Department of Physiology and Cell Biiology

 

 

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Terence Smith, Ph. D.

Professor


Professor Terence Smith is Director of the Dynamic Imaging Core in the Department of Physiology and Cell Biology., University of Nevada School of Medicine, Reno, Nevada USA.

He was honored with the Janssen Award (AGA) for excellence in basic research in Digestive Sciences in 2003.

He graduated (1970) with a BSc (Hons-Physics) and MSc (Solid State Physics) from the University of Sussex, UK. Following studies in low temperature physics and biophysics, he became a PhD student of Professors Mollie Holman and David Hirst (who first classified enteric AH and S neurons) in the Neuroscience group at Monash University, Australia. Following graduation (1984), he had Post Doctoral Fellowships with Kenton Sanders (Reno) and Marcello Costa and John Furness (Adelaide). He then became an Assistant Professor at the University of Virginia, returning to Reno as an Associate Professor in 1995. Dr. Smith has published over 100 well cited articles in prestigious journals, including Nature.

The major thrust of our laboratory is how the intrinsic (enteric) nervous system within the gut wall regulates bowel motility and secretion. In particular, to determine how the enteric) nervous system and intrinsic pacemaker networks regulate motility in different regions of the gastrointestinal (GI) tract. To do this we use a variety of techniques that include: intracellular microelectrode recordings from myenteric neurons and smooth muscle; patch clamping of functionally identified enteric neurons (DiI retrograde labeling); dot marker arrays and spatio-temporal maps to tract gut movements and fluorescent imaging of pacemaker cells and enteric neurons. In particular, we are using fluorescent imaging techniques to better understand the spread of excitability through intestinal smooth muscle, Interstitial Cells of Cajal (ICC) and enteric neurons. Our aim is to integrate activity in all these networks in order to understand how they interact with one another and generate the different motility patterns of the GI tract.

In particular, we are using fluorescent imaging techniques to better understand the spread of excitability through intestinal smooth muscle, Interstitial Cells of Cajal (ICC) and enteric neurons. Our aim is to integrate activity in all these networks in order to understand how they interact with one another and generate the different motility patterns of the GI tract.

Our group has proposed several paradigm shifts in GI physiology, including:

1) the two muscle layers of the muscularis externa are synchronously (not reciprocally) activated during peristaltic reflexes;

2) there are different functional classes of myenteric sensory interneurons that respond to either circumferential or longitudinal stretch;

3) The large intestine contains sensory AH neurons that respond to increases in muscle tension and sensory interneurons that respond to increases in muscle stretch. Therefore, these systems are analogous to Golgi tendon organs and muscle spindles in the somatic nervous system.

4) there is muscle tone dependent and stretch dependent peristalsis;

5) fecal matter regulates the propagation of colonic MMCs by generating local reflex activity.

6) most significantly, we have recently discovered another reflex in the gut wall that underlies colonic accommodation and slow transit. Transit through the human colon is extremely slow (30-48hrs) compared to that through the small intestine (2-4hrs), despite the colons much shorter length. This inhibitory reflex is triggered by colonic elongation that causes intrinsic sensory interneurons that respond to longitudinal stretch to release nitric oxide to inhibit nerve circuits underlying peristalsis. This inhibitory reflex is a natural physiological response triggered by accumulating fecal matter that elongates the colon.

Movies (Click on movie to view)

Movie 1 - A cross sectional preparation labeled with antibodies to the Kit receptor. ICC-MY form the top of the Y and ICC-SEP form the upright of the Y. ICC-IM are the elongated groups of ICC at either side of the Y.

Movie 1 Confocal reconstruction of ICC-MY and ICC-SEP networks (High Quality .mov)

Movie 1 Confocal reconstruction of ICC-MY and ICC-SEP networks (High Quality .wmv)

Movie 1 Confocal reconstruction of ICC-MY and ICC-SEP networks (Low Quality .mov)

Movie 1 Confocal reconstruction of ICC-MY and ICC-SEP networks (Low Quality .wmv)

Movie 2 - High powered view (x20) of the ICC-MY network in a flat-sheet preparation from which the longitudinal muscle had been dissected away. Traces are from individual ICC-MY taken from the ROI around individual ICC-MY. The ST-Map was constructed from the whole FOV. Note the apparent spread of activity spread from bottom to top of FOV. Movie played at 4x normal speed.

Movie 2 Spread of pacemaker activity through ICC-MY network. ( .mov)

Movie 2 Spread of pacemaker activity through ICC-MY network. ( .wmv)

Movie 3 - Medium powered view (x10) of ICC-MY and ICC-SEP networks in a cross-sectional preparation that was background subtracted. ICC-MY network runs horizontally and the ICC-SEP network runs from top to bottom. Movie shows Ca2+ transients spreading along the ICC-MY network then down ICC-SEP. Individual colored traces are taken from similar colored ROIs in the ICC-MY network (red, orange) and ICC-SEP network (yellow, green). Movie played at 4x normal speed.

Movie 3 Propagation of pacemaker activity down ICC-SEP ( .mov)

Movie 3 Propagation of pacemaker activity down ICC-SEP ( .wmv)

Movie 4 - Low powered view (x4) of a cross-sectional preparation. Movie shows Ca2+ transients in circular muscle bundles. Traces are from ROIs on neighboring circular muscle bundles. Note that activity in each circular muscle is likely due to Ca2+ action potentials. Activity in the 3 bundles was similar but out of phase, which gives a dynamic effect of switching between bundles. Movie played at 4x normal speed.

Movie 4 Activity in circular muscle bundles ( .mov)

Movie 4 Activity in circular muscle bundles ( .wmv)

Collaborators

Grant Hennig, Ph.D. (Assistant Professor)
[Computer analysis of fluorescent signals; Imaging of gut movements using dot marker arrays]

Eamond Dickson Ph.D. (Postdoctoral Fellow)
[Electrophysiological analysis of enteric reflexes triggered by colonic elongation]

Pieter Bayguinov BS (Graduate student)
[Fluorescent Imaging of activity in enteric neurons and intestinal smooth muscle in intact tissues]

Dante Heredia (Graduate student)
[Function of different 5-H T receptors in colonic propulsion]



Search For Dr. Smith's Publications In PubMed


Selected Publications

I) Flourescent calcium imaging of the intact gut

I) Flourescent calcium imaging of the intact gut
Lee HT, Hennig GW, Park KJ, Bayguinov PO, Ward SM, Sanders KM, Smith TK (2008). Heterogeneities in ICC Ca2+ activity within canine large intestine. Gastroenterology (In Press).
Lee H-T, Hennig GW, Fleming NW, Keef KD, Spencer NJ, Ward SM, Sanders KM & Smith TK (2007) Septal interstitial cells of Cajal conduct pacemaker activity to excite muscle bundles in human jejunum Gastroenterology 133(3):907-17.

Lee H-T, Hennig GW, Fleming NW, Keef KD, Spencer NJ, Ward SM, Sanders KM & Smith TK (2007) The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine. Gastroenterology 132(5):1852-65.

Park KJ, Hennig GW, Lee HT, Spencer NJ, Ward SM, Smith TK, Sanders KM. (2006) Spatial and temporal mapping of pacemaker activity in interstial cells of Cajal in mouse ileum in situ. Am J Physiol Cell Physiol 290(5):C1411-27.

Tack J. Smith TK (2004). Calcium imaging of gut activity. Neurogastroenterol Motil. 16 Suppl 1:86-95.

Hennig GW, Hirst GD, Park KJ, Smith CB, Sanders KM, Ward SM, Smith TK (2004) Propagation of pacemaker activity in the guinea-pig antrum. J. Physiol (Lond). 556.2, 585-599.

Hennig G., Smith CB, O’Shea DM, Smith TK (2002) Patterns of intracellular and intercellular calcium waves in longitudinal muscle of murine large intestine J. of Physiol (Lond) 543:233-53.

Stevens RJ, Publicover NG & Smith TK (2000) Propagation and neural regulation of calcium waves in longitudinal and circular muscle layers of guinea-pig small intestine? Gastroenterology, 118: 892-904.

Stevens RJ, Publicover NG & Smith TK (1999) Induction and regulation of Ca2+ waves by enteric neural reflexes. Nature, 399: 62-66.

Publicover NG, Smith TK & Stevens, RJ (1999) Fluorescent imaging of propagation of excitability in gastrointestinal muscles. In: Reporters, Dyes, and Instrumentation, 3600: 42-50. San Jose, California, Society SPIE Conference on Molecular Imaging of Photo-Optical Instrumentation Engineers, Washington, U.S.A.

II) Calcium Imaging and Electrophysiology of Enteric Neurons
Reis, HR, Vanden Berghe P, Romano-Silva MA & Smith TK (2006) GABA-induced calcium signaling in cultured enteric neurons is reinforced by activation of cholinergic pathways Neuroscience 139(2):485-94.

Smith TK, Kang SH, Vanden Berghe P (2003) Calcium channels in enteric neurons. Curr Opin Pharmacol. 3(6):588-93.

Kang SH, Vanden Berghe P, Smith TK (2003) Calcium-activated chloride current in cultured myenteric neurons from murine proximal colon Amer J Physiol Cell ;284(4):C839-47.
Vanden Berghe P, Kenyon JL, Smith TK (2002) Mitochondrial Ca2+ uptake regulates the excitability of myenteric neurons. J. of Neuroscience 22(16):6962-6971.

Smith TK, Burke EP, Shuttleworth, CWR (1999) Topographical and electrophysiological characteristics of highly excitable S neurons in the myenteric plexus of guinea-pig ileum J. Physiol (Lond), 517.3: 817-830.

Shuttleworth CWR, Smith TK (1999) Action potential-dependent calcium transients in myenteric S neurons of the guinea-pig ileum. Neuroscience 92(2), 751-62.

Shuttleworth CWR, Smith TK (1997) Relationship between calcium transients and after hyperpolarizations in guinea-pig myenteric neurons. J. Auton. Nerv. Syst. 65, 129-139.

III) Enteric reflexes and Migrating motor complexes
Heredia DJ, Dickson EJ, Hennig GW, Lee HT, Bayguinov PO, Spencer NJ, Smith TK (2008). Localized release of 5-HT by a fecal pellet regulates migrating motor complexes in murine colon. Gastroenterology (In Press).

Dickson EJ, Hennig GW, Heredia DJ, Lee HT, Bayguinov PO, Spencer NJ, Smith TK (2008). Polarized intrinsic neural reflexes in response to colonic elongation. J Physiol (Lond).1;586(Pt 17):4225-40.

Dickson, EJ, Spencer NJ, Bayguinov PO, Heredia DJ, Hennig GW, Smith TK (2007) An intrinsic occult reflex underlies accommodation and slow transit in the distal large bowel Gastroenterology 132(5):1912-24.

Spencer NJ, Dickson EJ, Hennig GW, Smith TK (2006) Sensory elements within the circular muscle are essential for mechanotransduction of ongoing peristaltic reflex activity in guinea-pig distal colon. J Physiol (Lond) 15;576(Pt 2):519-31.

Spencer NJ, Hennig GW, Bayguinov P, Park KJ, Lee HT, Heredia DJ, Sanders KM, Smith TK (2006) Activation of neuronal circuitry and Ca2+ waves in longitudinal and circular muscle during colonic MMCs and the consequences of rectal aganglionosis in mice. Am J Physiol Gastrointest Liver Physiol. 2006 Oct 5; [Epub ahead of print]

Smith TK, Spencer NJ, Hennig GW (2004) Mechanosensory transduction in the enteric nervous system. Physiological News. 58, 1-3.

Spencer NJ, Smith TK (2004) Mechanosensory S-neurons rather than AH neurons appear to generate a rhythmic motor pattern in guinea-pig distal colon. J. Physiol (Lond). 558(Pt 2):577-96.

Smith TK, Oliver GR, Hennig GW, Vanden Berghe P, Kang SH, Spencer N (2003) A smooth muscle tone-dependent stretch-activated migrating motor pattern in isolated guinea-pig distal colon. J. Physiol (Lond) 551(Pt 3):955-69.

Spencer NJ, Sanders KM, Smith TK (2003) Migrating motor complexes do not require electrical slow waves in the mouse small intestine J. Physiol (Lond) 15;553(Pt 3):881-93.

Spencer N, Hennig, GW, Smith TK (2003) Stretch-activated neuronal pathways to longitudinal and circular muscle in guinea pig distal colon. Amer J Physiol 284(2):G231-G241.

Spencer N, Hennig G, Smith TK (2002) A rhythmic motor pattern activated by circumferential stretch in guinea-pig distal colon J. Physiol (Lond) 545(Pt 2):629-48.


REVIEWS:

Smith TK, Spencer NJ, Hennig GW (2007) Recent advances in enteric neurobiology: mechanosensory internerneurons Neurogastroenterol Motil. 9(11):869-78.

Smith TK, Dickson EJ, Hennig GW, Bayguinov PO, Spencer NJ (2007) Colonic elongation activates an intrinsic reflex that underlies slow transit and accommodation Physiological News 69: 33-35.

Shea-Donohue T, Cook IJ, de Giorgio R, Tonini M, Dent J, Costa M, Grundy D, Sanders KM, Schemann M, Smith TK, Brookes SJ; the varenna group (2005) A teaching module on irritable bowel syndrome. Neurogastroenterol & Motil. 17 Suppl 3:20-40.

Costa M, Sanders KM, Schemann M, Smith TK, Cook IJ, de Giorgio R, Dent J, Grundy D, Shea-Donohue T, Tonini M, Brookes SJ; the varenna group (2005) A teaching module on cellular control of small intestinal motility. Neurogastroenterol & Motil. 2005 Oct;17 Suppl 3:4-19.

Brookes SJ, Cook IJ, Costa M, de Giorgio R, Dent J, Grundy D, Sanders KM, Schemann M, Shea-Donohue T, Smith TK, Tonini M; the varenna group (2005). Education project for pathophysiology of gastrointestinal motility. Neurogastroenterol & Motil. 17 Suppl 3:2-3.

Smith TK, Hennig GW, Spencer N (2005) Sensory transduction in the ENS Physiological News 58: 1-3.

Tack J, Smith TK (2004). Calcium imaging of gut activity. Neurogastroenterol & Motil. 16 Suppl 1:86-95.

Smith TK, Kang SH, Vanden Berghe P (2003) Calcium channels in enteric neurons. Curr Opin Pharmacol. 3(6):588-93.

Sanders, KM & Smith,TK (2003) Neural regulation of colonic motor function. In: Colonic Diseases, Ed. Timothy Koch, M.D., Humana Press, Inc. Ch 3, 35-52.