Brainstem circuits controlling gastrointestinal function

Pennsylvania State Univ Hershey Med Ctr, Hershey PA

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Abstract

Project summary Functional gastrointestinal (GI) motility disorders, including functional dyspepsia, are very common, often chronic and disabling, conditions that account for a large proportion of consultations with primary care and specialist physicians. The pathophysiology of these disorders remains incompletely understood, but several lines of evidence point toward impairment of the vagal sensory-motor loop connecting the gut to the central nervous system (CNS) and back. Visceral sensory information is conveyed to the CNS via vagal afferent nerve fibers, which terminate within the brainstem in the nucleus tractus solitarius (NTS). Neurons of the NTS assimilate this sensory information and project to integrative CNS centers involved in metabolic homeostasis, as well as to the adjacent dorsal motor nucleus of the vagus, which provides the preganglionic vagal motor output and, ultimately, coordinates GI vago-vagal reflexes. An extraordinary degree of adaptive plasticity is required to ensure that vagally-regulated GI functions respond properly to a variety of intrinsic and extrinsic (taste, stress, food, environmental conditions etc) factors, but the neural mechanisms responsible for this remodeling are not well understood. Our recent data indicate that the levels of cAMP in vagal brainstem circuits play a critical role in their adaptive plasticity. While these adaptive responses are essential to adjust to ever-changing physiological conditions, mal-adaptation or untimely deviations may lie behind the vagally-mediated exacerbation of meal- and/or stress-induced functional dyspepsia. Indeed, our preliminary data demonstrate that meal- and stress-related peptides induce radical modifications of vago-vagal reflex activities. We will combine electrophysiological (patch clamp recordings), in vivo functional (gastric tone and motility measurements) and molecular (single cell RT-PCR) approaches with the aim of defining the neural and cellular mechanisms controlling the plasticity of vagal brainstem circuits. Our overarching hypothesis is that selective activation of different groups of metabotropic glutamate receptors (mGluR) by vagal afferent inputs controls the plastic response of GI brainstem circuits to stress- and feeding-related hormones. Our overarching hypothesis predicts that inhibitory brainstem vago-vagal circuits are normally quiescent. This dormancy is determined by the low basal release of glutamate from subsets of vagal afferent fibers interacting with Gi/o-coupled mGluRs on NTS neurons. Following a meal, however, hormones or neuromodulators that increase cAMP levels overcome the dampening effects of mGluR activation, induce receptor trafficking on discrete neuronal circuits and dictate the appropriate vagal motor output. In physiological conditions, these plastic changes are essential to fulfill the digestive processes, however, derangements or untimely deviations may have pathophysiological consequences such as the vagally-mediated meal- and/or stress-induced functional dyspepsia. We anticipate that the results generated in this funding cycle will provide the background information necessary to develop novel therapeutic approaches to the treatment of those functional gastrointestinal motility disorders exacerbated by stress or digestive malfunctions.