Neural mechanisms of increased anxiety in serotonin 1A receptor-deficient mice

描述(由申请人提供)：目前的提案旨在了解焦虑症的神经生物学机制。进一步了解焦虑症仍然是一个关键的公共卫生目标，因为这些疾病在发病率和相关成本方面给社会带来了巨大的负担。来自人类和动物研究的数据表明，5-羟色胺系统，特别是一种特殊的5-羟色胺受体--1A受体(5-HT1AR)，与焦虑的产生和/或调节有关。激活5-HT1AR的药物，如5-羟色胺再摄取抑制剂或5-HT1AR激动剂，对人类和动物都是抗焦虑的。因此，5-HT1AR在发育过程中的基因缺失导致成年后焦虑样行为增加的强健表型。了解5-HT1AR缺乏导致焦虑相关行为增加的确切机制有望增加我们对焦虑的神经生物学的理解。我们最近发现，在5-HT1AR基因敲除小鼠中，有证据表明与焦虑相关的海马区活动增加，表现为theta振荡增加。这些数据与最近的研究结果一致，这些发现表明，腹侧海马区的损伤会增加焦虑。拟议的实验将检验由此产生的假设，即海马体活动增加解释了5-HT1AR缺陷小鼠焦虑增加的表型。特别是，我们将结合分子遗传和体内神经记录在行为小鼠，以解决三个关键问题。首先，我们将使用5-HT1AR的组织特异性表达来询问海马体受体是否足以逆转在基因敲除中看到的行为和生理表型。其次，在焦虑相关的任务中，我们将同时记录野生型和基因敲除小鼠的腹侧海马体和下游结构，以确定这些结构是否以及如何协调它们的活动。第三，我们将测试具体增加theta振荡是否必要且足以导致与焦虑相关的行为增加。解决这三个问题将澄清5-HT1AR缺乏导致焦虑增加的机制。此外，他们可能识别产生焦虑的特定神经区域的特定活动模式，为治疗干预提供新的功能靶点。公共卫生相关性这项建议本质上是翻译性质的，旨在阐明精神疾病的神经生物学基础。它的目的是识别与焦虑有关的大脑活动的特定模式。建立这样的关系将为一种旨在扰乱这些特定模式的抗焦虑疗法的新方法奠定基础。

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the neurobiological mechanisms underlying anxiety disorders. Furthering the understanding of anxiety disorders remains a key public health goal, as these disorders represent a large burden to society in morbidity and related costs. Data from human and animal studies implicate the serotonin system, and specifically one particular serotonin receptor, the 1A receptor (5-HT1AR), in the generation and/or regulation of anxiety. Agents which activate the 5-HT1AR, such as serotonin reuptake inhibitors or 5-HT1AR agonists, are anxiolytic both in humans and in animals. Accordingly, genetic deletion of the 5-HT1AR during development results in a robust adult phenotype of increased anxiety-like behavior. Understanding the precise mechanisms by which 5-HT1AR deficiency results in increased anxiety-related behavior promises to add to our understanding of the neurobiology of anxiety. We have recently found evidence of an anxiety-related increase in hippocampal activity, in the form of increased theta oscillations, in 5-HT1AR knockout mice. These data are in agreement with recent findings demonstrating that lesions of the ventral hippocampus increase anxiety. The proposed experiments will test the resulting hypothesis that the increased hippocampal activity accounts for the phenotype of increased anxiety in 5-HT1AR- deficient mice. In particular, we will combine molecular genetic and in vivo neural recordings in behaving mice to address three key questions. First, we will use tissue- specific expression of the 5-HT1AR to ask whether hippocampal receptors are sufficient to reverse the behavioral and physiological phenotypes seen in the knockouts. Second, we will record simultaneously from the ventral hippocampus and downstream structures in wild-type and knockout mice during anxiety-related tasks, to determine if and how these structures coordinate their activity. Third, we will test whether specifically increasing theta oscillations is necessary and sufficient to cause increased anxiety- related behavior. Addressing these three issues will clarify the mechanisms by which 5- HT1AR deficiency causes increased anxiety. Furthermore, they may identify specific patterns of activity in specific neural areas which generate anxiety, providing novel functional targets for therapeutic intervention. Public Health Relevance This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of brain activity which relate to anxiety. Establishing such relationships would set the stage for a novel approach to anxiolytic therapies, aimed at disrupting these specific patterns.