A combination of physiological and anatomical studies are proposed to investigate the role of the medullary raphe and the hypothalamus in controlling gastro-intestinal eliminative reflex circuits. The effects of electrical and chemical stimulation of nucleus raphe obscuras/pallidus (nRO/nRP) and the paraventricular nucleus (PVN) of the hypothalamus on the external anal sphincter (EAS) will be examined in the cat. Microinjection of peptides (oxytocin [OXY]) and vasopressin [AVP]), thyrotropin releasing hormone (TRH) and serotonin (5-HT) into Onuf's nucleus will be used to assess the effects of endogenous ligands of the descending systems on EAS tone, recto-anal reflexes, and EAS motoneuron (MN) excitability. Antagonists to 5-HT, OXY and AVP will be used to attempt to reverse the effects of stimulation. Descending projections from nRO/nRP (and adjacent structures) an PVN to Onuf's nucleus in the sacral spinal cord, which contains the MNs innervating the EAS, will be studied with tracing techniques, electron microscopy (EM), and immunohistochemistry (IHC). Our hypothesis is that these descending inputs make direct synaptic contacts with the proximal dendrites and somata of sphincter MNs. Anatomical data strongly suggest that these spinal cord parasympathetic/somatic networks share a number of structural and functional similarities with parasympathetic/somatic control circuits in the medulla. Together, these studies should provide an anatomical and functional analysis of some of the central circuits responsible for forebrain/brainstem descending control of distal gut eliminative reflexes and may allow comparisons with such control of proximal gut reflexes with which we are very familiar. In addition, the proposed studies may yield insights into the etiology of incontinence associated with gastrointestinal diseases, neurological disorders (such as autonomic failure stroke, and spinal cord trauma), and aging, and will add information concerning a unique motoneuron type resistant to motoneuron diseases like ALS.
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