Impaired attention & hippocampal dysfunction in developing abnormal avoidance

注意力受损

• 批准号: 7684515
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684515
• 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）： 选择性关注受损可能是发展焦虑症的危险因素，例如创伤后应激障碍（PTSD），普通焦虑症，恐慌发作和恐惧症。在双胞胎中的研究已经确定，海马体积小于正常水平是PTSD的危险因素。随后的研究表明，较小的体积与海马依赖学习任务的损伤有关，这表明体积差异反映了功能功能障碍。最后，动物的海马损害导致选择性注意力受损。当前的建议将研究海马功能障碍，注意力障碍和异常回避性的发展之间的关系。异常回避是所有焦虑症的核心特征，而异常回避的发展与PTSD的轨迹相似。因此，了解导致异常回避的神经生物学机制将提高我们对所有焦虑症的核心特征的了解。 拟议的研究的假设是，注意力的损害会导致异常回避的发展。注意力障碍的一个促成因素是海马功能障碍。拟议的一组研究将利用动物模型来检查海马在注意力和回避中的影响。提出了三个目标。 AIM 1将确定Sprague Dawley（SD）大鼠海马系统的损害是否会损害注意力并引起异常回避的发展。 AIM 2将研究海马在Wistar Kyoto（WKY）大鼠中是否正常工作。这种大鼠菌株对压力敏感，具有升高的惊吓和行为抑制性状，表现出选择性注意力障碍并发展出异常的回避性。在此目标中的研究将确定WKY大鼠中海马功能障碍是否可以解释注意力障碍和避免异常。 AIM 3将评估抗精神病药氟哌啶醇是否可以恢复注意力并防止海马功能障碍和WKY大鼠在SD中的异常避免。拟议的研究将提供有关注意力受损，海马功能障碍与异常回避发展之间关系之间关系的重要知识。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。这个问题对退伍军人的健康尤为重要，因为由于与战斗服务相关的极端压力，大量退伍军人可能会发展与焦虑有关的疾病。 公共卫生相关性： 尽管军事人员可能对类似于非军事人群类似的焦虑症具有脆弱性和敏感性，但部署，战争和战争时间服务的极端和持续压力增强了发展焦虑症的可能性。实际上，据估计，发展出焦虑症的退伍军人比一般人群高4倍。因此，焦虑症是VA医学和精神病学服务的主要重点。基础科学研究的重点是机理说明脆弱性因素如何与压力相互作用有可能有助于理解PTSD和其他焦虑症的病因基础。这项研究的成功将为制定预防程序并确定药理治疗的目标，从而为VA节省大量成本，并允许医疗专家将精力集中在较少的患者身上。