下假设：抑郁症引起的LHB和RMTG射击模式的变化是抑郁症中的行为和认知缺陷的基础。总体而言，这些研究调查了以下主张：基本电路LHB-RMTG-VTA的失调参与对不良事件的不良适应反应。从这些实验中获得的结果将成为NIMH研究领域标准（RDOC）努力基于跨诊断界限的神经生物学指标来定义精神障碍的重点。大脑奖励系统功能障碍具有明显的抑郁症，精神分裂症，躁郁症和药物滥用。鉴于促进的临床前和临床数据的增长，这些研究具有明显的转化相关性。