In utero programming of CRF neurons by glucocorticoids

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DESCRIPTION (provided by applicant): Mounting evidence supports the theory that inopportune and/or excessive exposure of a developing fetus to glucocorticoids (GCs) during critical windows of gestation results in the acquisition of behavioral, neuroendocrine and physiological disorders as adults. This phenomenon has been referred to as "fetal programming". Synthetic GCs are routinely administered to pregnancy women at high risk for preterm labor and delivery. Disorders in the offspring arising from synthetic GCs include disturbances of the hypothalamo-pituitary-adrenal (HPA) axis, altered fear/anxiety, metabolic disorders and hypertension. Since excessive GC production in adults promotes hypertension, hyperglycemia/insulin resistance and dyslipidemia, developmental programming of increased HPA function and related behaviors is potentially integral in the establishment of these disorders. In offspring exposed to synthetic GCs in utero, expression of corticotropin releasing factor (CRF) is increased in both the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN) at adulthood. CRF is the primary neuropeptide regulating anterior pituitary ACTH secretion, and a major modulator of fear/anxiety. We propose that programming CRF neuron development and expression in the PVN and CeA is central in the GC-programmed excessive HPA activity and high anxiety phenotype. AIM 1 will determine if maternal delivery of synthetic GCs increases both CRF expression and the number of CRF neurons in the PVN and CeA and determine the timing of the onset of increased expression as well as the developmental window of susceptibility. AIM 2 will determine if AVP expression in the mpPVN is programmed via maternal administration of synthetic glucocorticoids. AIM 3 direclty examines the role of CRF in programming fear/anxiety and the increased function of the HPA axis in response to in utero exposure to maternally administered synthetic glucocorticoids. Aim 3 will also assess the role of the BNST vs. amgydala as the site of CRF action in the programming of fear/anxiety. AIM 4 will determine if GC stimulation of the amygdala is essential for maintaining increased CRF expression in the CeA and PVN, increased anxiety/fear and increased HPA function in the offspring of pregnant rats which received synthetic GCs.