A Synaptic Locus Controlling Behavioral Depression

描述（由申请人提供）：抑郁症是一种常见疾病，在人类中引起显著的发病率和死亡率。目前对潜在的分子、细胞或电路机制的理解很差。目前，治疗干预的机制还不清楚，而且往往不成功。重要的是要从机制上理解抑郁症，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，我提出了一个具体的假设，关于大脑奖励回路中突触的改变可能导致行为抑郁。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（一种调解前脑和中脑结构之间交流的核）的活动增加，即这些神经元提供“失望”信号。LHb神经元投射并调节富含多巴胺的区域，如腹侧被盖区（VTA），该区域控制寻求奖励行为并参与抑郁症。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 - LHb神经元上的兴奋性突触明显更强。此外，抑制传递到LHb神经元可以减轻啮齿动物抑郁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导致抑郁。因此，LHb中的这些神经元提供异常强烈的“失望”信号，导致寻求奖励行为减少，这是重度抑郁症的核心特征。我将结合分子、细胞、基因和行为技术，在啮齿动物抑郁症模型中验证这一假设。

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.