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.

Public Health Relevance

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 without increasing gastric pressure. 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. Many GI hormones released following meal ingestion exert dramatic control over these vagally-mediated GI functions and such adaptive responses are essential to adjust to ever-changing physiological conditions. 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 GI 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 GI 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 GI-related autonomic homeostatic circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078364-05
Application #
8704922
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Hershey
State
PA
Country
United States
Zip Code
17033
McMenamin, C A; Travagli, R A; Browning, K N (2018) Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions. Neurogastroenterol Motil 30:
Browning, Kirsteen N; Verheijden, Simon; Boeckxstaens, Guy E (2017) The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation. Gastroenterology 152:730-744
McMenamin, Caitlin A; Travagli, R Alberto; Browning, Kirsteen N (2016) Inhibitory neurotransmission regulates vagal efferent activity and gastric motility. Exp Biol Med (Maywood) 241:1343-50
Troy, Amanda E; Simmonds, Sarah S; Stocker, Sean D et al. (2016) High fat diet attenuates glucose-dependent facilitation of 5-HT3 -mediated responses in rat gastric vagal afferents. J Physiol 594:99-114
Travagli, R Alberto; Anselmi, Laura (2016) Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol 13:389-401
Browning, Kirsteen N (2015) Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 9:413
McMenamin, Caitlin A; Browning, Kirsteen N (2014) Highlights in basic autonomic neurosciences: Diet-induced enteric, vagal and brainstem dysfunction. Auton Neurosci 186:1-4
Browning, Kirsteen N; Hajnal, Andras (2014) The effects of bariatric surgery: will understanding its mechanism render the knife unnecessary? Expert Rev Gastroenterol Hepatol 8:1-4
Babic, Tanja; Browning, Kirsteen N (2014) The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 722:38-47
Doheny, K K; Palmer, C; Browning, K N et al. (2014) Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants. Neurogastroenterol Motil 26:832-40

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