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; much of the sleep- related evidence was generated under the auspices of this grant. The fundamental hypothesis of this proposal is that promotion of non-rapid eye movement sleep (NREMS) and GH secretion are independent, albeit synchronized, functions of the 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 altered sleep associated with perturbations of the somatotropic axis and identification of hypothalamic structures and neurons indicating the sleep-promoting activity of GHRH. We also extend our work to the cerebral cortex to determine if GHRH and its receptors are involved in the regulation of neuronal assembly functional state.
In Aim 1 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 us immunohistochemistry to map the distribution of GHRH-receptor expressing neurons and determine which transmitter localizes with the GHRH-receptor.
In Aim 2, we focus on how ghrelin modifies sleep. We test the hypothesis that injection of ghrelin into the lateral hypothalamus will promote feeding, but inhibit sleep, whereas injection into areas around the periventricular nucleus may promote sleep. We also determine sleep in mice lacking ghrelin or its receptor.
Aim 3 investigates the cortical involvement of GHRH in EEG synchronization. Preliminary data demonstrate regulated expression and functionality of both GHRH and the GHRH receptor in the cortex. We will determine whether the cortical GHRH-GHRH-R system plays a role in EEG synchronization and the cell types expressing these substances. 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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