The paraventricular nucleus (PVN) of hypothalamus has emerged as an integration and coordination center in hypothalamus for neuroendocrine and autonomic visceral responses and implicates the importance of this nucleus in maintenance of homeostasis. Organisms are often subject to stressors which disrupt the body's homeostasis. Such alterations generate a set of endocrine and neural adaptations that form a stress response with resultant increased levels of pituitary ACTH. The paraventricular nucleus - particularly the CRF-containing neurons - plays a significant role in the neural response to stressful stimuli. The CRF neuron is the nidus and dominant component in the regulation of pituitary ACTH. ACTH regulates the adrenal glucocorticoids and they in turn exert a negative feedback effect on hypothalamus. We propose to elucidate subgroups of CRF-immunoreactive neurons in PVN as identified by their coexpression of a second peptide neurotransmitter. Identification and characterization of these subgroups will provide an anatomical substrate to investigate subsets of neurons that may be differentially and specifically regulated by hormonal feedback and neural inputs, and activated in response to different stress paradigms. Different experimental paradigms of stress have been used to examine neuronal plasticity in the central nervous system. We propose the use of the rat kindling model of epileptic seizure elicitation as a reliable and powerful experimental paradigm to study neuronal plasticity in PVN. Significant advantages of using this model over other paradigms of stress include the unique opportunity to monitor neuronal events in activated PV neurons at well defined stages in the development of kindling. The immunocytochemical detection of c-fos will be used as a tool to identify activated neurons. It is hypothesized that the progressive nature of kindling is accompanied by fundamental anatomical and neurochemical changes. Peptides of particular interest in adaptive responses to stress activation include CRF, vasopressin, oxytocin, enkephalin (ENK) and cholecystokinin (CCK). The expression of these peptides in activated PV neurons at defined stages in kindling development will be analyzed in the proposed experiments. Immunocytochemistry at the light and EM levels and in situ hybridization methodology will be used in these studies. The clinical significance of these studies is also recognized and they will provide new insights on the effects of epileptic seizures on central control of the pituitary- adrenal axis.
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