A Late Sensitive Period for the Development of Anxiety Disorders

焦虑症发展的晚期敏感期

• 批准号: 7979939
• 负责人: Eduardo David Leonardo
• 金额: $ 40.32万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979939
• 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）：当前建议的目的是表征焦虑和情绪障碍的晚期敏感时期。 迄今为止的证据表明，在动物模型的后发育过程中，血清素能系统的破坏会导致焦虑和情绪与情绪相关的行为改变了成年动物。 特别是有证据表明，在产后第三周需要正确的信号传导5-HT1A受体，以开发介导焦虑的正常电路。 因此，此时发生的破坏可能导致异常电路的从头形成。 在当前的提案中，我们打算检验以下假设：在初始电路形成后也存在以后的敏感周期。 在我们的模型中，一旦形成了焦虑和抑郁行为的正常电路，就会有一个脆弱的时期，在此期间，电路仍然不稳定且容易受到破坏。 在此模型中，此时5 - HT1A信号的破坏通过异常成熟和已经形成的电路的异常成熟和稳定而导致异常电路。 提出的实验旨在定义晚期脆弱性的确切窗口。 我们将使用依赖于5-HT1A受体的可逆敲除的转基因小鼠方法来做到这一点。 此外，使用5-HT1A自动和异源受体的可逆敲除我们打算确定负责晚期窗口的特定受体群体。 公共卫生相关性：尤其是5-HT1A受体，通常与焦虑和抑郁症的病因和治疗有关。 对于5-HT1A受体，有模型系统的证据表明存在敏感周期，在此期间，正常的5-HT1A功能可能特别关键。 最近，在人类中，已经确定了影响5-HT1A受体表达水平的功能性多态性，从而增加了对压力和抑郁的敏感性。诸如该应用程序提出的研究可能会阐明这种关联的机制，并且可能指出，当治疗干预措施可能具有最大作用时，在发育中特别重要的时间。