Growth hormone (GH) releasing hormone (GHRH) is a hypothalamic neurocrine that stimulates pituitary GH release and that has become one of the best documented sleep-regulatory substances. The fundamental hypothesis of this proposal is that promotion of non-rapid eye movement sleep (NREMS) and GH secretions are independent, albeit synchronized, functions of hypothalamic GHRH-containing neurons. Evidence in support of this hypothesis includes; 1) deep NREMS is associated with GH secretion in several species; 2) GHRH promotes NREMS in rats, mice, rabbits, and humans; 3) inhibition of endogenous GHRH inhibits spontaneous NREMS and GHRH-enhanced NREMS; 4) inhibition of GH does not block GHRH enhanced sleep; 5) GHRH enhances sleep when injected into the medial preoptic region; 6) hypothalamic GHRH and GHRH levels vary with sleep propensity; and 7) negative feedback mechanisms of the somatotropic system inhibit GH secretion and NREMS simultaneously. The broad objective of the current proposal is to determine the role of GHRH in sleep changes associated with chronic or acute alterations within the somatotropic system and the localization and regulation of the hypothalamic sleep-promoting GHRHergic system.
In Specific Aim #1, spontaneous sleep and sleep responses to sleep deprivation will be studied in mutant and transgenic strains of rats and mice with various alterations to the somatotropic system.
In Specific Aim #2 we will determine the role of GHRH in the sleep effects of ghrelin (a newly discovered somatotropic hormone) and of somatostatin (using octreotide, a synthetic somatostatin analog) and will distinguish the mechanisms of the various behavioral and endocrine responses to both peptides.
In Specific Aim #3 we will study the hypothalamic GHRHergic network involved in sleep regulation. We will determine the importance of the connections between the mediobasal hypothalamus and the anterior hypothalamic/preoptic region for sleep by means of small semicircular cuts placed in front of the arcuate nucleus. We will also use in situ hybridization to map the distribution of GHRH-receptor expressing neurons and determine which transmitter localizes with the GHRH-receptor. Finally, in Specific Aim #4 cultured hypothalamic neurons will be used in conjunction with measurement of intracellular Ca++ to determine colocalization of GHRH receptors with neurotransmitters and interleukin-1 receptors within cells and to study the regulation of GHRH-receptor expression in these cells. Preliminary data are presented for each specific aim to demonstrate feasibility. Anticipated results are expected to support the hypothesis that GHRH is a key regulatory component of NREMS and provide cellular mechanistic explanations for the involvement of GHRH in sleep regulation.
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