Anxiety development in 5-HT1A autoreceptor knockout mice, interaction with stress

5-HT1A 自身受体敲除小鼠的焦虑发展、与压力的相互作用

• 批准号: 7938760
• 负责人: SHERYL G BECK
• 金额: $ 47.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938760
• 关键词: ARHGEF5 gene; Acute; Address; Adult; Affect; Age; Age of Onset; Animal Model; Anxiety; Anxiety Disorders; Area; Arousal; Attention; Autoreceptors; Behavior; Behavioral; Behavioral Genetics; Behavioral Paradigm; Brain; Brain Part; Categories; Characteristics; Cognitive; Conflict (Psychology); Cues; Data; Development; Developmental Process; Discipline; Disease; Distant; Down-Regulation; Early treatment; Electrophysiology (science); Environment; Environmental Impact; Epidemiology; Etiology; Event; Fright; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Programming; Genetic Risk; Genetic Variation; Genotype; Goals; Heterozygote; Human; Individual; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Life; Measures; Mediating; Mental Depression; Mental disorders; Modeling; Modification; Monoamine Oxidase A; Morbidity - disease rate; Mus; Mutation; Nervous system structure; Neurons; Organism; Pathway interactions; Phenotype; Physiology; Population; Psychiatry; Public Health; Publications; Readiness; Research; Risk; Sampling; Serotonin; Serotonin Receptor 5-HT1A; Shapes; Stress; Structure; System; Techniques; Testing; Time; Translational Research; United States; anti social; base; conditioned fear; cost; critical developmental period; critical period; early onset; environmental stressor; gene environment interaction; maltreatment; mortality; neural circuit; postnatal; prevent; programs; public health relevance; raphe nuclei; receptor; research study; response; restraint stress; stressor; therapeutic target; trait; vigilance

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science, Gene x environment x development (GxExD) studies of brain function and mental disorders. Gene x environment epidemiology and psychiatry research studies have only recently been used and the findings of these studies have come into the limelight of the etiology of psychiatric disorders. Most research does not combine the examination of all three factors, i.e., genes, environment and development, but usually includes the examination of gene x environment, gene x development, or development x environment, often producing inconsistent findings. In many cases the genetic disposition is understood and development in terms of how it influences brain structure, but how the environment alters brain function to interact with the genetic and development factors is unknown. The challenge, then is to determine how the genetic predisposition, development of the relevant neural circuitry of the nervous system and the environment interact to alter brain function to produce the psychiatric disorder. In this application, using an animal model, we propose to examine all three factors using genetic, behavioral, electrophysiological and morphological/anatomical techniques. The disorder under investigation is anxiety. Anxiety can be defined as a state of cognitive and behavioral preparedness that an organism mobilizes in response to a future or distant potential threat. In its non-pathological form anxiety can be divided into two categories: 1) state anxiety, which is an acute adaptive response of heightened vigilance and arousal that enables an organism to navigate an unfamiliar environment of unknown danger, and 2) trait anxiety which is a measure of an individual's baseline reactivity or tendency to generate anxious responses. In its pathological form, anxiety is a maladaptive state that impairs the ability of an organism to respond optimally to its environment. Anxiety disorders are highly prevalent and are associated with high levels of morbidity and mortality as well as high cost. It is estimated that anxiety disorders may affect up to 20% of the population at some point in their lifetime with an annual estimated cost of $44 billion dollars in the United States alone. The mean age of onset for an anxiety disorder is 11. This early onset is consistent with the finding that individual levels of trait anxiety are established at an early age and are fairly constant over a lifetime. Thus, both trait anxiety and anxiety disorders are likely to be determined by early developmental processes or events that affect the way an individual's brain is "wired". Prior to the publication of landmark studies like those by Caspi et al demonstrating how early maltreatment interacts with the monoamine oxidase A genotype to yield antisocial behavior and how the 5-HTT transporter interacts with adverse early adult events to increase risk of depression, our understanding of how early environmental conditions might differentially impact the expression of underlying genetic risk had been limited, as these two fields of inquiry had been the purvey of two separate disciplines, i.e., genetic and epidemiological. Neither approach alone is capable of providing a full explanation of the environmental and genetic contributions to behavior. This is because genes do not generate behaviors directly. Rather, they act in developmental pathways that first generate neurons and then circuits and finally systems that mediate behavioral responses. The genetic program therefore unfolds in a predictable manner that samples the surrounding environment and is in turn shaped by it. In such a model, one would predict that the effect of any given environment will depend on the developmental program that is unfolding at the time. Thus, gene x environment interactions are perhaps more appropriately conceived of as gene x environment x development, with some time periods being more susceptible to environmental manipulation than others. We will test this hypothesis with the use of a genetically manipulated animal model, the 5-HT1A autoreceptor KO mouse, to determine the critical period for its influence on the serotonergic raphe nuclei in producing anxiety and the potential impact of environmental stress to amplify the genetic effect. PUBLIC HEALTH RELEVANCE: Recently attention has been focused on how genetic variation interacts with the environment and development. The goal of the proposed research is to determine how lack of the 5-HT1A receptor interacts with the development of a crucial neural circuit of the raphe and an environmental stressor. This research is relevant to public health because knowledge of the early neurodevelopmental modifications that lead to the future occurrence of anxiety/depression will define therapeutic targets for early intervention which may prevent the development of mental illness in adulthood.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）转化科学，基因X环境X开发（GXEXD）对脑功能和精神障碍的研究。基因X环境流行病学和精神病学研究直到最近才被最近使用，这些研究的发现才成为精神疾病病因的焦点。大多数研究并未结合所有三个因素的检查，即基因，环境和发展，但通常包括对基因X环境，基因X开发或开发X环境的检查，通常会产生不一致的发现。在许多情况下，从遗传处理方面就可以理解和发展，从它如何影响大脑结构方面，但是环境如何改变脑功能与遗传和发育因素相互作用是未知的。然后，挑战是确定遗传倾向，神经系统的相关神经回路的发展以及环境如何相互作用以改变大脑功能以产生精神障碍。在此应用中，使用动物模型，我们建议使用遗传，行为，电生理学和形态/解剖技术检查所有三个因素。正在研究的疾病是焦虑。焦虑可以定义为一种认知和行为准备的状态，该状态是生物体响应未来或遥远的潜在威胁而动员的。在其非病理形式的焦虑中可以分为两类：1）状态焦虑，这是警惕和唤醒的急性适应性反应，使有机体能够驾驭陌生的危险环境，而2）特质焦虑是）衡量个人基线反应性或产生焦虑反应的趋势。焦虑是一种不良适应状态，可损害生物体对环境最佳反应的能力。焦虑症高度流行，与高水平的发病率和高昂的成本有关。据估计，焦虑症在其一生中的某个时候可能会影响多达20％的人口，仅在美国，估计估计成本为440亿美元。焦虑症的平均发作年龄为11。这种早期发作与发现各个特质焦虑的发现是在幼年时期建立的，并且在一生中相当恒定。因此，特质焦虑和焦虑症都可能取决于影响个人大脑“有线”方式的早期发育过程或事件。在发布地标研究（如Caspi等人）之前早期环境条件如何差异化影响潜在遗传风险的表达受到限制，因为这两个探究领域是两个单独的学科的验证，即遗传和流行病学。这两种方法都不能单独提供对环境和遗传行为贡献的完整解释。这是因为基因不会直接产生行为。相反，它们在发育途径中的作用，该途径首先产生神经元，然后是介导行为反应的系统。因此，遗传程序以可预测的方式展开，该方式可以采样周围环境，而其又是由其塑造的。在这样的模型中，人们会预测，任何给定环境的效果都将取决于当时正在展开的发展计划。因此，基因X环境相互作用可能更适当地认为是基因X环境X的发展，而某些时间段比其他时间更容易受到环境操纵的影响。我们将通过使用遗传操纵的动物模型，5-HT1A自身受体KO小鼠来检验该假设影响。 公共卫生相关性：最近关注遗传变异如何与环境和发展相互作用。拟议的研究的目的是确定缺乏5-HT1A受体如何与Raphe和环境压力源的关键神经回路的发展相互作用。这项研究与公共卫生有关，因为了解导致焦虑/抑郁症未来发生的早期神经发育修饰的知识将定义早期干预的治疗靶标，这可能会阻止成年后精神疾病的发展。