Postganglionic sympathetic neurons located in the prevertebral ganglia (PVG) provide ongoing sympathetic tone to the entire gastrointestinal (GI) tract. In addition, these neurons coordinate motor, secretory and vascular functions via reflexes initiated by intestinofugal afferent neurons (IFANs) located in the wall of the intestine. The overall hypothesis to be tested by these proposed studies is that the mechanisms by which information is transmitted through the PVG are altered during intestinal inflammation. Experiments proposed in this application will test this hypothesis by addressing three specific aims.
Specific Aim 1 tests the hypothesis that TNBS-induced colitis causes a loss of IFANs that result in the increased expression of functional purinergic and glutamatergic ligand-gated ion channels in PVG neurons.
Specific Aim 2 tests the hypothesis that the expression and function of 12A adrenergic receptors (ARs) on the terminal fields of PVG neurons in the ileum is increased following the onset of TNBS or acetic acid induced colitis.
Specific Aim 3 tests the hypothesis that purinergic and glutamatergic synaptic transmission in the PVG and a change in the expression of 12A ARs during colitis result in altered motor function in the small intestine. The overall hypothesis of this proposal is supported by preliminary data indicating several distinct changes in the physiology of PVG neurons during colitis. Inflammation causes an increased excitability of PVG neurons and a change in the ionotropic receptors that contribute to fast synaptic communication. This would likely contribute to increased sympathetic outflow to the GI tract. In addition, colitis is associated with an increased expression of autoinhibitory 12A ARs on the axon terminal fields of PVG neurons. By impeding invading action potentials from causing norepinephrine release, enhanced 12A ARs would result in a reduction of sympathetic outflow to more normal levels. The temporal relationship between these changes in the physiology of PVG neurons and altered ileal motor function will elucidate potential contributing mechanisms to clinically relevant bowel dysfunction. Collectively, the experiments proposed are a systematic approach to understanding the change in function of PVG neurons during colitis. The results of these experiments are likely to provide an understanding of new mechanisms by which the physiology of PVG neurons is regulated and may provide insight to the development of novel therapeutic agents that target the PVG to regulate GI motility. Public Health Relevance: Changes in the structure and function of the nerves that supply the gastrointestinal tract contribute to both symptoms commonly encountered during intestinal inflammation, as well as symptoms that can persist long after the initial insult. Sympathetic autonomic nerve cells, which integrate signals from nerve cells in the brain and spinal cord with signals from nerve cells in the gastrointestinal tract, have not previously been studied for their contribution to altered gut function;therefore specific changes in these cells will be examined during inflammation of the large intestine, or colitis. The results of these studies are expected to provide an understanding of new mechanisms by which the nervous system control of movements of gastrointestinal contents is altered during colitis and will provide insight to the development of new therapies for the treatment of bowel dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076665-05
Application #
8217087
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2008-04-01
Project End
2013-04-30
Budget Start
2012-02-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$296,186
Indirect Cost
$100,166
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Brierley, Stuart M; Linden, David R (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat Rev Gastroenterol Hepatol 11:611-27
Linden, David R (2014) Hydrogen sulfide signaling in the gastrointestinal tract. Antioxid Redox Signal 20:818-30
Sha, Lei; Linden, David R; Farrugia, Gianrico et al. (2013) Hydrogen sulfide selectively potentiates central preganglionic fast nicotinic synaptic input in mouse superior mesenteric ganglion. J Neurosci 33:12638-46
Linden, David R (2013) Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis. Neurosci Lett 545:91-5
Linden, D R; Furne, J; Stoltz, G J et al. (2012) Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS. Br J Pharmacol 165:2178-90
Asuzu, D T; Hayashi, Y; Izbeki, F et al. (2011) Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging. Neurogastroenterol Motil 23:e309-23