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

基本信息

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
项目类别：
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

项目摘要

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）：当前的建议旨在了解焦虑症的神经生物学机制。促进对焦虑症的理解仍然是一个关键的公共卫生目标，因为这些疾病代表了社会在发病率和相关成本方面的巨大负担。来自人类和动物研究的数据暗示了5-羟色胺系统，特别是一种特定的5-羟色胺受体1A受体（5-HT1AR），在焦虑的产生和/或调节中。激活5-HT1AR的药物，例如5-羟色胺再摄取抑制剂或5-HT1AR激动剂，在人类和动物中都是抗焦虑药。因此，在发育过程中，5-HT1AR的遗传缺失导致焦虑样行为增加的稳健成人表型。了解5-HT1AR缺乏导致与焦虑相关的行为增加的确切机制有望增加我们对焦虑神经生物学的理解。我们最近发现，在5-HT1AR敲除小鼠中，海马活动与theta振荡的形式增加的证据相关。这些数据与最近的发现一致，表明腹侧海马病变会增加焦虑症。提出的实验将测试由此产生的假设，即增加的海马活性构成了5-HT1AR缺乏小鼠焦虑症的表型。特别是，我们将在行为小鼠中结合分子遗传和体内神经记录，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受体是否足以逆转敲除中的行为和生理表型。其次，我们将在与焦虑相关的任务中同时记录野生型和敲除小鼠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性。第三，我们将测试是否需要专门增加theta振荡是必要的，并且足以引起与焦虑相关的行为的增加。解决这三个问题将阐明5- HT1AR缺乏会导致焦虑增加的机制。此外，他们可以在特定的神经区域中确定特定的活动模式，这些神经区域引起焦虑，为治疗干预提供了新的功能靶标。公共卫生相关性本质本质上是自然翻译的，旨在阐明精神病的神经生物学基质。它旨在确定与焦虑有关的大脑活动的特定模式。建立这种关系将为抗焦虑疗法的新方法奠定基础，旨在破坏这些特定模式。