Stress is a powerful stimulus that modulates animal behavior and the functioning of the nervous system. In people, stress negatively impacts a variety of psychiatric conditions relevant to the clinical mission of the Department of Veterans Affairs, including depression, anxiety and substance abuse. In particular, exposure to severe stress is associated with posttraumatic stress disorder (PTSD), both in military and civilian populations. These conditions are a major health issue for our veteran population and available treatments are at best partially effective. There is a pressing need to better understand the effect of stress on the functioning of the brain in order to design better treatments for stress related disorders. Studies in humans and animals have indicated that the amygdala is a brain region involved in mediating the behavioral responses to stress, and patients'with PTSD show elevated activity in this brain region. In particular the basolateral complex of the amygdala (BLA) is critical to normal and pathological amygdala functioning. The BLA's response to stress has been shown to involve synaptic plasticity of the excitatory, glutamatergic connections within this brain region. While complex synaptic plasticity is a complex phenomenon, many studies have indicated that it involves the NMDA and AMPA subtypes of glutamate receptor, as well as the signal transduction protein CaMKII. Manipulations that block the activity of these proteins block behavioral responses to stress. There is evidence that the response of these proteins to altered activity levels and stress involves altered patterns of localization. It is the goal of this proposal to study this issue in more detail using immunohistochemical localization of the NR1 and GluR1 subunits of the NMDA and AMPA receptors and CaMKII and high resolution electron microscopic examination. We will use a rodent model of repeated, severe stress- repeated immobilization stress to study the effect of stress in the BLA. We will begin by determining the time course of how stress alters the localization of these proteins in the BLA. We will next use an in vitro system to assess how these proteins are affected by altered activity patterns in the BLA and how prior stress exposure modifies the amygdala's response to activity. Finally, we will use post-embedding immunogold labeling to study how stress affects the composition of the postsynaptic density in the BLA. These studies will provide a detailed understanding of the molecular architecture of excitatory neurotransmission in the BLA and determine how this is altered by prior stress exposure. This information will enhance our understanding of stress affects in this critical brain region and suggest possible molecular targets for novel therapies for stress related disorders, including PTSD.
Stress plays a significant role in modifying behavior and may lead to, or worsen, a variety of psychiatric conditions relevant to the clinical mission of the Department of Veterans Affairs. Stress can precipitate or worsen episodes of depression and a variety of different anxiety disorders. Stress is associated with worsening symptoms in schizophrenia. Stress is associated with relapse in alcohol and drug abuse and dependence. In particular, we now recognize that severe stressors can be associated with the development of post-traumatic stress disorder (PTSD) in both civilian and military populations. These conditions afflict large numbers of our veteran population. Substantial resources have been committed to the care of these patients, and further, these disorders can increase a patient's use of healthcare resources for other medical problems. While importance of stress and stress related illnesses is clearly established, our treatments remain partially effective at best. Here we propose research to better understand the effect of stress in a critical brain region, the amygdala. The amygdala is a brain region involved in PTSD and the brain's response to stress. Stress has been shown to alter the circuitry and functioning of the amygdala. In this proposal we will investigate how the organization of key molecules, involved in excitatory communication in the amgygdala, is altered by stress. The results of the proposed studies will further our understanding of stress induced changes in the amygdala and suggest specific molecular targets for new drug treatments for stress related disorders, including PTSD.
