NEURAL REGULATION OF THE FETAL PARAVENTRICULAR NUCLEUS

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INTRODUCTION: The hypothalamo-pituitary adrenal (HPA) axis is the final common pathway for glucocorticoid (GC) secretion in response to challenges to homeostasis. Adult HPA axis function is modified by inhibitory hippocampal (HC) inputs, but the role of the fetal HC is unknown. The purpose of the present proposal is to gain fundamental new knowledge about integrative control of adrenocorticotropin (ACTH) secretion by the fetal sheep HC: 1) in response to acute hypotension and 2) during the pre- parturient fetal ACTH rise. HYPOTHESES: 1) Neuronal inputs from the fetal HC via the fornix to the hypothalamus modify fetal HPA axis functions that result in a) the fetal plasma ACTH response to acute (10 min) hypotension and b) the initiation of parturition. 2) GC feedback at the fetal HC modifies HC neural input to the fetal HPA axis altering its activity level during both a) the fetal ACTH response to acute hypotension and b) the initiation of parturition. 3) Antenatal GCs exert feedback globally in the brain altering fetal HC and HPA axis activity level differently than GC feedback at the HC alone. SPECIFIC AIMS: To investigate the roles of 1) neuronal inputs via the fornix from the HC to the hypothalamus in a) the HPA axis hormonal response to acute hypotension and b) the timing of parturition; 3) GC feedback at the level of the whole central nervous system on the HC activity modifying the hormonal response of the fetal HPA axis to acute hypotension. METHODS: 1) Chronic instrumentation of age dated fetal sheep. 2) Fornix transections and HC GC crystal implants done stereotaxically at 120 +/-1, GC infusions at 130 +/-1 days of gestational age (dGA). 3) Hypotensive challenges done at two critical developmental stages, 132 +/-1 and 142 +/- 1 dGA. 4) Radioimmunoassay of fetal peripheral plasma ACTH, vasopressin (AVP) and cortisol and maternal cortisol and progesterone 5) Immunocytochemical staining and in situ hybridization for corticotropin- releasing hormone AVP, GC receptors I (CR/MR) and II (GR), c-fos mRNA and protein and glial fibrillary acid protein in fetal HC and hypothalamus. RATIONALE: The PI is currently the only investigator in North America performing the fetal stereotaxic neurosurgical techniques necessary to investigate HC control of the HPA. The fetal sheep is the most widely used model to study the integration of neural and endocrine control of the fetal adrenal. The studies outlined above will determine fetal HC contributions to HPA axis function during both homeostatic challenge and the normal hypothalamic development that controls the timing of parturition. The results of these studies will improve understanding of fetal stress responses and regulation of both term and pre-term parturition.