The expression of the cellular oncogene c-fos is a general response of cells to a variety of extracellular stimuli. Fos, the product of the c- fos gene, is a nuclear DNA binding protein which is synthesized by neurons in response to synaptic input. As a consequence, the anatomic pattern of brain c-fos expression following a physiologic stimulus gives, at least in part, a picture of the pattern of synaptic activity. This allows Fos immunocytochemistry to be used in functional metabolic mapping of the brain in a manner similar to 2-deoxyglucose autoradiography. Fos immunocytochemistry, however, provides cellular resolution, a dramatic advantage for certain investigations. We propose to use Fos immunocytochemistry to study neuroendocrine regulation. Two systems will be examined. The hypothalamic- neurohypophysial system controls vasopressin and oxytocin secretion from the posterior pituitary gland and is involved in the control of fluid balance, parturition and lactation. The anatomic pathways involved in the control of this system will be mapped using Fos immunocytochemistry, and the cellular resolution of the technique will be exploited to identify the neurotransmitter content of individual neurons. The second system studied will be the corticotropin-releasing hormone (CRH) neurons of the paraventricular nucleus of the hypothalamus. These neurons control ACTH secretion from the anterior pituitary gland and participate in the response to environmental stress. They can be subdivided into subsets depending on co-localization of neuropeptides. We shall determine if various modalities of stimulation of this system (adrenalectomy, stress, corticosteroid excess) differentially stimulate these subsets. Since the parvocellular neurons of hypothalamus do not lend themselves to electrophysiologic study, Fos immunocytochemistry may yield important new information concerning the functional organization of the paraventricular nucleus and the brain's response to stressful stimuli. A final goal will be to use immunoprecipitation and polyacrylamide gel electrophoresis to characterize the Fos immunoreactive antigens expressed in hypothalamus and to use Northern blotting to characterize the mRNA species expressed. These experiments are designed to extend our knowledge of neuroendocrine regulation in mammalian brain and to further validate the use of Fos immunocytochemistry in neuroanatomic functional mapping at the cellular level.
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