A Late Sensitive Period for the Development of Anxiety Disorders

描述（由申请人提供）：当前提案的目的是描述焦虑和情绪障碍发展的晚期敏感期。迄今为止的证据表明，在动物模型的出生后发育过程中，血清素能系统的破坏会导致成年动物焦虑和情绪相关行为的改变。特别是，有证据表明，在出生后第三周，通过5- HT1A受体的适当信号传导是调节焦虑的正常回路发育所必需的。因此，此时发生的中断可能导致异常电路的重新形成。在目前的提案中，我们打算测试在初始电路形成后也存在较晚敏感期的假设。在我们的模型中，一旦服务于焦虑和抑郁相关行为的正常回路形成，就会有一个脆弱期，在此期间，回路保持不稳定，容易受到干扰。在该模型中，此时5- HT1A信号的中断通过异常成熟和已经形成的电路的稳定导致异常电路。提出的实验旨在确定晚期漏洞的确切窗口。我们将使用一种转基因小鼠方法来做到这一点，这种方法依赖于5- HT1A受体的可逆敲除。此外，使用5- HT1A自身和异受体的可逆敲除，我们打算确定负责晚窗口的特定受体群体。

DESCRIPTION (provided by applicant): The aim of the current proposal is to characterize a late sensitive period for the development of anxiety and mood disorders. Evidence to date suggests that disruption of the serotonergic system during post--‐natal development in animal models results in altered anxiety and mood related behaviors in the full grown adult animal. In particular, there is evidence that proper signaling through 5--‐HT1A receptors is required in the third postnatal week for the development of normal circuits that mediate anxiety. Thus, disruptions of occurring at this time likely result in the de novo formation of aberrant circuits. In the current proposal, we intend to test the hypothesis that a later sensitive period also exists after the initial circuitry has formed. In our model, once normal circuitry that sub--‐serves anxiety and depression related behavior has formed, there is a vulnerable period during which time the circuits remain unstable and vulnerable to disruption. In this model, disruption of 5--‐HT1A signaling at this time results in aberrant circuitry through aberrant maturation and stabilization of the circuits that have already formed. The experiments proposed are aimed at defining the exact window of late vulnerability. We will do this using a transgenic mouse approach that relies on reversible knockouts of the 5--‐HT1A receptor. In addition, using reversible knockouts of 5--‐ HT1A auto and heteroreceptors, we intend to identify the specific population of receptors that is responsible for the late window.