A striking feature of mood and anxiety disorders is their frequent coexistence with functional bowel disorders, such as irritable bowel syndrome. Conversely, psychiatric symptoms are prevalent in subjects diagnosed with functional bowel disorders, which occur in 10-20% of adults. These clinical observations implicate neural substrates linking the brain and gastrointestinal tract in pathology that is prevalent in the adult population. In the current application, a specific circuit linking the forebrain and gastrointestinal tract is proposed. It is proposed that Barrington's nucleus, via divergent projections to the brain noradrenergic nucleus, locus coeruleus (LC) and autonomic parasympathetic nuclei, is in a position to co-regulate brain noradrenergic activity and autonomic parasympathetic activity and thereby coordinate forebrain activity with gastrointestinal function. The proposed aims will provide anatomic and functional evidence for this hypothesis:
The specific aims are: (1) Identify regions of the gastrointestinal tract that are linked to the LC via Barrington's nucleus. Transsynaptic tracing (using pseudorabies virus) from the colon, cecum and bladder will be combined with retrograde tract tracing from the LC to determine whether Barrington's LC-projecting neurons also project to preganglionic neurons innervating these organs; (2) Characterize the physiological impact of Barrington's sacral spinal-projections on colon function. Barrington's nucleus has been studied only with regard to its role in micturition. Its projections to the sacral parasympathetic nucleus suggest that it also regulates distal colon function. This hypothesis will be tested by characterizing the effects of selective chemical stimulation of Barrington's nucleus on colonic intraluminal pressure: (3) Determine the role of Barrington's LC-projections in arousal elicited by colon or bladder distension. Colon and bladder distension increase LC discharge and produce arousal as indicated by forebrain electroencephalographic (EEG) activation. The hypothesis that forebrain arousal elicited by colon or bladder distension is mediated by Barrington's projections to the LC will be determined using micro infusion of drugs to selectively inactivate the LC or Barrington's nucleus. Together, these AIMS will begin to elucidate the anatomy and functions of a novel circuit that it is in a position to coordinate forebrain and gastrointestinal activity; a circuit that could play a role in the prevalent disorders that are characterized by a coexistence of psychiatric and gastrointestinal symptoms.
