Corticotropin releasing factor (CRF-4l)-producing perikarya in the hypothalamic parvocellular paraventricular nuclei (pPVN) play an integral role in regulation of adenohypophysial adrenocorticotropin (ACTH) secretion, pro-opiomelanocortin (POMC) gene expression and, thus, in the regulation of adrenocortical secretion. The secretory activity of CRF-positive neurons is modulated by humoral factors (glucocorticoids, glucose, etc) and by numerous afferent fibers conveying information about interoceptive and exteroceptive stimuli. CRF-41 neurons receive heavy innervation from medullary cell groups which, themselves, receive a diverse array of visceral and somatosensory inputs. Therefore they are excellent candidates for mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to a number of visceral (e.g. hypovolemia, hypotension) and somatic (e.g. pain) stimuli. Efferents from medullary regions are the major source of inputs containing norepinephrine (NE), epinephrine (EPI), neuropeptide Y (NPY), and a peptide with activin-like immunoreactivity (IbetaA-LI) to the CRF-rich pPVN. These putative transmitters generally facilitate CRF-41 secretion, although the nature of adrenergic receptor subtypes mediating catecholamine actions remain controversial. Ultimately, mechanisms must exist to ensure coordination of gene expression and secretion. In the present proposal, we will test the hypothesis that, individually or in combination, NE and IbetaA-LI (a member of the TGF-beta growth factor family) participate in the coordination of CRF-41 secretion and gene expression. Because of the biochemical diversity of these transmitters and the likelihood that their release occurs in a specific manner dependent upon the stimulus characteristics (modality, amplitude, frequency, duration), we hypothesize that these transmitters differentially affect secretion and gene expression in the target cells via multiple intracellular pathways. Neurotransmitter release evokes both rapid and slow responses in neurons, thus permitting an immediate response to the stimulus as well as longer-term adaptive plasticity. It has been suggested that induction of the c-fos gene, which encodes a nuclear phosphoprotein with DNA binding properties consistent that of a transcriptional regulator, is a component of the signaling cascade by which specific transmitters may modulate neuronal gene expression. Therefore, we will evaluate whether any of these neurotransmitters activate the c-fos gene and then determine whether or not C-fos activation is correlated with CRF-41 secretion and/or gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033093-08
Application #
3231469
Study Section
Endocrinology Study Section (END)
Project Start
1992-09-30
Project End
1995-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sapolsky, R M; Plotsky, P M (1990) Hypercortisolism and its possible neural bases. Biol Psychiatry 27:937-52