Impaired attention & hippocampal dysfunction in developing abnormal avoidance

注意力受损

• 批准号: 8262608
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262608
• 关键词: Accounting; Affect; Animal Model; Animals; Antipsychotic Agents; Anxiety; Anxiety Disorders; Attention; Avoidance Learning; Basic Science; Behavioral inhibition; Blinking; Cells; Cues; Development; Disease; Event; Exposure to; Functional disorder; General Population; Goals; Haloperidol; Health; Hippocampus (Brain); Ibotenic Acid; Impairment; Inbred WKY Rats; Individual; Knowledge; Lead; Learning; Measures; Medial; Medical; Memory; Military Personnel; Modeling; Neonatal; Obsessive-Compulsive Disorder; Panic Attack; Patients; Persons; Pharmacological Treatment; Phobic anxiety disorder; Population; Post-Traumatic Stress Disorders; Predisposition; Prevention; Procedures; Process; Psychiatry; Psychopathology; Rat Strains; Reporting; Research; Risk Factors; Services; Shock; Sprague-Dawley Rats; Stimulus; Stress; System; Time; Twin Multiple Birth; Veterans; Vulnerable Populations; War; avoidance behavior; base; combat; conditioning; cost; entorhinal cortex; experience; insight; medical specialist; neurobiological mechanism; prevent; public health relevance; response; selective attention; stressor; success; therapy development; trait

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.

描述（由申请人提供）： 选择性注意力受损可能是患上焦虑症的危险因素，如创伤后应激障碍（PTSD）、广泛性焦虑症、惊恐发作和恐惧症。对双胞胎的研究表明，海马体积小于正常是PTSD的危险因素。随后的研究表明，较小的体积与海马依赖性学习任务的障碍有关，这表明体积差异反映了功能障碍。最后，动物海马损伤导致选择性注意力受损。目前的建议将调查海马功能障碍，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PTSD的发展轨迹平行。因此，理解导致异常回避的神经生物学机制将推进我们对所有焦虑症核心特征的认识。 这些研究的假设是，注意力受损导致异常回避的发展。注意力受损的一个促成因素是海马功能障碍。拟议的一系列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探讨海马系统损伤是否会影响SD大鼠的注意功能，并导致异常回避行为的发生。目的2：研究Wistar京都（WKY）大鼠海马功能是否异常。该大鼠品系是应激敏感的，具有升高的惊吓和行为抑制特征，表现出选择性注意力障碍并发展出异常回避。本研究将探讨WKY大鼠海马功能障碍是否是引起注意障碍和异常回避的原因。目的3：评价抗精神病药物氟哌啶醇是否能恢复海马功能障碍的SD大鼠和WKY大鼠的注意力，并防止异常回避的发展。这些研究将为注意力受损、海马功能障碍和异常回避的发展之间的关系提供重要的知识。这些信息将提供新的见解的方式，其中风险因素有助于焦虑症，并可能指向新的途径，在预防焦虑症。这个问题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。 公共卫生关系： 虽然军事人员可能具有与非军事人口类似的焦虑症的脆弱性和易患性，但部署，战争和战时服务的极端和持续的压力源增加了发展焦虑症的可能性。事实上，据估计，退伍军人患焦虑症的比率是普通人群的4倍。因此，焦虑症是VA医疗和精神病学服务的主要重点。基础科学研究侧重于脆弱性因素如何与压力相互作用的机制，有可能有助于理解PTSD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程序和确定药物治疗目标提供机会，从而为VA节省大量成本，并使医学专家能够将精力集中在更少的患者身上。