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

血清素 1A 受体缺陷小鼠焦虑增加的神经机制

• 批准号: 8098690
• 负责人: Joshua A Gordon
• 金额: $ 35.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098690
• 关键词: Accounting; Address; Adult; Agonist; Agreement; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Apical; Area; Behavior; Behavioral; Biological Assay; Brain; Clinical; Data; Dendrites; Dependence; Development; Disease; Dorsal; Emotional; Fright; Generations; Genetic; Genetic Recombination; Goals; Hippocampus (Brain); Human; Image; Knock-out; Knockout Mice; Learning; Lesion; Medial; Mediating; Mental disorders; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Nature; Neurobiology; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Play; Prefrontal Cortex; Property; Public Health; Regulation; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Societies; Staging; Structure; Structure of terminal stria nuclei of preoptic region; System; Techniques; Test Result; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Work; behavior test; cost; hippocampal pyramidal neuron; human data; in vivo; innovation; interest; neural patterning; neurobiological mechanism; neuromechanism; neurophysiology; novel; novel strategies; pre-clinical; public health relevance; receptor; receptor expression; relating to nervous system; research study

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.

描述（由申请人提供）：当前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费用方面给社会带来了巨大负担。来自人类和动物研究的数据表明，血清素系统，特别是一种特定的血清素受体，即 1A 受体 (5-HT1AR)，与焦虑的产生和/或调节有关。激活 5-HT1AR 的药物，例如血清素再摄取抑制剂或 5-HT1AR 激动剂，对人类和动物都具有抗焦虑作用。因此，发育过程中 5-HT1AR 的基因缺失会导致成年后焦虑样行为增加的强烈表型。了解 5-HT1AR 缺乏导致焦虑相关行为增加的精确机制有望增进我们对焦虑神经生物学的理解。我们最近在 5-HT1AR 基因敲除小鼠中发现了与焦虑相关的海马活动增加的证据，其形式是 θ 振荡增加。这些数据与最近的研究结果一致，表明腹侧海马体的病变会增加焦虑。拟议的实验将检验由此产生的假设，即海马活动增加是 5-HT1AR 缺陷小鼠焦虑增加表型的原因。特别是，我们将结合行为小鼠的分子遗传学和体内神经记录来解决三个关键问题。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，我们将同时记录野生型和基因敲除小鼠在焦虑相关任务期间的腹侧海马和下游结构，以确定这些结构是否以及如何协调其活动。第三，我们将测试专门增加 θ 振荡是否必要且足以导致焦虑相关行为增加。解决这三个问题将阐明 5-HT1AR 缺乏导致焦虑增加的机制。此外，他们可以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目标。公共卫生相关性 该提案本质上是转化性的，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相关的大脑活动的特定模式。建立这种关系将为一种新的抗焦虑疗法奠定基础，旨在破坏这些特定模式。