A Late Sensitive Period for the Development of Anxiety Disorders

焦虑症发展的晚期敏感期

• 批准号: 8124905
• 负责人: Eduardo David Leonardo
• 金额: $ 39.8万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124905
• 关键词: Adolescent; Adult; Affect; Age; Animal Model; Anxiety; Anxiety Disorders; Attention; Autoreceptors; Behavior; Behavioral Paradigm; Biological Models; Conflict (Psychology); Data; Depressive disorder; Development; Developmental Process; Etiology; G-Protein-Coupled Receptors; Genetic; Genetic Polymorphism; Goals; Human; Knock-out; Knockout Mice; Life; Light; Maintenance; Maps; Mediating; Mental Depression; Modeling; Mood Disorders; Moods; Mus; Nervous system structure; Neurons; Phenotype; Physiology; Plastics; Population; Predisposition; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Stress; System; Testing; Therapeutic Intervention; Time; Transgenic Mice; Wild Type Mouse; base; critical period; mature animal; novel; postnatal; public health relevance; raphe nuclei; receptor; receptor expression; receptor function; research study; response

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.

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，动物模型产后发育过程中血清素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，需要通过 5--HT1A 受体发出适当的信号，以形成介导焦虑的正常回路。 因此，此时发生的中断可能导致异常电路的从头形成。 在当前的提案中，我们打算测试以下假设：在初始电路形成后还存在后期敏感期。 在我们的模型中，一旦形成了服务于焦虑和抑郁相关行为的正常回路，就会出现一个脆弱期，在此期间，回路保持不稳定且容易受到干扰。 在此模型中，此时 5--HT1A 信号传导的破坏会通过已形成的电路的异常成熟和稳定而导致异常电路。 所提出的实验旨在确定晚期脆弱性的确切窗口。 我们将使用依赖于 5--HT1A 受体可逆敲除的转基因小鼠方法来做到这一点。 此外，利用 5-HT1A 自身和异质受体的可逆敲除，我们打算识别负责晚期窗口的特定受体群体。 公共卫生相关性：特别是 5-HT1A 受体和一般血清素能系统与焦虑和抑郁症的病因和治疗有关。 对于 5-HT1A 受体，来自模型系统的证据表明存在敏感期，在此期间正常的 5-HT1A 功能可能特别关键。 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，该多态性会增加对压力和抑郁的易感性。诸如本申请提出的研究之类的研究可能会阐明这种关联的机制，并可能指出治疗干预可能产生最大效果的发展中特别重要的时间。