DESCRIPTION (provided by applicant): Vagal brainstem circuits are vitally important in the co-ordination of food ingestion, gastrointestinal (GI) functions and autonomic homeostasis. The receptive relaxation reflex is a classical, vagally-mediated reflex activated upon distension of the esophagus (during swallowing, for example) that induces gastric relaxation and suppression of motility, allowing the stomach to accept ingesta isobarically. At the same time, this reflex is used as the first step in regulation of nutrient absorption and homeostasis. By decreasing gastric tone and motility, the receptive relaxation reflex delays gastric emptying, slows the rate at which chyme is transported to the intestine and, by consequence, regulates the rate of nutrient absorption. Data collected in recent years by several laboratories, including our own, has suggested that many GI hormones released following meal ingestion exert dramatic control over vagally-mediated GI functions. Adaptive responses within autonomic neural circuits are essential to adjust to ever-changing physiological conditions, indeed some of the most dramatic physiological variations occur as a consequence of meal ingestion. Blood glucose levels oscillate throughout the day and increase dramatically following food intake; adaptive autonomic sensory and motor responses are necessary to stabilize these fluctuations and maintain homeostasis. Acute changes in blood glucose levels, even within the physiological range, exert profound vagally-mediated effects on gastric motility and emptying. These glucose-induced responses are extremely important in minimizing otherwise dramatic, potentially damaging, excursions in blood glucose levels. Short-term plasticity within homeostatic neural circuits allows autonomic reflexes to be modulated, by either exaggerating or attenuating the output response, or by transforming the response pattern or duration. Even transient modulation in the strength of key synapses within autonomic circuits has the potential to induce short-term plasticity. Disruption or untimely variations in these adaptive responses, however, may cause inappropriately exaggerated reflexes and possibly even induce pathophysiological results. Exacerbation of the normal physiological response to meal ingestion, for example, may induce a variety of pathological conditions, including, for example, functional gastric motility disorders, obesity or cachexia. The specific mechanisms by which glucose can reorganize vagally-mediated gastrointestinal visceral reflexes are not well understood. Preliminary data from our laboratories strongly suggest that the receptive relaxation reflex could provide an ideal model system in which we can test specific, mechanistic hypotheses. We will use a variety of techniques including in vivo neurogastroenterology, immunocytochemistry and in vitro neurophysiology to test the overarching hypothesis that glucose regulates vagally-mediated gastrointestinal reflexes via brainstem sites of action. In short, we propose that the vagally-mediated gastrointestinal reflexes, such as the receptive relaxation reflex, are under the direct control of brainstem glucose levels and that glucose regulates the expression of neurotransmitter receptors on selected subpopulations of gastrointestinal vagal sensory neurons via modulation of protein kinase C-dependent pathways. This proposal will generate data that will lead to an improved understanding of mechanisms regulating the modulation of vago-vagal reflexes and how changes in metabolic and hormonal parameters affect the brainstem plasticity of ingestive and gastrointestinal-related autonomic homeostatic circuits.
|Effective start/end date||9/1/10 → 7/31/16|
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $302,434.00
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $290,689.00
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $284,467.00
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $268,465.00
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES: $271,897.00
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