Impaired attention & hippocampal dysfunction in developing abnormal avoidance

描述(由申请人提供)： 选择性注意力受损可能是患上创伤后应激障碍(PTSD)、广泛性焦虑症、恐慌症和恐惧症等焦虑症的风险因素。对双胞胎的研究证实，海马体体积小于正常是创伤后应激障碍的危险因素。随后的研究表明，较小的体积与海马体依赖学习任务中的损害有关，这表明体积差异反映了功能障碍。最后，动物的海马体损伤会导致选择性注意力受损。目前的建议将调查海马区功能障碍、注意力障碍和异常回避的发展之间的关系。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是平行的。因此，了解导致异常回避的神经生物学机制将促进我们对所有焦虑症的核心特征的了解。这项研究的假设是，注意力受损会导致异常回避的发展。注意力障碍的一个因素是海马体功能障碍。这组拟议的研究将利用动物模型来检查海马体在注意力和回避方面的影响。提出了三个目标。目的1确定SD大鼠海马区的损伤是否会损害注意力，导致异常回避的发生。目标2将调查Wistar京都(WKY)大鼠的海马体是否功能不正常。这种大鼠品系对压力敏感，具有高度的惊吓和行为抑制特征，表现出选择性注意障碍，并出现异常回避。这一目标的研究将确定WKY大鼠的海马区功能障碍是否可以解释注意障碍和异常回避。目的3评价抗精神病药物氟哌啶醇能否恢复SD大鼠和WKY大鼠的注意力，防止异常回避的发生。建议的研究将提供有关注意力受损、海马体功能障碍和异常回避发展之间的关系的重要知识。这些信息将为风险因素导致焦虑症的方式提供新的见解，并可能指出预防焦虑症的新途径。这一问题对退伍军人的健康尤其重要，因为有相当数量的退伍军人可能会因为与战斗服役相关的极端压力而患上焦虑症。 公共卫生相关性： 虽然军事人员可能与非军事人员类似，有焦虑症的脆弱性和易感性，但部署、战争和战时服役的极端和持续的应激源增加了患焦虑症的可能性。事实上，据估计，退伍军人患焦虑症的比例是普通人群的4倍。因此，焦虑症是退伍军人管理局医疗和精神病学服务的主要重点。基础科学研究侧重于对脆弱因素如何与压力相互作用的机械描述，有可能有助于理解创伤后应激障碍和其他焦虑症的病因学基础。这项研究的成功将为开发预防性程序和确定药物治疗的目标提供机会，从而为退伍军人管理局节省大量成本，并使医疗专家能够将精力集中在较少的患者身上。

DESCRIPTION (provided by applicant): Impaired selective attention may be a risk factor for developing anxiety disorders such as post- traumatic stress disorder (PTSD), general anxiety disorder, panic attack and phobias. Studies in twins have identified that a smaller than normal hippocampal volume is risk factor for PTSD. Subsequent studies demonstrated that the smaller volume is associated with impairments in hippocampal dependent learning tasks, suggesting the volumetric difference reflects a functional dysfunction. Finally, hippocampal damage in animals results in impaired selective attention. The current proposal will investigate the relationship between hippocampal dysfunction, attention impairment, and the development of abnormal avoidance. Abnormal avoidance is a core feature of all anxiety disorders, and the development of abnormal avoidance parallels the trajectory of PTSD. Thus, understanding the neurobiological mechanisms leading to abnormal avoidance will advance our knowledge of a core feature of all anxiety disorders. The hypothesis of the proposed studies is that impairment of attention leads to the development of abnormal avoidance. A contributing factor in the attention impairment is a hippocampal dysfunction. The proposed set of studies will utilize animal models to examine the influence of the hippocampus in attention and avoidance. Three aims are proposed. Aim 1 will determine the whether damage to the hippocampal system of Sprague Dawley (SD) rats can impair attention and cause the development of abnormal avoidance. Aim 2 will investigate whether the hippocampus is functioning improperly in Wistar Kyoto (WKY) rats. This rat strain is stress sensitive, has elevated startle and behavioral inhibition traits, demonstrates selective attention impairment and develops abnormal avoidance. Studies in this aim will determine whether hippocampal dysfunction in WKY rats could account for the attention impairment and abnormal avoidance. Aim 3 will assess whether the antipsychotic drug haloperidol can restore attention and prevent the development of abnormal avoidance in SD with hippocampal dysfunction and in WKY rats. The proposed studies will provide important knowledge concerning the relationship between impaired attention, hippocampal dysfunction and the development of abnormal avoidance. This information will provide new insights into the manner in which risk factors contribute to anxiety disorders and may point to new avenues in the prevention of anxiety disorders. This issue 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. PUBLIC HEALTH RELEVANCE: Although military personnel may have vulnerabilities and susceptibilities for anxiety disorders similar to the non-military population, the extreme and constant stressors of deployment, war and war time service enhance the likelihood of developing anxiety disorders. In fact, the rates of veterans developing anxiety disorders have been estimated to be 4 times higher than the general population. Accordingly, anxiety disorders are a major focus for VA medical and psychiatry services. Basic science research focused on a mechanistic account of how vulnerability factors interact with stress has the potential to contribute to an understanding of the etiological basis of PTSD and other anxiety disorders. The success of this research will provide the opportunity to develop preventative procedures and identify targets for pharmacological treatments, resulting in significant cost saving to the VA and allowing medical specialists to concentrate their efforts on fewer patients.