Convergent neuroanatomical and biological reports implicate corticotropin releasing factor ( 41 amino-acid peptide, as a key mediator in the endocrinological, behavioral. and autonomic responses stress. Results obtained during the last grant period provided evidence in rats that central CRY mediate psychological, and immune (interleukin- 1beta, IL-l) stress-induced alterations of GI motor function namely the delay in gastric emptying and stimulation of colonic transit in rats. The overall goals are to define the neuroanatomical substrata underlying C.F. and IL-1 actions in the brain to induce alterations of gastric an autonomic motor function and their implications at these sites to the stress response in rats. The objectives of this application are to establish that (l) C.F. acts in the locus coeruleus to activate noradrenergic neurons an stimulate colonic motor function through sacral parasympathetic cholinergic pathways. (2) endogenous C.F. released by environmental stress in the locks coeruleus activates neurons and stimulates colonic motor function; (3) C.F. in the paraventricular nucleus of the hypothalamus has opposite effects on preganglionic parasympathetic neurons in medulla and sacral spinal cord. leading to decreased gastric vagal outflow and increased cholinergic input to the colon (4) C.F. in the paraventricular nucleus of the hypothalamus accounts for the gastric stasis induced by central and peripheral injection of IL-1beta.
These aims will be achieved by combined neuropharmacological (microinjection of C.F. and/or antagonist or neurotoxins at these sites), neurohistochemical (c-fos expression in the brain and sacral spinal cord as a marker of neuronal system activity combined with double labelling of noradrenergic or C.F. neurons) and electrophysiological (recording o efferent activity in gastric vagus) methods of approach. All experiments will be performed in conscious rats with chronically implanted guide cannulas for microinjections and gastric and colonic catheters to deliver markers allowing measurement of transit except electrophysiological studies performed in rats under halothane anesthesia. These studies will advance knowledge on (I) brain sites regulating gastric and colonic motor function. (2) neuroanatomical and neurochemical circuitry through which central C.F. and IL-lbeta alter GI motor function. (3) brain sites and neurotransmitters involved in regulating parasympathetic outflow to the stomach and the colon, (4) IL-1 as mediator in the interaction between the immune system and gastric function. Overall, these studies will enhance knowledge on the pathways through which psychological and immunological stress induce alterations of GI motor function, and they may also have implications in stress related exacerbations of human irritable bowel syndrome.
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