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后期敏感期的特征。到目前为止的证据表明，动物模型出生后5-羟色胺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从头形成。在目前的方案中，我们打算检验这样一个假设，即在初始电路形成后，也存在较晚的敏感期。在我们的模型中，一旦为焦虑和抑郁相关行为提供服务的正常回路形成，就会有一个脆弱时期，在此期间回路仍然不稳定，容易受到干扰。在这个模型中，此时5-HT1a信号的中断会通过已经形成的电路的异常成熟和稳定而导致异常电路。建议的实验旨在定义后期漏洞的确切窗口。我们将使用转基因小鼠的方法来实现这一点，这种方法依赖于5-HT1a受体的可逆敲除。此外，利用5--HT1a自身和异源受体的可逆敲除，我们打算识别导致窗口延迟的特定受体群体。 公共卫生相关性：5-HT1a受体特别是5-羟色胺能系统通常与焦虑和抑郁障碍的病因和治疗有关。对于5-HT1a受体，模型系统有证据表明存在敏感期，在此期间正常的5-HT1a功能可能是特别关键的。最近，在人类中发现了一种影响5-HT1A受体表达水平的功能多态性，它会增加对应激和抑郁的易感性。像这项申请中提出的研究可能会阐明这种联系的机制，并可能指出治疗干预可能产生最大效果的发展过程中特别重要的时期。

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.