Impaired attention & hippocampal dysfunction in developing abnormal avoidance

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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.