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.

Public Health Relevance

Functional gastrointestinal motility disorders, including functional dyspepsia, are 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 is not understood completely, but several lines of evidence point towards the impairment of information processing between the gut and the brain. Under normal conditions, the upper gastrointestinal tract, i.e. the stomach and the small intestine, sends information regarding the state of the gut to specific brain areas via the sensory vagus nerve. The brain interprets this information and sends its response back to the gut via the motor portion of the vagus nerve. In order to control digestive processes properly, this gut-brain neural circuit requires precise adaptive mechanisms. While these adaptive responses are essential to adjust to ever-changing physiological conditions, mal-adaptation or untimely deviations may have pathophysiological consequences such as, for example, exacerbation of stress-induced functional gastrointestinal motility disorders. In the present proposal we will combine state-of-the-art physiological and biochemical techniques to investigate the neural processes occurring at the gut-brain interface in response to stress and feeding-related hormones. We anticipate that the information generated by the present proposal will provide the background necessary to develop novel therapeutic approaches to the treatment of functional gastrointestinal motility disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055530-15
Application #
8277999
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
1998-09-05
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
15
Fiscal Year
2012
Total Cost
$329,354
Indirect Cost
$116,180
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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
Browning, Kirsteen N; Babic, Tanja; Toti, Luca et al. (2014) Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor. J Physiol 592:4591-605
Babic, Tanja; Travagli, R Alberto (2014) Role of metabotropic glutamate receptors in the regulation of pancreatic functions. Biochem Pharmacol 87:535-42
Babic, Tanja; Travagli, R Alberto (2014) Acute pancreatitis decreases the sensitivity of pancreas-projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats. J Physiol 592:1411-21
Swartz, E M; Browning, K N; Travagli, R A et al. (2014) Ghrelin increases vagally mediated gastric activity by central sites of action. Neurogastroenterol Motil 26:272-82
Babic, Tanja; Browning, Kirsteen N (2014) The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 722:38-47
Browning, K N; Babic, T; Holmes, G M et al. (2013) A critical re-evaluation of the specificity of action of perivagal capsaicin. J Physiol 591:1563-80
Holmes, Gregory M; Browning, Kirsteen N; Babic, Tanja et al. (2013) Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone. J Physiol 591:3081-100
Babic, Tanja; Browning, Kirsteen N; Travagli, R Alberto (2011) Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. Am J Physiol Gastrointest Liver Physiol 300:G21-32
Browning, Kirsteen N; Travagli, R Alberto (2011) Plasticity of vagal brainstem circuits in the control of gastrointestinal function. Auton Neurosci 161:6-13

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