The overall goal of this study is to determine how sphincter od Oddi (SO) function can be regulated by inputs which modulate the activity of SO neurons. Understanding the regulation of SO function is clinically important as approximately 15% of the US population suffers from disease of the biliary system, and SO malfunction is a major contributor to morbidity associated with biliary tract disease. Our strategy is to make use of newly devised combinations of techniques to determine how the excitability of SO neurons is modulated, and to identify the regulatory inputs that drive and modulate these cells. Mounting evidence suggests that what were originally though of as distinct subpopulations of SO neurons (Tonic and Phasic) are actually two electrical phenotypes that the same SO neuron can express. The first specific aim is to establish the cellular mechanisms that cause SO neurons to changes their electrophysiological phenotype between excitable (tonic) and much less excitable (phasic) modes, and what physiological signals could initiate these shifts. We will test the novel hypothesis that neurohormonal inputs can act on these cells to up-and/or down-modulate a potassium conductance that inhibit neuronal excitability, and that these changes occur in synchrony with the feeding cycle. This form of phenopasticity, which will be evaluated in SO neurons, could occur in a similar manner in neurons throughout the gastrointestinal tract. The second specific aim is to test the hypothesis that SO neurons can be activated by mucosal CCK release through a neural internet between the duodenum and the SO. A neuron>SO projection will be confirmed and characterized with retrograde tracers and immunohistochemistry. A double chamber organ both will be used to determine whether activation of the duodenal myenteric plexus and agents that release CCK, cause and increase in neuronal activity in the SO. The third specific aim is to identify the origins and mediators of excitatory synaptic inputs to the SO neurons. To understand how local neurons control their effector tissue targets, it is crucial to identify the driving and modulatory signals received by those neurons. The studies of aim 3 will involve electrophysiological recording and immunohistochemistry, in combination with selective lesions and pharmacological analysis, to determine the origins and mediators of inputs that can regulate SO function. The proposal studies are highly feasible and promise to advance our understanding of the neurohormonal control of sphincter function. If our theories are substantiated, these studies will elucidate the major contributors of extrinsic control of SO function, demonstrate novel mechanisms of sphincter regulation, and question the dogma that a neuron has fixed electrophysiological phenotype.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Serrano, Jose
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University of Vermont & St Agric College
Anatomy/Cell Biology
Schools of Medicine
United States
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Balemba, Onesmo B; Salter, Matthew J; Mawe, Gary M (2004) Innervation of the extrahepatic biliary tract. Anat Rec A Discov Mol Cell Evol Biol 280:836-47
Ellis, Lisa M; Mawe, Gary M (2003) Distribution and chemical coding of cocaine- and amphetamine-regulated transcript peptide (CART)-immunoreactive neurons in the guinea pig bowel. Cell Tissue Res 312:265-74
Pozo, Maria J; Perez, Guillermo J; Nelson, Mark T et al. (2002) Ca(2+) sparks and BK currents in gallbladder myocytes: role in CCK-induced response. Am J Physiol Gastrointest Liver Physiol 282:G165-74
Guarraci, Fay A; Pozo, Maria J; Palomares, Sara M et al. (2002) Opioid agonists inhibit excitatory neurotransmission in ganglia and at the neuromuscular junction in Guinea pig gallbladder. Gastroenterology 122:340-51
Mawe, G M; Ellis, L M (2001) Chemical coding of intrinsic and extrinsic nerves in the guinea pig gallbladder: distributions of PACAP and orphanin FQ. Anat Rec 262:101-9
Linden, D R; Manning, B P; Bunnett, N W et al. (2001) Agonists of proteinase-activated receptor 2 excite guinea pig ileal myenteric neurons. Eur J Pharmacol 431:311-4
Alcon, S; Morales, S; Camello, P J et al. (2001) A redox-based mechanism for the contractile and relaxing effects of NO in the guinea-pig gall bladder. J Physiol 532:793-810
O'Donnell, A M; Ellis, L M; Riedl, M S et al. (2001) Distribution and chemical coding of orphanin FQ/nociceptin-immunoreactive neurons in the myenteric plexus of guinea pig intestines and sphincter of Oddi. J Comp Neurol 430:1-11
Manning, B P; Mawe, G M (2001) Tachykinins mediate slow excitatory postsynaptic transmission in guinea pig sphincter of Oddi ganglia. Am J Physiol Gastrointest Liver Physiol 281:G357-64
Kennedy, A L; Saccone, G T; Mawe, G M (2000) Direct neuronal interactions between the duodenum and the sphincter of Oddi. Curr Gastroenterol Rep 2:104-11

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