A Late Sensitive Period for the Development of Anxiety Disorders

描述（由申请人提供）：当前提案的目的是表征焦虑和情绪障碍发展的晚期敏感期。 迄今为止的证据表明，在动物模型中，在纳塔尔后发育过程中干扰多巴胺能系统导致完全成年动物的焦虑和情绪相关行为改变。 特别是，有证据表明，通过5-HT 1A受体的适当信号是必要的，在出生后第三周的正常电路的发展，调解焦虑。 因此，此时发生的中断可能导致异常回路的重新形成。 在目前的建议中，我们打算测试的假设，一个较晚的敏感期也存在后，最初的电路已经形成。 在我们的模型中，一旦形成了辅助焦虑和抑郁相关行为的正常回路，就会有一个脆弱的时期，在此期间，回路保持不稳定，容易受到破坏。 在该模型中，此时5-HT 1A信号传导的中断通过已经形成的回路的异常成熟和稳定而导致异常回路。 所提出的实验的目的是定义确切的窗口晚脆弱性。 我们将使用转基因小鼠的方法来实现这一点，该方法依赖于5-HT 1A受体的可逆敲除。 此外，使用5-HT 1A自身和异源受体的可逆敲除，我们打算鉴定负责晚期窗口的特定受体群体。 公共卫生相关性：特别是5-HT 1A受体和肾上腺素能系统通常与焦虑和抑郁障碍的病因学和治疗有关。 对于5-HT 1A受体，有来自模型系统的证据表明存在敏感期，在此期间正常的5-HT 1A功能可能特别关键。 最近，在人类中，影响5-HT 1A受体表达水平的功能多态性已被确定为增加对压力和抑郁症的易感性。诸如与本申请一起提出的研究可能揭示这种关联的机制，并且可能指出治疗干预可能具有最大效果的开发中特别重要的时间。

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. PUBLIC HEALTH RELEVANCE: The 5-HT1A receptor in particular and the serotonergic system in general has been implicated in both the etiology and treatment of anxiety and depressive disorders. For the 5-HT1A receptor there is evidence from model systems that sensitive periods exist during which normal 5-HT1A function may be particulary critical. Recently, in humans a functional polymorphism that affects 5-HT1A receptor expression levels has been identified that increases susceptibility to stress and depression. Studies such as the ones proposed with this application may shed light on the mechanism of this association and may point to particularly important time in development when therapeutic interventions could have maximal effect.