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，对于潜在的分子、细胞或电路机制尚不清楚。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。参与奖励系统的大脑部分的异常被认为起到了重要作用。外侧缰核(LHb)是奖赏回路的重要组成部分，提供“奖赏预测误差”信号：当一只动物收到的奖赏低于预期(即失望)或预期惩罚(即预期会有不好的事情)时，LHb是活跃的，这一信息通常被用来塑造未来的行为，以最大化奖赏和避免不愉快的事件。LHb过度活跃的人预计会很容易或持续感到失望，并通常预期会出现糟糕的结果。因此，许多对人类和啮齿动物的研究表明，LHb的过度活动导致了严重的抑郁症，这也就不足为奇了。这项资助建议研究LHb中的信息是如何在正常啮齿动物中处理的，并通过与抑郁有关的操作进行修改。

 DESCRIPTION (provided by applicant): Depression is a common disease that causes significant morbidity and mortality in humans. There is currently no clarity 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. Abnormalities in parts of the brain that participate in the reward system are thought to play important roles. The lateral habenula (LHb) is an important part of the reward circuit by providing `reward prediction error' signals: when an animal receives a reward that is less than expected (i.e. is disappointed) or anticipates punishment (i.e. expects something bad), the LHb is active, and this information is thought normally to be used to shape future behavior to maximize reward and avoid unpleasant events. An individual with overly active LHb would be expected to be easily or continually disappointed and generally expect bad outcomes. It is therefore not a surprise that a number of studies in humans and rodents indicate that excessive activity in the LHb contributes to major depression. This grant proposes to examine how information in the LHb is processed in normal rodents, and modified by manipulations related to depression.