A Synaptic Locus Controlling Behavioral Depression

描述（由申请人提供）：抑郁症是一种常见疾病，可导致人类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，治疗性干预在机制上还没有得到很好的理解，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，我提出了一个具体的假设，关于修改在一个突触在大脑奖励电路，可能有助于行为抑郁症。 最近的研究表明，当动物未能收到预期的积极奖励时，外侧缰核（LHb）中的神经元（一种调节前脑和中脑结构之间通信的核团）会增加它们的活动，即这些神经元提供“失望”信号。LHb神经元投射并调节多巴胺丰富的区域，如腹侧被盖区（VTA），其控制奖励寻求行为并参与抑郁症。我们的初步研究结果表明，在大鼠抑郁症模型中，与对照动物相比，腹侧被盖投射LHb神经元的兴奋性突触明显更强。 此外，抑制LHb神经元的传递缓解了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，异常增强兴奋性突触LHb神经元有助于抑郁症。因此，LHb中的这些神经元提供了一种异常强烈的“失望”信号，这导致了寻求奖励行为的减少，这是重度抑郁症的核心特征。我将结合联合收割机分子、细胞、遗传和行为技术，在啮齿动物抑郁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。我们在啮齿动物抑郁症模型中发现这些神经元上的突触过度兴奋。因此，减少这些突触的活动可能会减轻某些形式的重度抑郁症。

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.