Alterations in the expression of genes encoding hypothalamic neuroendocrine and autonomic effector peptides, and certain immediate- early gene markers of neuronal activation, will be followed, in situ, in response to various combinations of stress, central ablations, pharmacological manipulations, or perturbations in the steroid hormone environment, in order to clarify the neural circuits and mechanisms through which categorically different stressors come to elicit integrated and appropriately adaptive hypothalamic responses. An initial series of experiments will explore the mechanisms through the immune system mediator, interleukin-1 (IL-1), exerts its powerful stimulatory influence on stress-related hypothalamic mechanisms. Previous work supports the hypothesis that paracrine effects of prostaglandin E2 released from perivascular cells in the medulla as a consequence of IL-1 stimulation, and acting on a prostanoid receptor or near local catecholaminergic neurons that project to the hypothalamus, underlies the stimulatory effects of increased circulating IL-1 on stress-related hypothalamic effector neurons. This will be tested by determining whether the requisite molecules are expressed in the medulla, and by assessing whether medullary administration of. prostanoid agonists can mimic, and synthesis inhibitors block, IL-1 effects at the level of the hypothalamus. The specific involvement of medullary catecholaminergic neurons will be probed by assessing the ability of neurotoxin lesions at the level of the brainstem or delivery of adrenoceptor antagonists at the level of the hypothalamus to block hypothalamic responses to a systemic IL-1 challenge. The generality of the mechanism will be explored by determining whether disruption of ascending aminergic projections mitigates hypothalamic responses to more strenuous immune insults. A second major goal will be to employ an IEG- guided ablation strategy to identify the pathways through which ostensibly more complex, emotional or neurogenic, stress paradigms come to invoke integrated hypothalamic responses and the manner in which hypothalamic output may be modified as a consequence of repeated exposure to emotional stress. A final set of experiments will seek to characterize the neurotransmitter systems and receptor mechanisms mediating transcriptional activation of genes encoding peptides that govern pituitary-adrenal responses to stress, and the manner in which they are modulated tonically and phasically by the steroid hormone environment. The neural and neuroendocrine systems under scrutiny here play essential physiologic roles, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age- related deficits in learning and memory, and have been implicated in the etiology of affective disorders, including anorexia nervosa and major depression.
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