Hippocampus, synaptic plasticity and anxiety vulnerability

海马、突触可塑性和焦虑脆弱性

• 批准号: 8967080
• 负责人: Kevin C.H. Pang
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967080
• 关键词: Accounting; Affect; Agonist; Anxiety; Anxiety Disorders; Attenuated; Avoidance Learning; Basic Science; Behavior; Behavioral inhibition; Brain; Cycloserine; Development; Disease; Effectiveness; Electric Stimulation; Environment; Etiology; Evoked Potentials; Functional disorder; General Population; Health; Hippocampus (Brain); Human; Impairment; Inbred Strain; Inbred WKY Rats; Individual; Knowledge; Lateral; Lead; Learning; Long-Term Potentiation; Medial; Medical; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurotrophic Tyrosine Kinase Receptor Type 2; Opioid; Opioid Receptor; Patients; Perforant Pathway; Pharmaceutical Preparations; Post-Traumatic Stress Disorders; Psychiatry; Psychopathology; Risk; Risk Factors; Services; Sprague-Dawley Rats; Stress; Synaptic plasticity; System; Temperament; Testing; Time; Training; Veterans; War; Work; anxiety-related disorders; base; brain dysfunction; brain volume; combat; cost; dentate gyrus; medical specialist; mu opioid receptors; neurotrophic factor; prevent; public health relevance; stressor; therapy development; treatment of anxiety disorders

DESCRIPTION (provided by applicant): Risk factors for anxiety disorder are important in determining who ultimately develops the disorder. However, our understanding of risk factors is rudimentary. Identification of the mechanisms of risk factors would be a step forward in understanding the etiology of anxiety disorders. Reduced hippocampal volume, dysfunction of the brain-derived neurotrophin factor (BDNF) system and behavioral inhibition temperament are three anxiety risk factors identified in humans. The risk factor of reduced hippocampal volume is associated with impaired hippocampal-dependent learning, suggesting impaired hippocampal synaptic plasticity in individuals at risk. BDNF is important for synaptic plasticity. Thus, we hypothesize that impaired hippocampal synaptic plasticity may underlie the risk factors of both reduced hippocampal volume and BDNF dysfunction. The Wistar Kyoto (WKY) rat is an inbred strain that is stress sensitive, has a reduced hippocampal volume compared to the outbred Sprague Dawley (SD) rat, has an abnormal BDNF system and expresses a behavioral inhibition. In addition, WKY rats acquire active avoidance to a greater and more persistent degree than SD rats. Abnormal avoidance is a core feature of all anxiety disorders, and the development of abnormal avoidance parallels the trajectory of PTSD (cluster C). Thus, the proposed studies will test whether impaired synaptic plasticity in the hippocampus contributes to the development of abnormal avoidance learning in the presence and absence of behavioral inhibition temperament. Four aims are proposed. Aim 1 will determine whether BDNF-induced synaptic plasticity is impaired in the hippocampus of WKY rats and if NMDA and BDNF agonists can attenuate these impairments. Aim 2 will investigate the effects of drugs acting on NMDA and BDNF-TrkB receptors on avoidance learning. Aim 3 will determine if opioid-dependent LTP in the hippocampus is impaired in WKY rats. Opioid-dependent LTP does not require NMDA or TrkB receptors. Aim 4 will investigate whether drugs acting on opioid receptors can affect the development of abnormal avoidance responding. Because opioid-dependent LTP is independent of NMDA and TrkB receptors, the comparison of opioid LTP to NMDA- and BDNF-LTP will determine whether the development of abnormal avoidance requires impairment of a specific type of LTP (i.e., NMDA) or if impairment to any of the various forms of LTP in the hippocampus can lead to the development of abnormal avoidance. The proposed studies will start to elucidate the mechanisms and interactions of three risk factors for anxiety disorders. Understanding the etiology of anxiety disorders and mechanisms of risk factors will help in the development of treatments. This is especially important to the health of veterans because a significant number of veterans are likely to develop anxiety-related disorders as a result of the extreme stress associated with combat service.

描述（由申请人提供）： 焦虑症的风险因素在决定谁最终发展为焦虑症方面很重要。然而，我们对风险因素的理解是初步的。确定危险因素的机制将是理解焦虑症病因的一个步骤。海马体积减少、脑源性神经营养因子（BDNF）系统功能障碍和行为抑制气质是人类中确定的三个焦虑风险因素。海马体积减小的危险因素与海马依赖性学习受损相关，提示高危个体海马突触可塑性受损。BDNF对突触可塑性很重要。因此，我们推测海马突触可塑性受损可能是海马体积减少和BDNF功能障碍的危险因素的基础。Wistar京都（WKY）大鼠是应激敏感的近交系，与远交的Sprague道利（SD）大鼠相比具有减小的海马体积，具有异常的BDNF系统并表达行为抑制。此外，WKY大鼠比SD大鼠获得更大和更持久程度的主动回避。异常回避是所有焦虑症的核心特征，异常回避的发展与PTSD的发展轨迹平行（聚类C）。因此，拟议的研究将测试是否受损的海马突触可塑性有助于发展异常回避学习的存在和不存在的行为抑制气质。提出了四个目标。目的1：研究BDNF诱导的WKY大鼠海马突触可塑性是否受损，以及NMDA和BDNF激动剂是否能减轻这些损伤。目的二研究NMDA和BDNF-TrkB受体药物对回避学习的影响。目的3将确定WKY大鼠海马中阿片依赖性LTP是否受损。阿片依赖性LTP不需要NMDA或TrkB受体。目的4探讨阿片受体药物是否影响异常回避反应的发生。因为阿片样物质依赖性LTP不依赖于NMDA和TrkB受体，所以阿片样物质LTP与NMDA-和BDNF-LTP的比较将确定异常回避的发展是否需要特定类型的LTP（即，NMDA）或海马中各种形式的LTP中的任何一种受损都可能导致异常回避的发展。拟议的研究将开始阐明焦虑症的三个危险因素的机制和相互作用。了解焦虑症的病因和危险因素的机制将有助于治疗的发展。这对退伍军人的健康特别重要，因为相当数量的退伍军人可能会由于与战斗服务相关的极端压力而发展出与焦虑相关的疾病。