Skip to main content

New Insights on Extrinsic Innervation of the Enteric Nervous System and Non-neuronal Cell Types That Influence Colon Function

  • Conference paper
  • First Online:
The Enteric Nervous System II

Abstract

The enteric nervous system not only innervates the colon to execute various functions in a semi-autonomous manner but also receives neural input from three extrinsic sources, (1) vagal, (2) thoracolumbar (splanchnic), and (3) lumbosacral (pelvic) pathways, that permit bidirectional communication between the colon and central nervous system. Extrinsic pathways signal sensory input via afferent fibers, as well as motor autonomic output via parasympathetic or sympathetic efferent fibers, but the shared and unique roles for each pathway in executing sensory-motor control of colon function have not been well understood. Here, we describe the recently developed approaches that have provided new insights into the diverse mechanisms utilized by extrinsic pathways to influence colon functions related to visceral sensation, motility, and inflammation. Based on the cumulative results from anatomical, molecular, and functional studies, we propose pathway-specific functions for vagal, thoracolumbar, and lumbosacral innervation of the colon.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Spencer NJ, Dinning PG, Brookes SJ et al (2016) Insights into the mechanisms underlying colonic motor patterns. J Physiol 594:4099–116. PMC4967752

    Article  Google Scholar 

  2. Drumm BT, Rembetski BE, Baker SA et al (2019) Tonic inhibition of murine proximal colon is due to nitrergic suppression of Ca(2+) signaling in interstitial cells of Cajal. Sci Rep 9:4402. PMC6416298

    Article  Google Scholar 

  3. McClain J, Grubisic V, Fried D et al (2014) Ca2+ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice. Gastroenterology 146:497–507 e1. PMC3935238

    Article  Google Scholar 

  4. McClain JL, Fried DE, Gulbransen BD (2015) Agonist-evoked Ca(2+) signaling in enteric glia drives neural programs that regulate intestinal motility in mice. Cell Mol Gastroenterol Hepatol 1:631–645. PMC4673674

    Article  Google Scholar 

  5. Schneider S, Wright CM, Heuckeroth RO (2019) Unexpected roles for the second brain: enteric nervous system as master regulator of bowel function. Annu Rev Physiol 81:235–259

    Article  Google Scholar 

  6. Ward SM, Beckett EA, Wang X et al (2000) Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 20:1393–403. PMC6772355

    Article  Google Scholar 

  7. Yoo BB, Mazmanian SK (2017) The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46:910–926. PMC5551410

    Article  Google Scholar 

  8. Brookes SJ, Spencer NJ, Costa M et al (2013) Extrinsic primary afferent signalling in the gut. Nat Rev Gastroenterol Hepatol 10:286–296

    Article  CAS  Google Scholar 

  9. Brierley SM, Hibberd TJ, Spencer NJ (2018) Spinal afferent innervation of the colon and rectum. Front Cell Neurosci 12:467. PMC6288476

    Article  Google Scholar 

  10. Browning KN, Travagli RA (2014) Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol 4:1339–68. PMC4858318

    Google Scholar 

  11. Zeisel A, Hochgerner H, Lonnerberg P et al (2018) Molecular architecture of the mouse nervous system. Cell 174:999–1014 e22. PMC6086934

    Article  Google Scholar 

  12. Drokhlyansky E, Smillie CS, Van Wittenberghe N et al (2020) The human and mouse enteric nervous system at single-cell resolution. Cell 182:1606–1622 e23

    Article  Google Scholar 

  13. Wright CM, Schneider S, Smith-Edwards KM et al (2021) scRNA-Seq reveals new enteric nervous system roles for GDNF, NRTN, and TBX3. Cell Mol Gastroenterol Hepatol 11:1548

    Article  Google Scholar 

  14. May-Zhang AA, Tycksen E, Southard-Smith AN et al (2021) Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ. Gastroenterology 160:755–770 e26. PMC7878294

    Article  Google Scholar 

  15. Hockley JRF, Taylor TS, Callejo G et al (2019) Single-cell RNAseq reveals seven classes of colonic sensory neuron. Gut 68:633–644. PMC6580772

    Article  Google Scholar 

  16. Najjar SA, Davis BM, Albers KM (2020) Epithelial-neuronal communication in the colon: implications for visceral pain. Trends Neurosci 43:170–181. PMC7047572

    Article  Google Scholar 

  17. Smith-Edwards KM, Edwards BS, Wright CM et al (2021) Sympathetic input to multiple cell types in mouse and human colon produces region-specific responses. Gastroenterology 160:1208–1223 e4. PMC7956113

    Article  Google Scholar 

  18. Hibberd TJ, Feng J, Luo J et al (2018) Optogenetic induction of colonic motility in mice. Gastroenterology 155:514–528 e6. PMC6715392

    Article  Google Scholar 

  19. Smith-Edwards KM, Najjar SA, Edwards BS et al (2019) Extrinsic primary afferent neurons link visceral pain to colon motility through a spinal reflex in mice. Gastroenterology 157:522–536 e2. PMC6995031

    Article  Google Scholar 

  20. Rakhilin N, Barth B, Choi J et al (2016) Simultaneous optical and electrical in vivo analysis of the enteric nervous system. Nat Commun 7:11800. PMC4899629

    Article  Google Scholar 

  21. Li Z, Hao MM, Van den Haute C et al (2019) Regional complexity in enteric neuron wiring reflects diversity of motility patterns in the mouse large intestine. elife 8:e42914. PMC6391068

    Google Scholar 

  22. Costa M, Keightley LJ, Hibberd TJ et al (2020) Characterization of alternating neurogenic motor patterns in mouse colon. Neurogastroenterol Motil 33:e14047

    Google Scholar 

  23. Nestor-Kalinoski A, Smith-Edwards KM, Meerschaert K et al (2022) Unique neural circuit connectivity of mouse proximal middle and distal colon defines regional colonic motor patterns. Cell Mol Gastroenterol Hepatol 13(1):309–337.e3. S2352345X21001831. https://doi.org/10.1016/j.jcmgh.2021.08.016

  24. Espinosa-Medina I, Saha O, Boismoreau F et al (2016) The sacral autonomic outflow is sympathetic. Science 354:893–897. PMC6326350

    Article  Google Scholar 

  25. Lynn PA, Blackshaw LA (1999) In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon. J Physiol 518:271–82. PMC2269405

    Article  Google Scholar 

  26. Brierley SM, Jones RC 3rd, Gebhart GF et al (2004) Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127:166–178

    Article  Google Scholar 

  27. Meerschaert KA, Adelman PC, Friedman RL et al (2020) Unique molecular characteristics of visceral afferents arising from different levels of the Neuraxis: location of afferent Somata predicts function and stimulus detection modalities. J Neurosci 40:7216–7228. PMC7534907

    Article  Google Scholar 

  28. Traub RJ, Murphy A (2002) Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway. Pain 95:93–102

    Article  CAS  Google Scholar 

  29. Harrington AM, Caraballo SG, Maddern JE et al (2019) Colonic afferent input and dorsal horn neuron activation differs between the thoracolumbar and lumbosacral spinal cord. Am J Physiol Gastrointest Liver Physiol 317:G285–G303

    Article  CAS  Google Scholar 

  30. De Groat WC, Krier J (1978) The sacral parasympathetic reflex pathway regulating colonic motility and defaecation in the cat. J Physiol 276:481–500. PMC1282439

    Article  Google Scholar 

  31. Miller SM, Szurszewski JH (1997) Colonic mechanosensory afferent input to neurons in the mouse superior mesenteric ganglion. Am J Phys 272:G357–G366

    CAS  Google Scholar 

  32. Miller SM, Szurszewski JH (2002) Relationship between colonic motility and cholinergic mechanosensory afferent synaptic input to mouse superior mesenteric ganglion. Neurogastroenterol Motil 14:339–348

    Article  CAS  Google Scholar 

  33. Miller SM, Szurszewski JH (2003) Circumferential, not longitudinal, colonic stretch increases synaptic input to mouse prevertebral ganglion neurons. Am J Physiol Gastrointest Liver Physiol 285:G1129–G1138

    Article  CAS  Google Scholar 

  34. Sharkey KA, Lomax AE, Bertrand PP et al (1998) Electrophysiology, shape, and chemistry of neurons that project from guinea pig colon to inferior mesenteric ganglia. Gastroenterology 115:909–918

    Article  CAS  Google Scholar 

  35. Spencer N, McCarron SL, Smith TK (1999) Sympathetic inhibition of ascending and descending interneurones during the peristaltic reflex in the isolated guinea-pig distal colon. J Physiol 519(Pt 2):539–50. PMC2269523

    Google Scholar 

  36. Spencer NJ, Bywater RA, Klemm MF (1998) Effects of sympathetic nerve stimulation on membrane potential in the circular muscle layer of mouse distal colon. Neurogastroenterol Motil 10:543–552

    Article  CAS  Google Scholar 

  37. Gulbransen BD, Bains JS, Sharkey KA (2010) Enteric glia are targets of the sympathetic innervation of the myenteric plexus in the guinea pig distal colon. J Neurosci 30:6801–9. PMC6632550

    Article  Google Scholar 

  38. Bellono NW, Bayrer JR, Leitch DB et al (2017) Enterochromaffin cells are gut Chemosensors that couple to sensory neural pathways. Cell 170:185–198 e16. PMC5839326

    Article  Google Scholar 

  39. Matheis F, Muller PA, Graves CL et al (2020) Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss. Cell 180:64–78 e16. PMC7271821

    Article  Google Scholar 

  40. Bayliss WM, Starling EH (1900) The movements and the innervation of the large intestine. J Physiol 26:107–18. PMC1540523

    Article  Google Scholar 

  41. Dennis C, Eddy FD, Frykman HM et al (1948) The response to Vagotomy in idiopathic ulcerative colitis and regional enteritis. Ann Surg 128:479–93. PMC1514076

    Article  Google Scholar 

  42. Gray GW, Hendershot LC, Whitrock RM et al (1955) Influence of the parasympathetic nerves and their relation to the action of atropine in the ileum and colon of the dog. Am J Phys 181:679–687

    Article  CAS  Google Scholar 

  43. Hulten L, Jodal M, Lundgren O (1969) The effects of graded electrical stimulation or reflex activation of the sympathetic and the parasympathetic nerve supply on the regional blood flow in cat colon. Bibl Anat 10:312–315

    CAS  Google Scholar 

  44. Lannon J, Weller E (1947) The parasympathetic supply of the distal colon. Br J Surg 34:373–378

    Article  CAS  Google Scholar 

  45. Altschuler SM, Escardo J, Lynn RB et al (1993) The central organization of the vagus nerve innervating the colon of the rat. Gastroenterology 104:502–509

    Article  CAS  Google Scholar 

  46. Berthoud HR, Carlson NR, Powley TL (1991) Topography of efferent vagal innervation of the rat gastrointestinal tract. Am J Phys 260:R200–R207

    CAS  Google Scholar 

  47. Dapoigny M, Cowles VE, Zhu YR et al (1992) Vagal influence on colonic motor activity in conscious nonhuman primates. Am J Phys 262:G231–G236

    CAS  Google Scholar 

  48. Larauche M, Wang Y, Wang PM et al (2020) The effect of colonic tissue electrical stimulation and celiac branch of the abdominal vagus nerve neuromodulation on colonic motility in anesthetized pigs. Neurogastroenterol Motil 32:e13925. PMC7606494

    Article  Google Scholar 

  49. Tong WD, Ridolfi TJ, Kosinski L et al (2010) Effects of autonomic nerve stimulation on colorectal motility in rats. Neurogastroenterol Motil 22:688–93. PMC2952396

    Article  Google Scholar 

  50. Furness JB, Callaghan BP, Rivera LR et al (2014) The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol 817:39–71

    Article  Google Scholar 

  51. Travagli RA, Hermann GE, Browning KN et al (2003) Musings on the wanderer: what’s new in our understanding of vago-vagal reflexes? III. Activity-dependent plasticity in vago-vagal reflexes controlling the stomach. Am J Physiol Gastrointest Liver Physiol 284:G180–7. PMC3055655

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kristen M. Smith-Edwards .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Meerschaert, K.A., Davis, B.M., Smith-Edwards, K.M. (2022). New Insights on Extrinsic Innervation of the Enteric Nervous System and Non-neuronal Cell Types That Influence Colon Function. In: Spencer, N.J., Costa, M., Brierley, S.M. (eds) The Enteric Nervous System II. Advances in Experimental Medicine and Biology, vol 1383. Springer, Cham. https://doi.org/10.1007/978-3-031-05843-1_13

Download citation

Publish with us

Policies and ethics