Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Vagal neurocircuitry and its influence on gastric motility

Key Points

  • Brainstem vagovagal neurocircuits modulate the functions of the upper gastrointestinal tract

  • Neuronal communications between vagal sensory (nucleus tractus solitarius, NTS) and motor (dorsal motor nucleus of the vagus, DMV) nuclei are highly specialized and probably specific for function and target organ

  • NTS–DMV synaptic contacts are not static but undergo plastic changes to ensure that vagally regulated gastrointestinal functions respond appropriately to ever-changing physiological conditions or derangements

  • Gastrointestinal peptides influence vagovagal circuits via actions on both vagal afferent fibres and brainstem nuclei

  • Neurodegenerative alterations of the vagal neurocircuitry induce marked impairments of gastrointestinal functions

Abstract

A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Anatomical organization of the nucleus tractus solitarius and the dorsal motor nucleus of the vagus.
Figure 2: The brainstem neurocircuit comprising vagovagal reflexes.
Figure 3: Neurocircuits activated by gastrointestinal peptides.
Figure 4: Oxytocin receptor trafficking in the dorsal vagal complex and changes in gastric motility.

Similar content being viewed by others

References

  1. Sanders, K. M., Ward, S. M. & Koh, S. D. Interstitial cells: regulators of smooth muscle function. Physiol. Rev. 94, 859–907 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sharkey, K. A. Emerging roles for enteric glia in gastrointestinal disorders. J. Clin. Invest. 125, 918–925 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Furness, J. B. The enteric nervous system and neurogastroenterology. Nat. Rev. Gastroenterol. Hepatol. 9, 286–294 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Travagli, R. A., Hermann, G. E., Browning, K. N. & Rogers, R. C. Brainstem circuits regulating gastric function. Annu. Rev. Physiol. 68, 279–305 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pavlov, V. A. & Tracey, K. J. The vagus nerve and the inflammatory reflex — linking immunity and metabolism. Nat. Rev. Endocrinol. 8, 743–754 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Babic, T. & Travagli, R. A. Role of metabotropic glutamate receptors in the regulation of pancreatic functions. Biochem. Pharmacol. 87, 535–542 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Kentish, S. J. & Page, A. J. Plasticity of gastro-intestinal vagal afferent endings. Physiol. Behav. 136, 170–178 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Doheny, K. K. et al. Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis-risk in preterm infants. Neurogastroenterol. Motil. 26, 832–840 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93, 1043–1065 (1996).

  11. Souza, G. G. et al. Resilience and vagal tone predict cardiac recovery from acute social stress. Stress 10, 368–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Andresen, M. C. & Kunze, D. L. Nucleus tractus solitarius — gateway to neural circulatory control. Annu. Rev. Physiol. 56, 93–116 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Jean, A. Brainstem control of swallowing: neuronal network and cellular mechanisms. Physiol. Rev. 81, 929–969 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Bradley, R. M., King, M. S., Wang, L. & Shu, W. Neurotransmitter and neuromodulator activity in the gustatory zone of the nucleus tractus solitarius. Chem. Senses 21, 377–385 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Brookes, S. J., Spencer, N. J., Costa, M. & Zagorodnyuk, V. P. Extrinsic primary afferent signalling in the gut. Nat. Rev. Gastroenterol. Hepatol. 10, 286–296 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Berthoud, H. R., Blackshaw, L. A., Brookes, S. J. & Grundy, D. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol. Motil. 16 (Suppl. 1), 28–33 (2004).

    Article  PubMed  Google Scholar 

  17. Kalia, M. & Sullivan, J. M. Brainstem projections of sensory and motor components of the vagus nerve in the rat. J. Comp. Neurol. 211, 248–264 (1982).

    Article  CAS  PubMed  Google Scholar 

  18. Kalia, M., Fuxe, K. & Goldstein, M. Rat medulla oblongata. II. Dopaminergic, noradrenergic (A1 and A2) and adrenergic neurons, nerve fibers, and presumptive terminal processes. J. Comp. Neurol. 233, 308–332 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. Altschuler, S. M., Bao, X., Bieger, D., Hopkins, D. A. & Miselis, R. R. Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J. Comp. Neurol. 283, 248–268 (1989).

    Article  CAS  PubMed  Google Scholar 

  20. Barraco, R., El-Ridi, M., Parizon, M. & Bradley, D. An atlas of the rat subpostremal nucleus tractus solitarius. Brain Res. Bull. 29, 703–765 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, X., Fogel, R. & Renehan, W. E. Relationships between the morphology and function of gastric- and intestine-sensitive neurons in the nucleus of the solitary tract. J. Comp. Neurol. 363, 37–52 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Kubota, Y. et al. The distribution of cholecystokinin octapeptide-like structures in the lower brain stem of the rat: an immunohistochemical analysis. Neuroscience 9, 587–604 (1983).

    Article  CAS  PubMed  Google Scholar 

  23. Maley, B. E. Immunohistochemical localization of neuropeptides and neurotransmitters in the nucleus solitarius. Chem. Senses 21, 367–376 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Lin, L. H. & Talman, W. T. Nitroxidergic neurons in rat nucleus tractus solitarii express vesicular glutamate transporter 3. J. Chem. Neuroanat. 29, 179–191 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Larsen, P. J., Tang-Christensen, M., Holst, J. J. & Orskov, C. Distribution of glucagon-like peptide-1 and other preproglucagon- derived peptides in the rat hypothalamus and brainstem. Neurosci. 77, 257–270 (1997).

    Article  CAS  Google Scholar 

  26. Kessler, J. P. & Baude, A. Distribution of AMPA receptor subunits GluR1-4 in the dorsal vagal complex of the rat: a light and electron microscope immunocytochemical study. Synapse 34, 55–67 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Glass, M. J., Huang, J., Speth, R. C., Iadecola, C. & Pickel, V. M. Angiotensin, I. I. AT-1A receptor immunolabeling in rat medial nucleus tractus solitarius neurons: subcellular targeting and relationships with catecholamines. Neuroscience 130, 713–723 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Fong, A. Y., Stornetta, R. L., Foley, C. M. & Potts, J. T. Immunohistochemical localization of GAD67-expressing neurons and processes in the rat brainstem: subregional distribution in the nucleus tractus solitarius. J. Comp. Neurol. 493, 274–290 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Gross, P. M., Wall, K. M., Pang, J. J., Shaver, S. W. & Wainman, D. S. Microvascular specializations promoting rapid interstitial solute dispersion in nucleus tractus solitarius. Am. J. Physiol. 259, R1131–R1138 (1990).

    CAS  PubMed  Google Scholar 

  30. Smith, B. N., Dou, P., Barber, W. D. & Dudek, F. E. Vagally evoked synaptic currents in the immature rat nucleus tractus solitarii in an intact in vitro preparation. J. Physiol. 512, 149–162 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rinaman, L., Roesch, M. R. & Card, J. P. Retrograde transynaptic pseudorabies virus infection of central autonomic circuits in neonatal rats. Brain Res. Rev. Brain Res. 114, 207–216 (2000).

    Article  Google Scholar 

  32. Buijs, R. M., Chun, S. J., Niijima, A., Romijn, H. J. & Nagai, K. Parasympathetic and sympathetic control of the pancreas; a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. 431, 405–423 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Guyenet, P. G. The sympathetic control of blood pressure. Nat. Rev. Neurosci. 7, 335–346 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Goyal, R. K. & Chaudhury, A. Physiology of normal esophageal motility. J. Clin. Gastroenterol. 42, 610–619 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mittal, R. K. Motor Function of the Pharynx, Esophagus, and its Sphincters (Colloquium Life Science, 2011).

    Book  Google Scholar 

  36. Berthoud, H. R., Carlson, N. R. & Powley, T. L. Topography of efferent vagal innervation of the rat gastrointestinal tract. Am. J. Physiol. 260, R200–R207 (1991).

    CAS  PubMed  Google Scholar 

  37. Fox, E. A. & Powley, T. L. Longitudinal columnar organization within the dorsal motor nucleus represents separate branches of the abdominal vagus. Brain Res. 341, 269–282 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. Shapiro, R. E. & Miselis, R. R. The central organization of the vagus nerve innervating the stomach of the rat. J. Comp. Neurol. 238, 473–488 (1985).

    Article  CAS  PubMed  Google Scholar 

  39. Huang, X., Tork, I. & Paxinos, G. Dorsal motor nucleus of the vagus nerve: a cyto- and chemoarchitectonic study in the human. J. Comp. Neurol. 330, 158–182 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Browning, K. N., Renehan, W. E. & Travagli, R. A. Electrophysiological and morphological heterogeneity of rat dorsal vagal neurones which project to specific areas of the gastrointestinal tract. J. Physiol. 517, 521–532 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fogel, R., Zhang, X. & Renehan, W. E. Relationships between the morphology and function of gastric and intestinal distention-sensitive neurons in the dorsal motor nucleus of the vagus. J. Comp. Neurol. 364, 78–91 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Gao, H. et al. Morphological and electrophysiological features of motor neurons and putative interneurons in the dorsal vagal complex of rats and mice. Brain Res. 1291, 40–52 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Browning, K. N., Coleman, F. H. & Travagli, R. A. Characterization of pancreas-projecting rat dorsal motor nucleus of the vagus neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G950–G955 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Travagli, R. A., Gillis, R. A., Rossiter, C. D. & Vicini, S. Glutamate and GABA-mediated synaptic currents in neurons of the rat dorsal motor nucleus of the vagus. Am. J. Physiol. 260, G531–G536 (1991).

    CAS  PubMed  Google Scholar 

  45. Babic, T., Browning, K. N. & Travagli, R. A. Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G21–G32 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Sivarao, D. V., Krowicki, Z. K. & Hornby, P. J. Role of GABAA receptors in rat hindbrain nuclei controlling gastric motor function. Neurogastroenterol. Motil. 10, 305–313 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Browning, K. N., Coleman, F. H. & Travagli, R. A. Effects of pancreatic polypeptide on pancreas-projecting rat dorsal motor nucleus of the vagus neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G209–G219 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Hornby, P. J. et al. Medullary raphe: a new site for vagally mediated stimulation of gastric motility in cats. Am. J. Physiol. 258, G637–G647 (1990).

    CAS  PubMed  Google Scholar 

  49. Armstrong, D. M., Manley, L., Haycock, J. W. & Hersh, L. B. Co-localization of choline acetyltransferase and tyrosine hydroxylase within neurons of the dorsal motor nucleus of the vagus. J. Chem. Neuroanat. 3, 133–140 (1990).

    CAS  PubMed  Google Scholar 

  50. Schemann, M. & Grundy, D. Electrophysiological identification of vagally innervated enteric neurons in guinea pig stomach. Am. J. Physiol. 263, G709–G718 (1992).

    CAS  PubMed  Google Scholar 

  51. Guo, J. J., Browning, K. N., Rogers, R. C. & Travagli, R. A. Catecholaminergic neurons in rat dorsal motor nucleus of vagus project selectively to gastric corpus. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G361–G367 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Krowicki, Z. K., Sharkey, K. A., Serron, S. C., Nathan, N. A. & Hornby, P. J. Distribution of nitric oxide synthase in rat dorsal vagal complex and effects of microinjection of NO compounds upon gastric motor function. J. Comp. Neurol. 377, 49–69 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Chang, H. Y., Mashimo, H. & Goyal, R. K. Musings on the wanderer: what's new in our understanding of vago-vagal reflex?: IV. Current concepts of vagal efferent projections to the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G357–G366 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Cannon, W. B. & Leib, C. W. The receptive relaxation of the stomach. Am. J. Physiol. 29, 267–273 (1911).

    Article  Google Scholar 

  55. Langley, J. N. On inhibitory fibres in the vagus for the end of the oesophagus and the stomach. J. Physiol. 23, 407–414 (1898).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rogers, R. C., Hermann, G. E. & Travagli, R. A. Brainstem pathways responsible for oesophageal control of gastric motility and tone in the rat. J. Physiol. 514, 369–383 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Abrahamsson, H. Studies on the inhibitory nervous control of gastric motility. Acta Physiol. Scand. 390 (Suppl.), 1–38 (1973).

    CAS  Google Scholar 

  58. Desai, K. M., Sessa, W. C. & Vane, J. R. Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 351, 477–479 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. Tack, J., Caenepeel, P., Piessevaux, H., Cuomo, R. & Janssens, J. Assessment of meal induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia. Gut 52, 1271–1277 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Delgado-Aros, S. et al. Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia. Gastroenterology 127, 1685–1694 (2004).

    Article  PubMed  Google Scholar 

  61. Troncon, L. E., Thompson, D. G., Ahluwalia, N. K., Barlow, J. & Heggie, L. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 37, 17–22 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Holtmann, G., Goebell, H., Jockenhoevel, F. & Talley, N. J. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut 42, 501–506 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu, L. S. et al. A rat model of chronic gastric sensorimotor dysfunction resulting from transient neonatal gastric irritation. Gastroenterology 134, 2070–2079 (2008).

    Article  PubMed  Google Scholar 

  64. Rinaman, L., Card, J. P., Schwaber, J. S. & Miselis, R. R. Ultrastructural demonstration of a gastric monosynaptic vagal circuit in the nucleus of the solitary tract in rat. J. Neurosci. 9, 1985–1996 (1989).

    Article  CAS  PubMed  Google Scholar 

  65. Blackshaw, L. A., Page, A. J. & Young, R. L. Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways. Front. Neurosci. 5, 40 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hallock, R. M., Martyniuk, C. J. & Finger, T. E. Group III metabotropic glutamate receptors (mGluRs) modulate transmission of gustatory inputs in the brainstem. J. Neurophysiol. 102, 192–202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Young, R. L., Cooper, N. J. & Blackshaw, L. A. Anatomy and function of group III metabotropic glutamate receptors in gastric vagal pathways. Neuropharmacology 54, 965–975 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Browning, K. N., Zheng, Z., Gettys, T. W. & Travagli, R. A. Vagal afferent control of opioidergic effects in rat brainstem circuits. J. Physiol. 575, 761–776 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Page, A. J. et al. Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons. Gastroenterology 128, 402–410 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Jin, Y. H., Bailey, T. W. & Andresen, M. C. Cranial afferent glutamate heterosynaptically modulates GABA release onto second-order neurons via distinctly segregated metabotropic glutamate receptors. J. Neurosci. 24, 9332–9340 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gerber, U., Gee, C. E. & Benquet, P. Metabotropic glutamate receptors: intracellular signaling pathways. Curr. Opin. Pharmacol. 7, 56–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Niswender, C. M. & Conn, P. J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol. 50, 295–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Browning, K. N. & Travagli, R. A. Functional organization of presynaptic metabotropic glutamate receptors in vagal brainstem circuits. J. Neurosci. 27, 8979–8988 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Berthoud, H. R., Sutton, G. M., Townsend, R. L., Patterson, L. M. & Zheng, H. Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size. Physiol. Behav. 89, 517–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Drucker, D. J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Dufresne, M., Seva, C. & Fourmy, D. Cholecystokinin and gastrin receptors. Physiol. Rev. 86, 805–847 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Banks, W. A. The blood–brain barrier as a regulatory interface in the gut–brain axes. Physiol. Behav. 89, 472–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Kastin, A. J., Akerstrom, V. & Pan, W. Interactions of glucagon-like peptide-1 (GLP-1) with the blood–brain barrier. J. Mol. Neurosci. 18, 7–14 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Orts-Del'immagine, A. et al. Properties of subependymal cerebrospinal fluid contacting neurones in the dorsal vagal complex of the mouse brainstem. J. Physiol. 590, 3719–3741 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Noble, F. et al. International Union of Pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol. Rev. 51, 745–781 (1999).

    CAS  PubMed  Google Scholar 

  81. Campbell, J. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Browning, K. N. & Travagli, R. A. The peptide TRH uncovers the presence of presynaptic 5-HT1A receptors via activation of a second messenger pathway in the rat dorsal vagal complex. J. Physiol. 531, 425–435 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Browning, K. N., Kalyuzhny, A. E. & Travagli, R. A. Mu-opioid receptor trafficking on inhibitory synapses in the rat brainstem. J. Neurosci. 24, 9344–9352 (2004).

    Article  CAS  Google Scholar 

  84. Browning, K. N. & Travagli, R. A. Modulation of inhibitory neurotransmission in brainstem vagal circuits by NPY and PYY is controlled by cAMP levels. Neurogastroenterol. Motil. 21, 1309–e1126 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Browning, K. N., Kalyuzhny, A. E. & Travagli, R. A. Opioid peptides inhibit excitatory but not inhibitory synaptic transmission in the rat dorsal motor nucleus of the vagus. J. Neurosci. 22, 2998–3004 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Browning, K. N. & Travagli, R. A. Neuropeptide Y and peptide YY inhibit excitatory synaptic transmission in the rat dorsal motor nucleus of the vagus. J. Physiol. 549, 775–785 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Berthoud, H. R. Vagal and hormonal gut–brain communication: from satiation to satisfaction. Neurogastroenterol. Motil. 20 (Suppl. 1), 64–72 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Raybould, H. E. & Tache, Y. Cholecystokinin inhibits gastric motility and emptying via a capsaicin-sensitive vagal pathway in rats. Am. J. Physiol. 255, G242–G246 (1988).

    CAS  PubMed  Google Scholar 

  89. Woods, S. C. Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G7–G13 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Owyang, C. & Logsdon, C. D. New insights into neurohormonal regulation of pancreatic secretion. Gastroenterology 127, 957–969 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Andrews, P. L. & Sanger, G. J. Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr. Opin. Pharmacol. 2, 650–656 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Imeryuz, N. et al. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am. J. Physiol. 273, G920–G927 (1997).

    CAS  PubMed  Google Scholar 

  93. Grill, H. J. Leptin and the systems neuroscience of meal size control. Front. Neuroendocrinol. 31, 61–78 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Owyang, C. & Heldsinger, A. Vagal control of satiety and hormonal regulation of appetite. J. Neurogastroenterol. Motil. 17, 338–348 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Czaja, K., Burns, G. A. & Ritter, R. C. Capsaicin-induced neuronal death and proliferation of the primary sensory neurons located in the nodose ganglia of adult rats. Neuroscience 154, 621–630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Holzer, P. Capsaicin-sensitive afferent neurones and gastrointestinal propulsion in the rat. Arch. Pharmacol. 332, 62–65 (1986).

    Article  CAS  Google Scholar 

  97. South, E. H. & Ritter, R. C. Capsaicin application to central or peripheral vagal fibers attenuates CCK satiety. Peptides 9, 601–612 (1988).

    Article  CAS  PubMed  Google Scholar 

  98. Holzer, H. H., Turkelson, C. M., Solomon, T. E. & Raybould, H. E. Intestinal lipid inhibits gastric emptying via CCK and a vagal capsaicin-sensitive afferent pathway in rats. Am. J. Physiol. 267, G625–G629 (1994).

    CAS  PubMed  Google Scholar 

  99. Blackshaw, L. A., Page, A. J. & Partosoedarso, E. R. Acute effects of capsaicin on gastrointestinal vagal afferents. Neuroscience 96, 407–416 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Li, Y. & Owyang, C. Endogenous cholecystokinin stimulates pancreatic enzyme secretion via vagal afferent pathway in rats. Gastroenterology 107, 525–531 (1994).

    Article  CAS  PubMed  Google Scholar 

  101. Blackshaw, L. A. & Grundy, D. Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre. J. Auton. Nerv. Syst. 31, 191–202 (1990).

    Article  CAS  PubMed  Google Scholar 

  102. Zittel, T. T., Rothenhofer, I., Meyer, J. H. & Raybould, H. E. Small intestinal capsaicin-sensitive afferents mediate feedback inhibition of gastric emptying in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 267, G1142–G1145 (1994).

    Article  CAS  Google Scholar 

  103. Lloyd, K. C., Holzer, H. H., Zittel, T. T. & Raybould, H. E. Duodenal lipid inhibits gastric acid secretion by vagal, capsaicin-sensitive afferent pathways in rats. Am. J. Physiol. 264, G659–G663 (1993).

    CAS  PubMed  Google Scholar 

  104. Moran, T. H. Gut peptide signaling in the controls of food intake. Obesity (Silver Spring) 14, 250S–253S (2006).

    Article  CAS  Google Scholar 

  105. Browning, K. N., Babic, T., Holmes, G. M., Swartz, E. M. & Travagli, R. A. A critical re-evaluation of the specificity of action of perivagal capsaicin. J. Physiol. 591, 1563–1580 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Szolcsanyi, J., Joo, F. & Jancso-Gabor, A. Mitochondrial changes in preoptic neurons after capsaicin desensitization of the hypothalamic thermodetectors in rats. Nature 229, 116–117 (1971).

    Article  CAS  PubMed  Google Scholar 

  107. Ritter, S. & Dinh, T. T. Capsaicin-induced neuronal degeneration in the brain and retina of preweanling rats. J. Comp. Neurol. 296, 447–461 (1990).

    Article  CAS  PubMed  Google Scholar 

  108. Ritter, S. & Dinh, T. T. Capsaicin-induced neuronal degeneration: silver impregnation of cell bodies, axons, and terminals in the central nervous system of the adult rat. J. Comp. Neurol. 271, 79–90 (1988).

    Article  CAS  PubMed  Google Scholar 

  109. Holzer, P. Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve. Am. J. Physiol. 275, G8–G13 (1998).

    CAS  PubMed  Google Scholar 

  110. Kim, S. R. et al. Transient receptor potential vanilloid subtype 1 mediates cell death of mesencephalic dopaminergic neurons in vivo and in vitro. J. Neurosci. 25, 662–671 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jancso-Gabor, A., Szolcsanyi, J. & Jancso, N. Stimulation and desensitization of the hypothalamic heat-sensitive structures by capsaicin in rats. J. Physiol. 208, 449–459 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hajos, M., Obal, F. Jr., Jancso, G. & Obal, F. Capsaicin impairs preoptic serotonin-sensitive structures mediating hypothermia in rats. Neurosci. Lett. 54, 97–102 (1985).

    Article  CAS  PubMed  Google Scholar 

  113. Evangelista, S., Santicioli, P., Maggi, C. A. & Meli, A. Increase in gastric secretion induced by 2-deoxy-d-glucose is impaired in capsaicin pretreated rats. Br. J. Pharmacol. 98, 35–37 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Raybould, H. E., Holzer, P., Reddy, S. N., Yang, H. & Tache, Y. Capsaicin-sensitive vagal afferents contribute to gastric acid and vascular responses to intracisternal TRH analog. Peptides 11, 789–795 (1990).

    Article  CAS  PubMed  Google Scholar 

  115. Baptista, V., Browning, K. N. & Travagli, R. A. Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1092–R1100 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Sayegh, A. I. & Ritter, R. C. Vagus nerve participates in CCK-induced Fos expression in hind brain but not myenteric plexus. Brain Res. 878, 155–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. van de Wall, E. H., Duffy, P. & Ritter, R. C. CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R695–R703 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Viard, E., Zheng, Z., Wan, S. & Travagli, R. A. Vagally-mediated, non paracrine effects of cholecystokinin-8s on rat pancreatic exocrine secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G494–G500 (2007).

    Article  CAS  Google Scholar 

  119. Branchereau, P., Champagnat, J. & Denavit-Saubie, M. Cholecystokinin-gated currents in neurons of the rat solitary complex in vitro. J. Neurophysiol. 70, 2584–2595 (1993).

    Article  CAS  PubMed  Google Scholar 

  120. Baptista, V., Zheng, Z., Coleman, F. H., Rogers, R. C. & Travagli, R. A. Cholecystokinin octapeptide increases spontaneous glutamatergic synaptic transmission to neurons of the nucleus tractus solitarius centralis. J. Neurophysiol. 94, 2763–2771 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Appleyard, S. M. et al. Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. J. Neurosci. 25, 3578–3585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Browning, K. N., Wan, S., Baptista, V. & Travagli, R. A. Vanilloid, purinergic, and CCK receptors activate glutamate release on single neurons of the nucleus tractus solitarius centralis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R394–R401 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zheng, Z., Lewis, M. W. & Travagli, R. A. In vitro analysis of the effects of cholecystokinin (CCK) on rat brainstem motorneurons. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G1066–G1073 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Plata-Salaman, C. R., Fukuda, A., Oomura, Y. & Minami, T. Effects of sulphated cholecystokinin octapeptide (CCK-8) on the dorsal motor nucleus of the vagus. Brain Res. Bull. 21, 839–842 (1988).

    Article  CAS  PubMed  Google Scholar 

  125. Wan, S., Coleman, F. H. & Travagli, R. A. Cholecystokinin-8s excites identified rat pancreatic-projecting vagal motoneurons. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G484–G492 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Simasko, S. M. & Ritter, R. C. Cholecystokinin activates both A- and C-type vagal afferent neurons. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G1204–G1213 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Derbenev, A. V., Monroe, M. J., Glatzer, N. R. & Smith, B. N. Vanilloid-mediated heterosynaptic facilitation of inhibitory synaptic input to neurons of the rat dorsal motor nucleus of the vagus. J. Neurosci. 26, 9666–9672 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Peters, J. H., McDougall, S. J., Fawley, J. A., Smith, S. M. & Andresen, M. C. Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons. Neuron 65, 657–669 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Evans, C., Baxi, S., Neff, R., Venkatesan, P. & Mendelowitz, D. Synaptic activation of cardiac vagal neurons by capsaicin sensitive and insensitive sensory neurons. Brain Res. 979, 210–215 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Roth, G. I. & Yamamoto, W. S. The microcirculation of the area postrema of the rat. J. Comp. Neurol. 133, 329–340 (1968).

    Article  CAS  PubMed  Google Scholar 

  131. Dockray, G. J. Immunochemical evidence of cholecystokinin-like peptides in brain. Nature 264, 568–570 (1976).

    Article  CAS  PubMed  Google Scholar 

  132. Takagi, H. et al. Fine structural studies of cholecystokinin-8-like immunoreactive neurons and axon terminals in the nucleus of tractus solitarius of the rat. J. Comp. Neurol. 227, 369–379 (1984).

    Article  CAS  PubMed  Google Scholar 

  133. Holmes, G. M., Tong, M. & Travagli, R. A. Effects of brainstem cholecystokinin-8s on gastric tone and esophageal-gastric reflex. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G621–G631 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Stanley, S., Wynne, K., McGowan, B. & Bloom, S. Hormonal regulation of food intake. Physiol. Rev. 85, 1131–1158 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Date, Y. et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123, 1120–1128 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Holmes, G. M., Browning, K. N., Tong, M., Qualls-Creekmore, E. & Travagli, R. A. Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions. J. Physiol. 587, 4749–4759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kakei, M., Yada, T., Nakagawa, A. & Nakabayashi, H. Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in rat nodose ganglion neurons. Auton. Neurosci. 102, 39–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Wan, S., Coleman, F. H. & Travagli, R. A. Glucagon-like peptide-1 (GLP-1) excites pancreas-projecting preganglionic vagal motoneurons. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1474–G1482 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Grabauskas, G. et al. KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin. J. Physiol. 593, 3973–3989 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Arnold, M., Mura, A., Langhans, W. & Geary, N. Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J. Neurosci. 26, 11052–11060 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Fry, M. & Ferguson, A. V. Ghrelin modulates electrical activity of area postrema neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R485–R492 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Li, Y., Wu, X., Zhao, Y., Chen, S. & Owyang, C. Ghrelin acts on the dorsal vagal complex to stimulate pancreatic protein secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1350–G1358 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Holzer, P., Reichmann, F. & Farzi, A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis. Neuropeptides 46, 261–274 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Michel, M. C. et al. XVI. International union of pharmacology reccommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol. Rev. 50, 143–150 (1999).

    Google Scholar 

  145. Rozengurt, E. & Sternini, C. Taste receptor signaling in the mammalian gut. Curr. Opin. Pharmacol. 7, 557–562 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Maljaars, P. W., Peters, H. P., Mela, D. J. & Masclee, A. A. Ileal brake: a sensible food target for appetite control. A review. Physiol. Behav. 95, 271–281 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Chen, C. H., Stephens, R. L. Jr. & Rogers, R. C. PYY and NPY control of gastric motility via action on Y1 and Y2 receptors in the DVC. Neurogastroenterol. Motil. 9, 109–116 (1997).

    Article  CAS  PubMed  Google Scholar 

  148. Chen, C. H. & Rogers, R. C. Central inhibitory action of peptide YY on gastric motility in rats. Am. J. Physiol. 269, R787–R792 (1995).

    CAS  PubMed  Google Scholar 

  149. Yang, H., Li, W. P., Reeve, J. R., Rivier, J. & Tache, Y. PYY-preferring receptor in the dorsal vagal complex and its involvement in PYY stimulation in gastric acid secretion in rats. Br. J. Pharmacol. 123, 1549–1554 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Adrian, T. E. et al. Effect of peptide YY on gastric, pancreatic, and biliary function in humans. Gastroenterology 89, 494–499 (1985).

    Article  CAS  PubMed  Google Scholar 

  151. Yang, H. et al. Peripheral PYY inhibits intracisternal TRH-induced gastric acid secretion by acting in the brain. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G575–G581 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Schemann, M. & Tamura, K. Presynaptic inhibitory effects of the peptides NPY, PYY and PP on nicotinic EPSPs in guinea-pig gastric myenteric neurones. J. Physiol. 451, 79–89 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Avau, B., Carbone, F., Tack, J. & Depoortere, I. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol. Motil. 25, 720–732 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Latorre, R., Sternini, C. & De, G. R. & Greenwood-van, M. B. Enteroendocrine cells: a review of their role in brain–gut communication. Neurogastroenterol. Motil. 28, 620–630 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Stengel, A. & Tache, Y. Corticotropin-releasing factor signaling and visceral response to stress. Exp. Biol. Med. (Maywood) 235, 1168–1178 (2010).

    Article  CAS  Google Scholar 

  156. Stengel, A. & Tache, Y. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight. Annu. Rev. Physiol. 71, 219–239 (2008).

    Article  CAS  Google Scholar 

  157. Fukudo, S. IBS: autonomic dysregulation in IBS. Nat. Rev. Gastroenterol. Hepatol. 10, 569–571 (2013).

    Article  PubMed  Google Scholar 

  158. Khoo, J., Rayner, C. K., Feinle-Bisset, C., Jones, K. L. & Horowitz, M. Gastrointestinal hormonal dysfunction in gastroparesis and functional dyspepsia. Neurogastroenterol. Motil. 22, 1270–1278 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Franklin, T. B., Saab, B. J. & Mansuy, I. M. Neural mechanisms of stress resilience and vulnerability. Neuron 75, 747–761 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Panksepp, J. & Panksepp, J. B. Toward a cross-species understanding of empathy. Trends Neurosci. 36, 489–496 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Kelly, A. M. & Goodson, J. L. Social functions of individual vasopressin-oxytocin cell groups in vertebrates: what do we really know? Front. Neuroendocrinol. 35, 512–529 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Ulrich-Lai, Y. M. & Herman, J. P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397–409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Churchland, P. S. & Winkielman, P. Modulating social behavior with oxytocin: how does it work? What does it mean? Horm. Behav. 61, 392–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Gordon, I., Martin, C., Feldman, R. & Leckman, J. F. Oxytocin and social motivation. Dev. Cogn. Neurosci. 1, 471–493 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Zheng, J. et al. Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G946–G953 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  166. 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. 298, R157–R165 (2010).

    Article  CAS  PubMed  Google Scholar 

  167. Bulbul, M., Babygirija, R., Ludwig, K. & Takahashi, T. Central oxytocin attenuates augmented gastric postprandial motility induced by restraint stress in rats. Neurosci. Lett. 479, 302–306 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Babygirija, R., Bulbul, M., Cerjak, D., Ludwig, K. & Takahashi, T. Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice. Neurosci. Lett. 495, 77–81 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Bulbul, M. et al. Hypothalamic oxytocin attenuates CRF expression via GABAA receptors in rats. Brain Res. 1387, 39–45 (2011).

    Article  CAS  PubMed  Google Scholar 

  170. Murphy, D. et al. The hypothalamic–neurohypophyseal system: from genome to physiology. J. Neuroendocrinol. 24, 539–553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Richar, P., Moos, F. & Freund-Mercier, M.-J. Central effects of oxytocin. Physiol. Rev. 71, 331–370 (1991).

    Article  Google Scholar 

  172. Herman, J. P., Flak, J. & Jankord, R. Chronic stress plasticity in the hypothalamic paraventricular nucleus. Prog. Brain Res. 170, 353–364 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Raggenbass, M., Dubois-Dauphin, M., Charpak, S. & Dreifuss, J. J. Neurons in the dorsal motor nucleus of the vagus nerve are excited by oxytocin in the rat but not in the guinea pig. Proc. Natl Acad. Sci. USA 84, 3926–3930 (1987).

    Article  CAS  PubMed  Google Scholar 

  174. Raggenbass, M. & Dreifuss, J. J. Mechanism of action of oxytocin in rat vagal neurones: induction of a sustained sodium-dependent current. J. Physiol. 457, 131–142 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Flanagan, L. M., Olson, B. R., Sved, A. F., Verbalis, J. G. & Stricker, E. M. Gastric motility in conscious rats given oxytocin and an oxytocin antagonist centrally. Brain Res. 578, 256–260 (1992).

    Article  CAS  PubMed  Google Scholar 

  176. Fujimiya, M. & Inui, A. Peptidergic regulation of gastrointestinal motility in rodents. Peptides 21, 1565–1582 (2001).

    Article  Google Scholar 

  177. Holmes, G. M. et al. Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone. J. Physiol. 591, 3081–3100 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Babygirija, R., Bulbul, M., Yoshimoto, S., Ludwig, K. & Takahashi, T. Central and peripheral release of oxytocin following chronic homotypic stress in rats. Auton. Neurosci. 167, 56–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. Lewis, M. W., Hermann, G. E., Rogers, R. C. & Travagli, R. A. In vitro and in vivo analysis of the effects of corticotropin releasing factor on rat dorsal vagal complex. J. Physiol. 543, 135–146 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Browning, K. N. et al. Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor. J. Physiol. 592, 4591–4605 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Blake, C. B. & Smith, B. N. cAMP-dependent insulin modulation of synaptic inhibition in neurons of the dorsal motor nucleus of the vagus is altered in diabetic mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R711–R720 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Shuster, S. J., Riedl, M., Li, X., Vulchanova, L. & Elde, R. Stimulus-dependent translocation of κ opioid receptors to the plasma membrane. J. Neurosci. 19, 2658–2664 (1999).

    Article  CAS  PubMed  Google Scholar 

  183. Baltadzhieva, R., Gurevich, T. & Korczyn, A. D. Autonomic impairment in amyotrophic lateral sclerosis. Curr. Opin. Neurol. 18, 487–493 (2005).

    Article  PubMed  Google Scholar 

  184. Slim, M., Calandre, E. P. & Rico-Villademoros, F. An insight into the gastrointestinal component of fibromyalgia: clinical manifestations and potential underlying mechanisms. Rheumatol. Int. 35, 433–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  185. Aziz, N. A. et al. Weight loss in neurodegenerative disorders. J. Neurol. 255, 1872–1880 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Heemskerk, A. W. & Roos, R. A. Dysphagia in Huntington's disease: a review. Dysphagia 26, 62–66 (2011).

    Article  PubMed  Google Scholar 

  187. Fasano, A., Visanji, N. P., Liu, L. W., Lang, A. E. & Pfeiffer, R. F. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 14, 625–639 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Pfeiffer, R. F. Gastrointestinal involvement in Parkinson's disease: the horse or the cart. Acta Physiol. (Oxf.) 211, 271–272 (2014).

    Article  CAS  Google Scholar 

  189. Natale, G., Pasquali, L., Ruggieri, S., Paparelli, A. & Fornai, F. Parkinson's disease and the gut: a well known clinical association in need of an effective cure and explanation. Neurogastroenterol. Motil. 20, 741–749 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. Wedel, T. et al. Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon. Gastroenterology 123, 1459–1467 (2002).

    Article  PubMed  Google Scholar 

  191. Lebouvier, T. et al. Pathological lesions in colonic biopsies during Parkinson's disease. Gut 57, 1741–1743 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Edwards, L. L., Quigley, E. M., Harned, R. K., Hofman, R. & Pfeiffer, R. F. Characterization of swallowing and defecation in Parkinson's disease. Am. J. Gastroenterol. 89, 15–25 (1994).

    CAS  PubMed  Google Scholar 

  193. Pfeiffer, R. F. Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 2, 107–116 (2003).

    Article  PubMed  Google Scholar 

  194. Hardoff, R. et al. Gastric emptying time and gastric motility in patients with Parkinson's disease. Mov. Disord. 16, 1041–1047 (2001).

    Article  CAS  PubMed  Google Scholar 

  195. McDowell, K. & Chesselet, M. F. Animal models of the non-motor features of Parkinson's disease. Neurobiol. Dis. 46, 597–606 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Kuo, Y. M. et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Hum. Mol. Genet. 19, 1633–1650 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Blandini, F. et al. Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson's disease. Neurosci. Lett. 467, 203–207 (2009).

    Article  CAS  PubMed  Google Scholar 

  198. Colucci, M. et al. Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model. Auton. Neurosci. 169, 77–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Derkinderen, P. et al. Parkinson disease: the enteric nervous system spills its guts. Neurology 77, 1761–1767 (2011).

    Article  CAS  PubMed  Google Scholar 

  200. Zheng, L. F. et al. Alterations in TH- and ChAT-immunoreactive neurons in the DMV and gastric dysmotility in an LPS-induced PD rat model. Auton. Neurosci. 177, 194–198 (2013).

    Article  CAS  PubMed  Google Scholar 

  201. Stott, S. R. & Barker, R. A. Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson's disease. Eur. J. Neurosci. 39, 1042–1056 (2014).

    Article  PubMed  Google Scholar 

  202. Zhu, H. C., Zhao, J., Luo, C. Y. & Li, Q. Q. Gastrointestinal dysfunction in a Parkinson's disease rat model and the changes of dopaminergic, nitric oxidergic, and cholinergic neurotransmitters in myenteric plexus. J. Mol. Neurosci. 47, 15–25 (2012).

    Article  CAS  PubMed  Google Scholar 

  203. Annerino, D. M. et al. Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol. 124, 665–680 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Toti, L. & Travagli, R. A. Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain–gut axis. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G1013–G1023 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Goedert, M., Spillantini, M. G., Del, T. K. & Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. George, J. M. The synucleins. Genome Biol. 3, 3002.1–3002.6 (2002).

    Google Scholar 

  207. Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Parkinson's disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol. 79, 581–583 (1990).

    Article  CAS  PubMed  Google Scholar 

  208. Braak, H., De Vos, R. A., Bohl, J. & Del Tredici, K. Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci. Lett. 396, 67–72 (2006).

    Article  CAS  PubMed  Google Scholar 

  209. Hawkes, C. H., Del, T. K. & Braak, H. A timeline for Parkinson's disease. Parkinsonism Relat. Disord. 16, 79–84 (2010).

    Article  PubMed  Google Scholar 

  210. Visanji, N. P., Brooks, P. L., Hazrati, L. N. & Lang, A. E. The prion hypothesis in Parkinson's disease: Braak to the future. Acta Neuropathol. Commun. 1, 2 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Braak, H., Rub, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  212. Zheng, L. F. et al. The role of the vagal pathway and gastric dopamine in the gastroparesis of rats after a 6-hydroxydopamine microinjection in the substantia nigra. Acta Physiol. (Oxf.) 211, 434–446 (2014).

    Article  CAS  Google Scholar 

  213. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  214. Greene, J. G. Causes and consequences of degeneration of the dorsal motor nucleus of the vagus nerve in Parkinson's disease. Antioxid. Redox Signal. 21, 649–667 (2014).

    Article  CAS  PubMed  Google Scholar 

  215. Burke, R. E., Dauer, W. T. & Vonsattel, J. P. A critical evaluation of the Braak staging scheme for Parkinson's disease. Ann. Neurol. 64, 485–491 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging. Neuropathol. Appl. Neurobiol. 34, 284–295 (2008).

    Article  CAS  PubMed  Google Scholar 

  217. Brettschneider, J., Del, T. K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109–120 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Hawkes, C. H., Del, T. K. & Braak, H. Parkinson's disease: the dual hit theory revisited. Ann. NY Acad. Sci. 1170, 615–622 (2009).

    Article  PubMed  Google Scholar 

  219. Buckinx, R., Adriaensen, D., Nassauw, L. V. & Timmermans, J. P. Corticotrophin-releasing factor, related peptides, and receptors in the normal and inflamed gastrointestinal tract. Front. Neurosci. 5, 54 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Bale, T. L. & Vale, W. W. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Pharmacol. Toxicol. 44, 525–557 (2004).

    Article  CAS  PubMed  Google Scholar 

  221. Valentino, R. J., Pavcovich, L. A. & Hirata, H. Evidence for corticotropin-releasing hormone projections from Barrington's nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat. J. Comp. Neurol. 363, 402–422 (1995).

    Article  CAS  PubMed  Google Scholar 

  222. Tache, Y. & Bonaz, B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J. Clin. Invest. 117, 33–40 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Lenz, H. J., Raedler, A., Greten, H., Vale, W. W. & Rivier, J. E. Stress-induced gastrointestinal secretory and motor responses in rats are mediated by endogenous corticotropin-releasing factor. Gastroenterology 95, 1510–1517 (1988).

    Article  CAS  PubMed  Google Scholar 

  224. Martinez, V., Rivier, J., Wang, L. & Tache, Y. Central injecton of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks CRF- and stress-related alterations of gastric and colonic motor function. J. Pharmacol. Exp. Ther. 280, 754–760 (1997).

    CAS  PubMed  Google Scholar 

  225. Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  226. Goedert, M., Falcon, B., Clavaguera, F. & Tolnay, M. Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies. Curr. Neurol. Neurosci. Rep. 14, 495 (2014).

    Article  CAS  PubMed  Google Scholar 

  227. Goedert, M. Alzheimer's and Parkinson's diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 349, 1255555 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    Article  CAS  PubMed  Google Scholar 

  229. Olanow, C. W. & Brundin, P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov. Disord. 28, 31–40 (2013).

    Article  CAS  PubMed  Google Scholar 

  230. Hansen, C. et al. α-synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Lee, H. J. et al. Direct transfer of α-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 285, 9262–9272 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to thank NIH grants DK 55530, DK 78364 and DK 99350 and the Michael J. Fox Foundation for Parkinson's Disease for their support; we are also very grateful to K. N. Browning for critical comments on previous versions of the manuscript and for checking the grammar (because we do not want to “write as we speak”). We also thank C. M. Travagli and Z. Travagli for support and encouragement.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally to this work.

Corresponding author

Correspondence to R. Alberto Travagli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Travagli, R., Anselmi, L. Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol 13, 389–401 (2016). https://doi.org/10.1038/nrgastro.2016.76

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2016.76

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing