1977 Kobe University School of Medicine, Kobe, Japan
1985 Graduate School of Hyogo College of Medicine, Nishinomiya, Japan
1990 Postdoctoral Fellow, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
Professional Training and Employment
1985 Assistant Professor, Second Department of Surgery, Hyogo College of Medicine,
1990 Vice President, Sadamitsu Hospital, Kakogawa, Japan
1992 Research Investigator, Division of Gastroenterology, University of Michigan,
Ann Arbor, MI
1996 Assistant Research Scientist, Division of Gastroenterology, University of Michigan,
Ann Arbor, MI
2000 Associate Professor, Department of Surgery, Duke University, Durham, NC
2007 Professor, Department of Surgery, Duke University, Durham, NC
2008 Professor, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
Dr. Takahashi's research interest is brain-gut axis and nerve-gut interaction in gastrointestinal (GI) motility.
Table of Contents:
a. Pathophysiological role of nitric oxide of the myenteric plexus
Nitric oxide (NO) has been demonstrated as an important inhibitory neurotransmitter in GI tract. NO of the stomach plays an important role in mediating accommodation reflex 1, 2. NO of the pylorus regulates gastric emptying in rats 3, 4 and dogs 5. NO of the proximal colon contributes to fecal storage and absorption of excess fluid 6. NO enhances colonic transit by mediating descending relaxation and facilitating propulsion of the colonic contents 7.
NO is produced by the activation of neuronal NO synthase (nNOS) in the myenteric plexus. Expression of nNOS is altered by extrinsic denervation 8, 9, diabetes 10, colitis 11 and aging 12. The pathophysiological significance of nNOS of the myenteric plexus was summarized in his review article 13.
- Takahashi T, Owyang C. Vagal control of nitric oxide and vasoactive intestinal polypeptide release in the regulation of gastric relaxation in rat. J Physiol (Lond) 1995;484:481-92.
- Takahashi T, Owyang C. Characterization of vagal pathways mediating gastric accommodation reflex in rats. J Physiol (Lond) 1997;504:479-88.
- Ishiguchi T, Nishioka S, Takahashi T. Inhibitory neural pathway regulating gastric emptying in rats. J Auton Nerv Syst 2000;79:45-51.
- Ishiguchi T, Takahashi T, Itoh H, Owyang C. Nitrergic and purinergic regulation of the rat pylorus. Am J Physiol 2000;279:G740-7.
- Ueno T, Uemura K, Harris MB, Pappas TN, Takahashi T. Role of vagus nerve in postprandial antropyloric coordination in conscious dogs. Am J Physiol Gastrointest Liver Physiol 2005;288:G487-95.
- Takahashi T, Owyang C. Regional differences in the nitrergic innervation between the proximal and the distal colon in rats. Gastroenterology 1998;115:1504-12.
- Mizuta Y, Takahashi T, Owyang C. Nitrergic regulation of colonic transit in rats. Am J Physiol 1999;277:G275-9.
- Nakamura K, Takahashi T, Taniuchi M, Hsu CX, Owyang C. Nicotinic receptor mediates nitric oxide synthase expression in the rat gastric myenteric plexus. J Clin Invest 1998;101:1479-89.
- Nakao K, Takahashi T, Utsunomiya J, Owyang C. Extrinsic neural control of nitric oxide synthase expression in the myenteric plexus of rat jejunum. J Physiol (Lond) 1998;507:549-60.
- Takahashi T, Nakamura K, Itoh H, Sima AA, Owyang C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 1997;113:1535-44.
- Mizuta Y, Isomoto H, Takahashi T. Impaired Nitrergic Innervation in Rat Colitis Induced by Dextran Sulfate Sodium. Gastroenterology 2000;118:714-723.
- Takahashi T, Qoubaitary A, Owyang C, Wiley JW. Decreased expression of nitric oxide synthase in the colonic myenteric plexus of aged rats. Brain Res 2000;883:15-21.
- Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003;38:421-30.
b. Contractile effects of orphanin FQ in rat colon (supported by NIH RO1)
Orphanin FQ (OFQ) structurally resembles dynorphin A. OFQ-immunopositive neuronal fibers were found in the colonic myenteric plexus 14. In situ hybridization revealed that OFQ receptor-mRNA was expressed in the colonic myenteric plexus but not in the muscle layers. OFQ causes significant contractions in the rat colon but not in the stomach or small intestine in vitro.
The mechanisms and sites of action of OFQ seem to be region specific; OFQ inhibits cholinergic transmission in the stomach and small intestine, whereas OFQ stimulates colonic contraction via inhibiting purinergic inhibitory motor neurons within the myenteric plexus 15. OFQ accelerates colonic transit by promoting migrating colonic contractions, while dynorphin A delays colonic transit by causing non-migrating colonic contractions 16.
- Yazdani A, Takahashi T, Bagnol D, Watson SJ, Owyang C. Functional Significance of a Newly Discovered Neuropeptide, Orphanin FQ, in Rat Gastrointestinal Motility. Gastroenterology 1999;116:108-117.
- Takahashi T, Bagnol D, Schneider D, Mizuta Y, Ishiguchi T, Le PK, Galligan JJ, Watson SJ, Owyang C. Orphanin FQ causes contractions via inhibiting purinergic pathway in the rat colon. Gastroenterology 2000;119:1054-63.
- Takahashi T, Mizuta Y, Owyang C. Orphanin FQ, but not dynorphin A, accelerates colonic transit in rats. Gastroenterology 2000;119:71-9.
c. Effects of hyperglycemia on gastric emptying (supported by VA-Merit Award)
Hyperglycemia associated with diabetes alters gastric motor function. Acute hyperglycemia inhibits gastric distension-induced pyloric relaxation via vagal dependent mechanisms 17. Acute hyperglycemia impairs postprandial coordination between the antrum and pylorus in conscious rats 18, 19. Acute hyperglycemia attenuates the neuronal activity of the dorsal motor nucleus of vagi 20. In contrast, accelerated gastric emptying and augmented antro-pyloric coordinations are observed 2 weeks after streptozotocin (STZ)-injection in rats 21.
Ghrelin regulates postprandial contractions 22 as well as interdigestive contractions of the stomach in rodents 22-26. Accelerated gastric emptying observed in the early stage of diabetes is mediated via an increased ghrelin release 21, 27.
- Ishiguchi T, Nakajima M, Sone H, Tada H, Kumagai A, Takahashi T. Gastric distension-induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat. J Physiol 2001;533:801-13.
- Ishiguchi T, Amano T, Matsubayashi H, Tada H, Fujita M, Takahashi T. Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats. Am J Physiol Regul Integr Comp Physiol 2001;281:R1522-30.
- Ishiguchi T, Tada H, Nakagawa K, Yamamura T, Takahashi T. Hyperglycemia impairs antro-pyloric coordination in conscious rats. Auton Neurosci 2002;95:112-120.
- Takahashi T, Matsuda K, Kono T, Pappas TN. Inhibitory effects of hyperglycemia on neural activity of the vagus in rats. Intensive Care Med 2003;29:309-11.
- Ariga H, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T. Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus? Am J Physiol Regul Integr Comp Physiol 2008;294:R1807-12.
- Ariga H, Nakade Y, Tsukamoto K, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T. Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats. Regul Pept 2008;146:112-6.
- Ariga H, Tsukamoto K, Chen C, Mantyh C, Pappas TN, Takahashi T. Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol Motil 2007;19:675-80.
- Taniguchi H, Ariga H, Zheng J, Ludwig K, Mantyh C, Pappas TN, Takahashi T. Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats. Am J Physiol Gastrointest Liver Physiol 2008;295:G403-11.
- Zheng J, Ariga H, Taniguchi H, Ludwig K, Takahashi T. Ghrelin regulates gastric phase III-like contractions in freely moving conscious mice. Neurogastroenterol Motil 2009;21:78-84.
- Bulbul M, Babygirija R, Zheng J, Ludwig K, Xu H, Lazar J, Takahashi T. Food intake and interdigestive gastrointestinal motility in ghrelin receptor mutant rats. J Gastroenterol 2011;46:469-78.
- Ariga H, Imai K, Ludwig K, Takahashi T. Gastric emptying, plasma ghrelin and autonomic nerve activity in diabetic rats. Neurosci Lett 2012;514:77-81.
d. Mechanism of acupuncture on GI motility (supported by NIH R21)
Although acupuncture has been used to treat gastrointestinal symptoms in China for more than 3,000 years, mechanism of the beneficial effects of acupuncture remains unclear. According to the Traditional Chinese Medicine, the energy force (known as Qi) runs through the body. This Qi energy enters the body through specific acupuncture points and flows to deeper organ structures, bringing life-giving nourishment of a subtle energetic nature. Meridians are classified on the basis of the direction in which Qi flows on the surface of the body. If the flow of Qi is insufficient, unbalanced or interrupted, illness may occur. However, these ancient concepts of Qi and meridians have no counterpart in modern studies of chemistry, biology and physics. To date, scientists have been unable to find evidence that supports their existence. In humans, more than 300 acupuncture points are located along the meridians. Despite the fact that the specific acupuncture points are used for treating specific symptoms and/or diseases, it is not fully understood how their specificity applies and how the needling at acupuncture points works. There was no clear evidence to demonstrate the existence of acupuncture points or meridians. Present evidence does not conclusively support that acupuncture points or meridians are electrically distinguishable.
On the other hand, numerous studies demonstrated that somatic afferents from the skin and muscle are involved in the control of GI motor functions. Acupuncture treatment involves the insertion of thin needles into the skin and underlying muscle layer. Inserted acupuncture needles are now often stimulated by electricity under various frequencies of 1-100 Hz (electroacupuncture; EA). Thus, this procedure stimulates the somatic afferent nerves of the skin and muscles 28, 29.
We showed that acupuncture on the ST-25 (abdomen) causes a relaxation of the stomach 30, while acupuncture on the lower leg (ST-36) causes a contraction in rats 31. Acupuncture-induced gastric relaxation is mediated via somato-sympathetic reflex. Its afferent limb is composed of abdominal cutaneous and muscle afferent nerves and its efferent limb is the gastric sympathetic nerve. The reflex center is within the medulla 30, 32. In contrast, the contractile effects of acupuncture at ST-36 are mediated via vagal efferent pathway 31, 33.
Nucleus tractus solitarius (NTS) is the primary brainstem relay for visceral information from cardiovascular, respiratory and GI systems. NTS is adjacent to the dorsal motor nucleus of the vagus (DMV) and composes the dorsal vagal complex (DVC). DVC integrates vago-vagal reflex which play a major role in the regulation of GI function. NTS also receives somatic afferent inputs. NTS neurons are activated by cutaneous mechanical stimulus, suggesting that somatic stimulation induced by acupuncture is conveyed to the NTS through the spinal cord. To obtain the anatomical evidences of possible neural pathways in mediating acupuncture-induced gastric motor responses, we studied c-Fos immunohistochemistry of the brain stem in response to acupuncture. We showed that somatic afferents activated by acupuncture at ST-36 is conveyed to the medio-caudal and caudal NTS and stimulates the DMV neurons. In contrast, somatic afferents activated by acupuncture at ST-25 is conveyed to the medio-caudal NTS and stimulates the rostral ventrolateral medulla (RVLM) neurons. The RVLM neurons are known as premotor sympatho-excitatory neurons that provide drive to the sympathetic preganglionic neurons in the intermediolateral nucleus of the spinal cord 34.
Acupuncture at ST-36 accelerates colonic motility and transit in normal conditions in conscious rats. The stimulatory effect acupuncture is mediated via a sacral parasympathetic efferent pathway (pelvic nerve) 35. On the other hand, acupuncture at ST-36 attenuates accelerated colonic transit induced by restraint stress in rats 32. Acupuncture improves imbalance of autonomic function under the restraint stress in rats 36. Our recent study showed that acupuncture upregulates hypothalamic oxytocin expression which acts as an anti-stressor agent and mediates restored colonic dysmotility following chronic stress 37.
In conscious dogs, acupuncture at the wrist prevents emesis induced by vasopressin. The anti-emetic effect of acupuncture is mediated via a central opioid pathway 38, 39. Acupuncture at ST-36 reduces rectal distension-induced blood pressure changes in conscious dogs. The anti-nociceptive effect of acupuncture is also mediated via a central opioid pathway 40. Migrating motor complex (MMC) is well characterized by the appearance of GI contractions in the interdigestive state. Maintaining gastric MMC is an important factor to prevent the postprandial dyspeptic symptoms 41-43. Acupuncture at ST-36 restores impaired interdigestive gastric MMC induced by acoustic stress via increasing vagal activity in dogs 44.
Our studies suggest that acupuncture is useful to treat the patients with functional GI disorders, like functional dyspepsia (FD) and irritable bowel syndromes (IBS) 28, 29, 45.
- Takahashi T. Mechanism of acupuncture on neuromodulation in the gut--a review. Neuromodulation 2011;14:8-12; discussion 12.
- Takahashi T. Effect and mechanism of acupuncture on gastrointestinal diseases. Int Rev Neurobiol 2013;111:273-94.
- Tada H, Fujita M, Harris M, Tatewaki M, Nakagawa K, Yamamura T, Pappas TN, Takahashi T. Neural mechanism of acupuncture-induced gastric relaxations in rats. Dig Dis Sci 2003;48:59-68.
- Tatewaki M, Harris M, Uemura K, Ueno T, Hoshino E, Shiotani A, Pappas TN, Takahashi T. Dual effects of acupuncture on gastric motility in conscious rats. Am J Physiol Regul Integr Comp Physiol 2003;285:R862-72.
- Iwa M, Nakade Y, Pappas TN, Takahashi T. Electroacupuncture elicits dual effects: stimulation of delayed gastric emptying and inhibition of accelerated colonic transit induced by restraint stress in rats. Dig Dis Sci 2006;51:1493-500.
- Imai K, Ariga H, Chen C, Mantyh C, Pappas TN, Takahashi T. Effects of electroacupuncture on gastric motility and heart rate variability in conscious rats. Auton Neurosci 2008;138:91-8.
- Iwa M, Tateiwa M, Sakita M, Fujimiya M, Takahashi T. Anatomical evidence of regional specific effects of acupuncture on gastric motor function in rats. Auton Neurosci 2007;137:67-76.
- Iwa M, Matsushima M, Nakade Y, Pappas TN, Fujimiya M, Takahashi T. Electroacupuncture at ST-36 accelerates colonic motility and transit in freely moving conscious rats. Am J Physiol Gastrointest Liver Physiol 2006;290:G285-92.
- Imai K, Ariga H, Takahashi T. Electroacupuncture improves imbalance of autonomic function under restraint stress in conscious rats. Am J Chin Med 2009;37:45-55.
- Yoshimoto S, Babygirija R, Dobner A, Ludwig K, Takahashi T. Anti-stress effects of transcutaneous electrical nerve stimulation (TENS) on colonic motility in rats. Dig Dis Sci 2012;57:1213-1221.
- Tatewaki M, Strickland C, Fukuda H, Tsuchida D, Hoshino E, Pappas TN, Takahashi T. Effects of acupuncture on vasopressin-induced emesis in conscious dogs. Am J Physiol Regul Integr Comp Physiol 2005;288:R401-8.
- Takahashi T, Tsuchida D, Pappas TN. Central effects of morphine on GI motility in conscious dogs. Brain Res 2007;1166:29-34.
- Iwa M, Strickland C, Nakade Y, Pappas TN, Takahashi T. Electroacupuncture reduces rectal distension-induced blood pressure changes in conscious dogs. Dig Dis Sci 2005;50:1264-70.
- Nakajima H, Mochiki E, Zietlow A, Ludwig K, Takahashi T. Mechanism of interdigestive migrating motor complex in conscious dogs. J Gastroenterol 2010;45:506-14.
- Takahashi T. Mechanism of interdigestive migrating motor complex. J Neurogastroenterol Motil 2012;18:246-57.
- Takahashi T. Interdigestive migrating motor complex -its mechanism and clinical importance. J Smooth Muscle Res 2013;49:99-111.
- Taniguchi H, Imai K, Ludwig K, Takahashi T. Effects of acupuncture on stress-induced gastrointestinal dysmotility in conscious dogs. Medical Acupuncture 2012;24:43-49.
- Takahashi T. Acupuncture for functional gastrointestinal disorders. J Gastroenterol 2006;41:408-17.
e. Stress-induced GI motility disorders (supported by NIH RO1)
Stress is one of the most important contributing factors in the pathogenesis of functional GI disorders. Patients with serious stress frequently complain of GI symptoms and these symptoms are, at least in part, due to GI motility disorders. Restrain stress delays solid gastric emptying in rats. The inhibitory effect of restraint stress on gastric emptying is mediated via central corticotropin releasing factor (CRF), CRF2 receptors and peripheral sympathetic neurons 46, 47. Restraint stress augments postprandial gastric motility and impairs the coordination between the antrum and pylorus in rats 48-50.
In contrast to gastric emptying, restrain stress accelerates colonic transit in rats 51-53. The stimulatory effect of restraint stress on colonic transit is mediated via central CRF1 receptors, peripheral parasympathetic neurons and 5-HT3 receptors 51, 54-57.
- Nakade Y, Tsuchida D, Fukuda H, Iwa M, Pappas TN, Takahashi T. Restraint stress delays solid gastric emptying via a central CRF and peripheral sympathetic neuron in rats. Am J Physiol Regul Integr Comp Physiol 2005;288:R427-32.
- Nakade Y, Tsukamoto K, Pappas TN, Takahashi T. Central glucagon like peptide-1 delays solid gastric emptying via central CRF and peripheral sympathetic pathway in rats. Brain Res 2006;1111:117-21.
- Nakade Y, Tsuchida D, Fukuda H, Iwa M, Pappas TN, Takahashi T. Restraint stress augments postprandial gastric contractions but impairs antropyloric coordination in conscious rats. Am J Physiol Regul Integr Comp Physiol 2006;290:R616-24.
- Bulbul M, Babygirija R, Ludwig K, Takahashi T. Central orexin-A increases gastric motility in rats. Peptides 2010;31:2118-22.
- Bulbul M, Babygirija R, Zheng J, Ludwig KA, Takahashi T. Central orexin-A changes the gastrointestinal motor pattern from interdigestive to postprandial in rats. Auton Neurosci 2010;158:24-30.
- Nakade Y, Fukuda H, Iwa M, Tsukamoto K, Yanagi H, Yamamura T, Mantyh C, Pappas TN, Takahashi T. Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol 2007;292:G1037-44.
- Nakade Y, Mantyh C, Pappas TN, Takahashi T. Fecal pellet output does not always correlate with colonic transit in response to restraint stress and corticotropin-releasing factor in rats. J Gastroenterol 2007;42:279-82.
- Masere C, Nakade Y, Zheng J, Babygirija R, Ludwig K, Takahashi T. Chronic restraint stress has no more stimulatory effects on colonic motility in rats. Neurosci Lett 2009, PMID: 19429023;453:147-50.
- Nakade Y, Pappas TN, Takahashi T. Peripheral plasma corticotropin-releasing factor concentration does not correlate with augmented colonic motility in response to restraint stress in rats. Clin Exp Pharmacol Physiol 2008;35:934-7.
- Tsukamoto K, Nakade Y, Mantyh C, Ludwig K, Pappas TN, Takahashi T. Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats. Am J Physiol Regul Integr Comp Physiol 2006, PMID: 16284082;290:R1537-41.
- Tsukamoto K, Ariga H, Mantyh C, Pappas TN, Yanagi H, Yamamura T, Takahashi T. Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats. Am J Physiol Regul Integr Comp Physiol 2007, PMID: 17442783;293:R64-9.
- Takahashi T, Nakade Y, Fukuda H, Tsukamoto K, Mantyh C, Pappas TN. Daily intake of high dietary fiber slows accelerated colonic transit induced by restrain stress in rats. Dig Dis Sci 2008;53:1271-7.
f. Anti-stress effect of central oxytocin on GI motility
Functional GI disorders are common in the general population and stress is widely believed to play a major role in the development of functional GI disorders. Patients with serious stress frequently complain of GI symptoms and these symptoms are, at least in part, due to GI motility disorders. In modern society, individuals encounter various types of physical, mental and social stress on a daily basis. GI symptoms may develop when we fail to adapt to various stressors of our daily life (chronic stress).
A growing body of evidence suggests that stress stimuli, both acute and chronic, import different physiological mechanisms and neuroendocrine responses. Oxytocin is mainly synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Central oxytocin has an anxiolytic effect and attenuates the hypothalamic–pituitary–adrenal (HPA) axis in response to stress 58. Anti-stress effect of oxytocin is due to its inhibitory effect on CRF mRNA expression at the PVN 59. The inhibitory effect of oxytocin on CRF mRNA expression is mediated via GABAA receptors 60.
Repeated experience with the same stressor produces habituation, or diminution of behavioral responses and HPA axis responses. We have recently demonstrated that GI dysmotility (delayed gastric emptying and accelerated colonic transit) observed in acute restraint stress is completely restored to normal following repeated stress loading for 5 consecutive days (chronic homotypic stress) in rats 53, 61 and mice 62. Restored gastric emptying and colonic transit following chronic homotypic stress are antagonized by ICV injection of oxytocin antagonists 59, 62. Increased oxytocin mRNA expression and reduced CRF mRNA expression at the PVN are observed following chronic homotypic stress 59, 62. To further study the involvement of oxytocin in mediating the adaptation mechanism following chronic homotypic stress, we utilized oxytocin knockout (KO) mice. We showed that oxytocin KO mice fails to restore gastric emptying and colonic transit following chronic homotypic stress 63, 64. These suggest that central oxytocin is involved in mediating the adaptation mechanism in response to chronic homotypic stress in rodents.
In contrast to chronic homotypic stress, delayed gastric emptying and accelerated colonic transit are still observed, when rats receives different types of stress (chronic heterotypic stress) for 7 days 59, 65. Increased CRF expression and reduced oxytocin expression at the PVN were observed following chronic heterotypic stress 59, 65.
The social interaction of daily life as well as a positive environment continuously activates the system of oxytocin release in both males and females. We have recently shown that social buffering (paired housing) restores delayed gastric emptying following chronic heterotypic stress in rats 66. Paired housing decreased CRF mRNA and increased oxytocin mRNA expression at the PVN following chronic heterotypic stress in rats 66. We also showed that affiliative behaviors upregulates hypothalamic oxytocin expression, which in turn attenuates stress responses 67. Our study will provide the scientific benefit of social attachment to overcome our daily life stress.
Epidemiological studies suggest considerable overlap between FD and IBS. About half of the FD patients fulfill the Rome II criteria for IBS. We propose that the restoration of gastric and colonic dysmotility in both chronic homotypic and heterotypic stress occurs through the mechanisms of upregulation of oxytocin and attenuation of CRF expression. Our study will contribute to a better understanding of the mechanism and treatment of functional GI disorders, both of FD and IBS, associated with stress.
- Bulbul M, Babygirija R, Ludwig K, Takahashi T. Central oxytocin attenuates augmented gastric postprandial motility induced by restraint stress in rats. Neurosci Lett 2010;479:302-6.
- Zheng J, Babygirija R, Bulbul M, Cerjak D, Ludwig K, Takahashi T. Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats. Am J Physiol Gastrointest Liver Physiol 2010;G946-53.
- Bulbul M, Babygirija R, Cerjak D, Yoshimoto S, Ludwig K, Takahashi T. Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats. Brain Res 2011;1387:39-45.
- Zheng J, Dobner A, Babygirija R, Ludwig K, Takahashi T. Effects of repeated restraint stress on gastric motility in rats. Am J Physiol Regul Integr Comp Physiol 2009;R1358-65.
- Babygirija R, Zheng J, Ludwig K, Takahashi T. Central oxytocin is involved in restoring impaired gastric motility following chronic repeated stress in mice. Am J Physiol Regul Integr Comp Physiol 2010;298:R157-65.
- Babygirija R, Zheng J, Bulbul M, Cerjak D, Ludwig K, Takahashi T. Sustained delayed gastric emptying during repeated restraint stress in oxytocin knockout mice. J Neuroendocrinol 2010;22:1181-6.
- Babygirija R, Bülbül M, Cerjak D, Ludwig K, Takahashi T. Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice. Neurosci Lett 2011;495:77-81.
- Yoshimoto S, Cerjak D, Babygirija R, Bulbul M, Ludwig K, Takahashi T. Hypothalamic circuit regulating colonic transit following chronic stress in rats. Stress 2012;15:227-36.
- Babygirija R, Zheng J, Bulbul M, Ludwig K, Takahashi T. Beneficial effects of social attachment to overcome daily stress. Brain Res 2010;1352:43-9.
- Babygirija R, Cerjak D, Yoshimoto S, Gribovskaja-Rupp I, Bulbul M, Ludwig K, Takahashi T. Affiliative behavior attenuates stress responses of GI tract via up-regulating hypothalamic oxytocin expression. Auton Neurosci 2012;169:28-33.
g. Autonomic regulation of colorectal motility
Several disease processes of the colon and rectum, including constipation and incontinence, have been associated with abnormalities of the autonomic nervous system. However, the autonomic innervation to the colon and rectum are not fully understood. We showed that vagal innervation extends to the distal colon, while the pelvic nerve has projections in the distribution of the rectum through the mid colon. This suggests a pattern of dual parasympathetic innervation in the left colon. Parasympathetic fibers regulate colorectal contractions via muscarinic receptors, while hypogastric nerve mainly regulates colorectal relaxations via beta-adrenoceptors 68.
Clinical studies showed that disturbed colonic motility induced by extrinsic nerves damage is restored over time. Parasympathetic denervation causes a significant delay in colonic transit at postoperative day (POD) 1 69, compared with sham operation. Delayed transit is gradually restored by POD 7 after the denervation 70, 71. Restored colonic transit is antagonized by the administration of 5-HT3 and 5HT4 receptors antagonists at POD 7. 5-HT3 and 5-HT4 receptors mRNA expression are significantly increased in the mucosal/submucosal layer at POD 3 or POD 7, whereas no significant differences are observed in the longitudinal muscle layers adherent with the myenteric plexus. These suggest that up-regulation of 5-HT3 and 5-HT4 receptors expression in the mucosal/submucosal layer is involved to restore the delayed transit after the parasympathetic denervation in rats 70, 72.
Colonic peristalsis is mainly regulated via intrinsic neurons in the guinea pigs. In isolated guinea-pig colon, we investigated regional differences in peristalsis evoked by intrinsic electrical nerve stimulation. Electrical nerve stimulation of distal colon is the most likely region to elicit a peristaltic wave, compared with the mid or proximal colon 73. Pellet propulsion in the guinea pig's distal colon depends on nitric oxide to provide appropriate balance of force between proximal and distal contraction. Circular muscles contract both proximal and distal to the pellet, and the polarity of pellet progression depends on the balance of the two forces 74. Extrinsic autonomic regulation of colonic motility is poorly understood in the guinea pigs. We have recently shown that pelvic nerve stimulates colonic peristalsis via nicotinic, muscarinic and nitrergic pathways. In contrast, sympathetic nerve inhibits colonic peristalsis via alpha-2 adrenoceptors 75.
- Tong WD, Ridolfi TJ, Kosinski L, Ludwig K, Takahashi T. Effects of autonomic nerve stimulation on colorectal motility in rats. Neurogastroenterol Motil 2010;22:688-93.
- Ridolfi TJ, Tong WD, Takahashi T, Kosinski L, Ludwig KA. Sympathetic and parasympathetic regulation of rectal motility in rats. J Gastrointest Surg 2009;13:2027-33.
- Tong W, Kamiyama Y, Ridolfi TJ, Zietlow A, Zheng J, Kosinski L, Ludwig K, Takahashi T. The role of 5-HT3 and 5-HT4 receptors in the adaptive mechanism of colonic transit following the parasympathetic denervation in rats. J Surg Res 2011;171:510-6.
- Ridolfi TJ, Tong WD, Kosinski L, Takahashi T, Ludwig KA. Recovery of colonic transit following extrinsic nerve damage in rats. Scand J Gastroenterol 2011;46:678-83.
- Gribovskaja-Rupp I, Takahashi T, Ridolfi T, Kosinski L, Ludwig K. Upregulation of mucosal 5-HT3 receptors is involved in restoration of colonic transit after pelvic nerve transection. Neurogastroenterol Motil 2012;24:472-8, e218.
- Kwak JM, Babygirija R, Gribovskaja-Rupp I, Takahashi T, Yamato S, Ludwig K. Regional difference in colonic motility response to electrical field stimulation in Guinea pig. J Neurogastroenterol Motil 2013;19:192-203.
- Gribovskaja-Rupp I, Kwak JM, Takahashi T, Ludwig K. Nitric oxide regulates polarity of guinea pig distal colon pellet propagation and circular muscle motor response. J Gastroenterol 2014;49:835-42.
- Gribovskaja-Rupp I, Kwak J, Babygirija R, Takahashi T, Ludwig K. Autonomic nerve regulation of colonic peristalsis in guinea pigs. J Neurogastroenterol Motil 2014;20:185-96.
Fellowships and several educational opportunities are available at Dr. Takahashi’s laboratory. The positions are open to medical students and physicians who wish to gain additional experience in gastrointestinal physiology. Trainees typically become involved in several ongoing projects. Much of the research relates to gastrointestinal motility and physiology, but also several projects are focused on investigating inflammatory mechanisms of the colon, effects of acupuncture, and novel approaches to surgical conditions. For further questions regarding educational opportunities, please contact Toku Takahashi (firstname.lastname@example.org).
- Kazumi Nakamura, MD (1996-1997)
- Kenji Hosoda, MD (1996-1998)
- Koji Nakao, MD (1997-1999)
- Yohei Mizuta, MD, PhD (1997-1998)
- Tadashi Ishiguchi, MD (1998-2000)
- Hitoshi Tada, MD (2000-2001)
- Mikio Fujita, MD, PhD (2000-2001)
- Toru Kono, MD, PhD (2001)
- Akiko Shiotani, MD, PhD (2002)
- Naoki Kihara, MD (2001-2002)
- Sebastian G. de la Fuente, MD (2000-2003)
- Kazunori Fujino, MD (2003-2004)
- Kenichiro Uemura, MD (2002-2004)
- Makoto Tatewaki, MD, PhD (2002-2004)
- Tomio Ueno, MD, PhD (2002-2004)
- Jose Balestrini, BS (2002-2004)
- Woo Yong Lee, MD (2003-2004)
- Masahiro Iwa, PhD (2004-2005)
- Hiroyuki Fukuda, MD (2003-2005)
- Daisuke Tsuchida, MD (2003-2005)
- Yoji Takami, MD (2003-2005)
- Yukiomi Nakade, MD, PhD (2004-2006)
- Kiyoshi Tsukamoto, MD (2005-2006)
- Constant Masere, MD (2005-2006)
- Hajime Ariga, MD (2005-2007)
- Kenji Imai, PhD (2006-2007)
- Erito Mochiki, MD, PhD (2006-2007)
- Hitoshi Nakajima, MD (2007-2008)
- Hiroshi Taniguchi, PhD (2007-2008)
- Jun Zheng, MD, PhD (2007-2009)
- Aaron Zietlow, BS (2008-2009)
- Weidong Tong, MD (2008-2010)
- Yoichi Kamiyama, MD, PhD (2009-2010)
- Tim Ridolfi, MD (2008-2010)
- Mehmet Bulbul, VMD, PhD (2009-2010)
- Jonathan Ramprasad, MD (2009-2010)
- Diana Cerjak, BS (2009-2011)
- Sazu Yoshimoto, PhD (2010-2011)
- Jung-Myun Kwak, MD (2011-2012)
- Irena Rupp Gribovskaja, MD (2010-2013)
- Reji Babygirija, BS, MS (2008-2014)