The mammalian hypothalamus represents the site at which the final integration of adaptive neuroendocrine and autonomic responses to stress is effected. Messenger RNAs encoding neuropeptide markers for hypothalamic neuroendocrine and autonomic effector neurons, and certain immediate-early gene products that serve as inducible indices of neurons activated by extracellular stimuli, will be followed, in situ, in response to various combinations of stress, perturbations in the hormonal milieu, and discrete central and peripheral ablations in order to define and characterize functional circuits mediating adaptive and integrated visceromotor responses to specific challenges. An initial set of studies will test the generality and specificity with which circumventricular structures associated with the lamina terminalis mediate coordinate and differential effects of chronic hyperosmotic challenge on hypothalamic neurosecretory cell types. Parallel experiments will determine whether an immune system challenge (systemic cytokine injection) may be conveyed to hypothalamic effector neurons via interoceptive pathways involving the abdominal vagus and medullary catecholaminergic neurons. A second set of experiments will employ a similar strategy to identify pathways subserving the initiation and maintenance of hypothalamic neuroendocrine and autonomic responses to intermittent footshock, a model for neurogenic stress. This will involve immediate-'early gene mapping in intact rats, and in animals with controlled steroid titers, to allow distinction between stress and steroid-sensitive components. This will be complemented with in situ assessments of relevant mRNAs in hypothalamic effector neurons, and evaluation of candidate afferent mediators of these stress effects using discrete fiber transection and excitotoxin lesioning techniques. A final group of studies will seek to refine understanding of the site(s) and mechanism(s) through which the inhibitory feedback control by adrenal corticosteroids of the central limb of the hypothalamo-pituitary-adrenal axis is exerted. Tetrodotoxtn-mediated synaptic blockade will be used in steroid-manipulated animals to estimate the extent to which steroid effects on hypothalamic targets may be mediated transsynaptically. Intracerebral administration of specific corticosteroid receptor antagonists will be coupled with perturbation in systemic hormone levels to determine whether feedback is a distributed function, requiring concurrent receptor occupancy at multiple sites. Focal extrahypothalamic administration of corticosteroids will be coupled with exposure to a specific stressor to determine whether feedback effects may be mediated specifically on pathways involved as sensory relays for a given modality. The circuitry under scrutiny here subserves functions essential to the survival of individuals and species, and relates directly to the many pathologies that are exacerbated by stress, including cardiovascular disease, immune system dysfunction, and affective disorders such as anorexia nervosa and major depression.
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