Hippocampus, synaptic plasticity and anxiety vulnerability

描述(由申请人提供)： 焦虑症的风险因素在决定谁最终患上焦虑症方面很重要。然而，我们对风险因素的了解还很初级。确定危险因素的机制将是理解焦虑症病因的一步。海马体体积缩小、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焦虑的三个危险因素。海马体体积减小的危险因素与海马体依赖学习受损有关，这表明高危个体的海马体突触可塑性受损。脑源性神经营养因子在突触可塑性中起重要作用。因此，我们假设海马区突触可塑性受损可能是导致海马区体积减少和脑源性神经营养因子功能障碍的危险因素。Wistar京都(WKY)大鼠是一种近交系大鼠，它对应激敏感，与近交系Spraogue Dawley(SD)大鼠相比，海马体体积缩小，具有异常的BDNF系统，并表现出行为抑制。此外，与SD大鼠相比，WKY大鼠获得更多和更持久的主动回避。异常回避是所有焦虑症的核心特征，异常回避的发展与创伤后应激障碍的发展轨迹(C群)平行。因此，拟议的研究将测试在存在和不存在行为抑制气质的情况下，海马区突触可塑性受损是否有助于异常回避学习的发展。提出了四个目标。目的1确定BDNF诱导的WKY大鼠海马区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2研究作用于NMDA和BDNF-TrkB受体的药物对回避学习的影响。目的3将确定WKY大鼠海马区阿片依赖LTP是否受损。阿片依赖的LTP不需要NMDA或TrkB受体。目的4将研究作用于阿片受体的药物是否会影响异常回避反应的发展。由于阿片依赖的LTP不依赖NMDA和TrkB受体，阿片类LTP与NMDA-和BDNF-LTP的比较将确定异常回避的发生是否需要特定类型的LTP(即NMDA)的损害，或者海马区各种形式的LTP的损害是否会导致异常回避的发生。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开发治疗方法。这对退伍军人的健康尤其重要，因为相当多的退伍军人可能会因为与战斗服务相关的极端压力而患上与焦虑相关的障碍。

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.