A Synaptic Locus Controlling Behavioral Depression

描述(由申请人提供)：抑郁症是一种常见的疾病，在人类中会导致显著的发病率和死亡率。目前对其潜在的分子、细胞或电路机制了解甚少。目前，治疗性干预的机制还不是很清楚，而且往往不成功。重要的是要从机制上理解抑郁症，以便开发有效的治疗方法。在这个项目中，基于相当多的初步数据，我提出了一个关于大脑奖励回路中突触的修饰可能导致行为抑郁的具体假设。最近的研究表明，当动物未能获得预期的积极奖赏时，外侧缰核(LHb)中的神经元会增加活动，即这些神经元提供“失望”信号。外侧缰核是前脑和中脑结构之间的媒介。LHB神经元投射并调节多巴胺丰富的区域，如腹侧被盖区(VTA)，这些区域控制着追求奖励的行为，并参与抑郁障碍。我们的初步结果表明，与对照动物相比，抑郁症大鼠模型中向VTA投射的LHb神经元的兴奋性突触明显增强。此外，抑制向LHb神经元的传递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神经元上兴奋性突触的异常增强导致了抑郁。因此，LHb中的这些神经元提供了异常强烈的“失望”信号，这导致了寻求奖励行为的减少，这是严重抑郁症的一个核心特征。我将结合分子、细胞、遗传和行为技术，在抑郁症的啮齿动物模型中测试这一假设。

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.