The ability to coordinate the behavioral, autonomic nervous system, and neuroendocrine system responses to stressors enhances an organism's chances of survival. The hypothalamic-pituitary-adrenal (HPA) axis is one of many physiological systems activated by a variety of stressors; the ability to regulate the initiation and cessation of adrenocortical activity is critical to life. Information about the internal and external environment are encoded, processed and compared at various loci within the central nervous system before converging upon the neurosecretory neurons in the parvocellular portion of the hypothalamic paraventricular nucleus (PVN) which elaborate corticotropin releasing factor (CRF). This hypothalamic peptide drives anterior pituitary gland synthesis and secretion of adrenocorticotropin (ACTH) which, in turn, activates adrenocortical synthesis and secretion of glucocorticoids. The glucocorticoids serve multiple roles throughout the organism including mobilization of the energy supply. Secretion of these steroids is believed to be self-limiting via glucocorticoid negative feedback actions at the pituitary gland and central nervous system. In spite of impressive advances, major questions remain concerning: (l) identification of central loci responsible for integration of internal and external information as well as emotional and physical aspects of the stressor, (2) determination of the site or sites at which glucocorticoids modulate overall activity of the HPA axis, and (3) mechanisms responsible for integration of behavioral, autonomic, and HPA axis responses to stressors. The amygdaloid complex is emerging as an important participant in each of these aspects. Its highly organized interrelations with other sensory areas (the thalamus and cortex), PVN, locus coeruleus, parabrachial nucleus and other brainstem regions suggests this nucleus as an important center for integration of behavioral, endocrine and sympathetic responses to stressors. The endowment of amygdaloid neurons with glucocorticoid receptors as well as its role in transmission of information from the hippocampus to the hypothalamus also implicates this structure as an important participant in glucocorticoid-mediated negative feedback modulation of HPA activity. Therefore, the focus of this proposal is to map the activity of subnuclei of the amygdaloid complex to various classes of stressors using c-Fos as a trans- synaptic marker and correlate this activation with ACTH and corticosterone secretion, then to assess the importance of these regions in mediation of HPA axis responsiveness to these individual and combined stressors using local ibotenic acid lesions of amygdaloid neurons (sparing fibers of passage) and, finally, to investigate participation of amygdala subnuclei in glucocorticoid feedback processes using local stereotaxic microinjection of glucocorticoid receptor agonists and antagonists. Overall, the proposed studies will evaluate the role of the amygdaloid complex in integration of convergent information necessary to activate the neuroendocrine, autonomic and behavioral aspects of the stress response as well as its role in mediation of glucocorticoid feedback activity. This information is of potential interest in the areas of pathophysiology of affective disorders as well as in syndromes characterized by memory and learning dysfunction.
