A Synaptic Locus Controlling Behavioral Depression

控制行为抑郁的突触位点

• 批准号: 8105891
• 负责人: ROBERTO MALINOW
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-12 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105891
• 关键词: Agreement; Amygdaloid structure; Animals; Antidepressive Agents; Attention; Behavior; Behavior Control; Behavioral; Behavioral Genetics; Brain; Brain Part; Brain region; Calcium; Calcium Channel; Cell Nucleus; Cell model; Chemosensitization; Communication; Control Animal; Control Locus; Cyclic AMP-Dependent Protein Kinases; Data; Depressed mood; Depressive disorder; Disease; Dopamine; Excitatory Synapse; Frequencies; Habenula; Human; Individual; Lateral; Learning; Major Depressive Disorder; Medial; Mediating; Memory; Mental Depression; Midbrain structure; Minority; Modeling; Modification; Molecular; Monkeys; Morbidity - disease rate; Neurons; Output; Positioning Attribute; Prosencephalon; Protein Kinase C; Rattus; Rewards; Rodent Model; Role; Serotonin; Signal Transduction; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic Intervention; Training; Ventral Tegmental Area; Viral; base; conditioned fear; depressive symptoms; dorsal raphe nucleus; effective therapy; gamma-Aminobutyric Acid; monoamine; mortality; neuromechanism; novel; postsynaptic; presynaptic; relating to nervous system; transmission process

DESCRIPTION (provided by applicant): Depression is a common disease that causes significant morbidity and mortality in humans. There is currently a poor understanding regarding the underlying molecular, cellular or circuit mechanisms. Presently, therapeutic intervention is not well understood mechanistically and often unsuccessful. It is important to derive a mechanistic understand of depressive disorders so that effective treatment can be developed. In this project, based on considerable preliminary data, I propose a specific hypothesis regarding modification at a synapse in the brain reward circuit that may contribute to behavioral depression. Recent studies show that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, increase their activity when an animal fails to receive an expected positive reward, i.e. these neurons provide a 'disappointment' signal. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA), which control reward-seeking behavior and participate in depressive disorders. Our preliminary results show that excitatory synapses onto VTA-projecting LHb neurons are about significantly stronger in rat models of depression compared to control animals. Furthermore, suppression of transmission onto LHb neurons relieves depressive-like behaviors in rodent models of depression. Thus, our central hypothesis is that aberrantly potentiated excitatory synapses onto LHb neurons contribute to depression. These neurons in the LHb thus provide an abnormally strong 'disappointment' signal, which leads to reduced reward-seeking behavior, a core feature of major depression. I will combine molecular, cellular, genetic and behavioral techniques to test this hypothesis in rodent models of depression. PUBLIC HEALTH RELEVANCE: Neurons in the lateral habenula provide 'disappointment' signals in the brain. We have found overactive excitation by synapses onto these neurons in rodent models of depression. Thus, reducing activity of these synapses may alleviate some forms of major depressive disorders.

描述（由申请人提供）：抑郁症是一种常见疾病，导致人类显着发病和死亡。目前对潜在的分子、细胞或电路机制了解甚少。目前，治疗干预的机制尚不清楚，而且常常不成功。对抑郁症有一个机制上的了解非常重要，这样才能开发出有效的治疗方法。在这个项目中，基于大量的初步数据，我提出了一个关于大脑奖励回路中可能导致行为抑郁的突触修饰的具体假设。 最近的研究表明，当动物未能获得预期的积极奖励时，外侧缰核（LHb）中的神经元（一种介导前脑和中脑结构之间沟通的核）会增加其活动，即这些神经元会提供“失望”信号。 LHb 神经元投射并调节富含多巴胺的区域，例如腹侧被盖区 (VTA)，该区域控制寻求奖励的行为并参与抑郁症。我们的初步结果表明，与对照动物相比，抑郁症大鼠模型中 VTA 投射的 LHb 神经元上的兴奋性突触明显更强。 此外，抑制 LHb 神经元的传输可以缓解抑郁症啮齿动物模型中的抑郁样行为。因此，我们的中心假设是，LHb 神经元上异常增强的兴奋性突触会导致抑郁。因此，LHb 中的这些神经元会提供异常强烈的“失望”信号，从而导致寻求奖励行为的减少，而寻求奖励的行为是重度抑郁症的核心特征。我将结合分子、细胞、遗传和行为技术，在抑郁症啮齿动物模型中检验这一假设。 公共卫生相关性：外侧缰核中的神经元在大脑中提供“失望”信号。我们发现在抑郁症啮齿动物模型中，这些神经元的突触过度活跃。因此，减少这些突触的活动可能会缓解某些形式的重度抑郁症。