Serge Campeau - US grants

Accumulating evidence indicates that the failure to terminate a stress response in a timely manner, or the failure to adapt appropriately to repeated stress, can produce pathological changes suspected to play a role in the etiology of a number of mood disorders including anxiety and depression. This proposal is based on the idea that a better understanding of the brain areas and mechanisms responsible for habituation to psychological stress might help to identify targets putatively involved in the dysregulation of brain circuits associated with some forms of affective disorders. The proposed studies employ an animal model of chronic intermittent psychological (audiogenic) stress, utilizing a paradigm in which rats habituate over time to the behavioral and endocrine indices of the stress. Initially, external parameters important in these habituation processes will be established, such as the relevance of contextual cues. Secondly, the importance of the stress-induced increase in glucocorticoids in the habituation process will be determined using adrenalectomized rats with basal levels of corticosterone replaced. The third series of studies is designed to determine the specific brain areas involved in the habituation of the endocrine and behavioral responses to psychological stress. Brain areas known to be critical in the acute response to audiogenic stress, namely the paraventricular nucleus of the hypothalamus will initially be targeted. This area will be inactivated temporarily with intranuclear injections of lidocaine during habituation training, but will be active on the test day. A final study to determine the role of the orbitofrontal cortex in habituation to audiogenic stress is planned, using chemical lesions of the area prior to habituation training. This nucleus is targeted because preliminary data suggested that the neuronal activity in this area increases following habituation to audiogenic stress. Throughout these experiments, indices of habituation to stress will be monitored, including observation of behavior and analysis of the plasma stress hormones adrenocorticotropin hormone and corticosterone.

DESCRIPTION (provided by applicant): Accumulating evidence indicates that stress can produce pathological changes suspected to play a role in the etiology of a number of psychiatric disorders. This proposal is based on the assumption that a better understanding of the brain systems mediating processive stressors (emotional, psychological situations) might help to identify some of the neural processes involved in the etiology of certain psychiatric disorders. The proposed studies employ animal models of processive stress to begin to trace and identify the neural systems that mediate the activation of a specific stress-responsive system,the hypothalamo-pituitary-adrenocortical (HPA) axis, that ultimately results in the release of the stress-related hormones glucocorticoids. The first aim is designed to assess which brain regions are specifically activated by exposure to two different processive stressors: audiogenic and predator odor stress. The usefulness of both these stimuli rests on the knowledge of their primary sensory neural pathways and the ability to employ intensities and concentrations that can be varied from non-stressful to stressful levels. This last characteristic can be exploited to tease apart the neural machinery that simply senses the stimuli from the brain areas specifically recruited when these stimuli reach stressful levels. With the help of this distinguishing feature, semi-quantitative in situ hybridization histochemistry will be used to detect the induction of the immediate-early gene c-fos, a marker of cellular activation, to determine brain regions specifically recruited by stressful levels of noise and predator odor. The second aim will determine if any of the brain regions specifically activated by the stressful component of noise and predator odor project directly to the "motor" neurons (paraventricular nucleus of the hypothalamus) of the HPA axis, using a combination of tract-tracing and Fos immunohistochemistry, in response to loud noise and predator odor. The functional relevance of the recruited regions projecting directly to the paraventricular hypothalamic nucleus will then be tested by ablating the cell bodies of these projecting neurons and determining if audiogenic and predator odor stress can still trigger an HPA axis response. The basic neurochemical phenotype of the cellular groups that project directly to the hypothalamic paraventricular nucleus and are necessary for HPA axis activation in response to processive stress will then be tested for the presence of the neurotransmitters GABA or glutamate, using a dual in situ hybridization technique.

[unreadable] DESCRIPTION (provided by applicant): The goal of this proposal is to better characterize the effects of physical activity on stress responsiveness, and specifically adaptation to prolonged, repeated or chronic stress. It is the prolonged or repeated exposure to stressful life events that is most frequently associated with the development or precipitation of several psychiatric and physical disorders. Stress reduction has been suggested as an important factor in the beneficial effects of physical activity on several aspects of physical and mental health. Surprisingly, a majority of studies indicate that physical activity has no effect on, or even potentiates several major indices of acute stress, including the sympathetically-mediated release of arterial catecholamines, and the hypothalamo-pituitary-adrenocortical (HPA) axis-mediated release of glucocorticoids. In marked contrast, our preliminary rodent studies indicate that six weeks of moderate voluntary physical activity significantly facilitates glucocorticoid adaptation to repeated loud noise exposure, as compared to sedentary rats. This may be a critical observation in that some of the disease-promoting effects of stress are attributed to prolonged elevations of circulating glucocorticoid levels. These findings suggest that physical activity may significantly regulate the adaptive mechanisms triggered by stress without necessarily altering responsiveness to novel acute stress situations. Therefore, the primary working hypothesis to be tested in this proposal is that moderate physical activity facilitates chronic stress adaptation. Therefore, the specific Aims of the present proposal will determine: How much voluntary physical activity is necessary to produce facilitation of stress adaptation to repeated loud noise exposures, as indexed by circulating glucocorticoid levels (Aim 1); where and how physical activity regulates HPA axis function in response to chronic intermittent loud noise exposure (Aim 2); and the important question of whether physical activity-induced facilitation of stress adaptation generalizes to another stress situation (restraint), and to response systems other than the HPA axis (circulating catecholamines, heart rate, body temperature, and locomotor activity - Aim 3). [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The goal of this proposal is to better characterize the effects of physical activity on stress responsiveness, and specifically adaptation to prolonged, repeated or chronic stress. It is the prolonged or repeated exposure to stressful life events that is most frequently associated with the development or precipitation of several psychiatric and physical disorders. Stress reduction has been suggested as an important factor in the beneficial effects of physical activity on several aspects of physical and mental health. Surprisingly, a majority of studies indicate that physical activity has no effect on, or even potentiates several major indices of acute stress, including the sympathetically-mediated release of arterial catecholamines, and the hypothalamo-pituitary-adrenocortical (HPA) axis-mediated release of glucocorticoids. In marked contrast, our preliminary rodent studies indicate that six weeks of moderate voluntary physical activity significantly facilitates glucocorticoid adaptation to repeated loud noise exposure, as compared to sedentary rats. This may be a critical observation in that some of the disease-promoting effects of stress are attributed to prolonged elevations of circulating glucocorticoid levels. These findings suggest that physical activity may significantly regulate the adaptive mechanisms triggered by stress without necessarily altering responsiveness to novel acute stress situations. Therefore, the primary working hypothesis to be tested in this proposal is that moderate physical activity facilitates chronic stress adaptation. Therefore, the specific Aims of the present proposal will determine: How much voluntary physical activity is necessary to produce facilitation of stress adaptation to repeated loud noise exposures, as indexed by circulating glucocorticoid levels (Aim 1); where and how physical activity regulates HPA axis function in response to chronic intermittent loud noise exposure (Aim 2); and the important question of whether physical activity-induced facilitation of stress adaptation generalizes to another stress situation (restraint), and to response systems other than the HPA axis (circulating catecholamines, heart rate, body temperature, and locomotor activity - Aim 3). [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall goal of this proposal is to explore the processes underlying long-term habituation to repeated intermittent stress. Emotional stressors elicit a range of behavioral, autonomic, and endocrine responses that normally help organisms cope with challenging situations. However, prolonged or repeated exposure to stressful life events is frequently associated with several psychopathologies and physical disorders. Thus, habituation to stress is likely a vital mechanism allowing organisms to reduce the impact of repeatedly experienced stress situations. Unfortunately, the neural mechanisms specifically mediating normal stress habituation are unknown. Based on current evidence and preliminary studies, a model is proposed where the site of plasticity associated with habituation to stress is located at the interface between an auditory signaling pathway and a central effector region that controls many, if not all, responses normally associated with stress. Aim 1 provides an important evaluation of the hypothesis that several response systems, as measured with behavioral, autonomic, and endocrine responses, will vary in parallel during repeated intermittent loud noise exposures, suggesting that only a few or perhaps a unique brain region undergoes the plastic changes associated with habituation. These results will guide the performance of most following studies, and provide some spatial and temporal guidance as the number of brain regions underlying this form of plasticity. In Aim 2, functional manipulations of the auditory thalamus and auditory cortex will help determine the location, along the auditory system, where the auditory signal necessary and sufficient for habituation is derived from. Studies in Aim 3 are designed to ascertain the sympathetic premotor areas specifically controlling some of the measured autonomic responses, and help rule out the possibility that habituation to repeated loud noise is mediated by plasticity in these regions. Finally, the anatomical/functional studies of Aim 4 are designed to firmly establish the anatomical interface between activated auditory inputs and putative central integrative effector regions activated by loud noise. The hypothesis that functional inactivation of such central integrative effector region(s) will block habituation to repeated loud noise stress is also assessed.