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Neurogastroenterology Laboratory

sensory neurons, ans, gut, motility, striated muscle, fascia, dura...

Mast cells (blue) and sensory nerve fibres (red)
labelled close to the superior sagittal sinus of a
preparation of mouse dura, demonstrating the close
association between these very different types of cells

Research Summary

Sensory neurons play a key role in the function of our nervous system. In many cases, they initiate behaviours when they detect a change in the body’s internal or external environment. Sensory neurons can trigger conscious sensations, which may lead to voluntary behaviour, or they can initiate automatic reflexes with very little elective control. In some cases, inappropriate sensations can be problematic – pain and itch are two well-known examples.

The sensory neurons that mediate sensations from the viscera are particularly poorly understood. Work in our laboratory over a number of years has allowed us to relate the firing activity of visceral sensory neurons with their axonal branching and their all-important transduction sites.  This is leading to an account of all of the major types of extrinsic sensory neurons in the gastrointestinal tract.  It has also become apparent that the link between functional sensitivity and neural structure is also poorly understood for many organ systems of the body.  Given the prevalence of multiple types of pain syndromes, we have been keen to extend our approach to somatic structures, while continuing to investigate the viscera.

Research Projects

In 2015 we published a study showing that a major class of visceral nociceptors - the so-called "vascular afferents" can be studied in simplified blood vessel/nerve preparations. These neurons are sensitive to mechanical distortion in any axis, including luminal distension of vessels (Humenick A et al 2015 J Physiol;593(16):3693-3709). In 2016 we made recordings from these sensory neurons in more complex tubular preparations of gut which could be stimulated by modest distension to show propulsive motility patterns. We characterised the responses of these neurons during this activity and showed that they are potently activated by even low levels of distension that evoke peristaltic contractions. A new type of statistical analysis has been developed through our collaborators, Dr Lukasz Wiklendt and A/Prof Phil Dinning.

Tim Hibberd completed his PhD in 2014 in the laboratory, studying enteric "viscerofugal" neurons which combine properties of sensory neurons and interneurons. A collaboration with the group of Professor Mark Taylor in the School of Engineering followed on from this work and applied sophisticated Digital Image Correlation (DIC) techniques to determine the exact nature of the mechanical stimuli that evoked firing by viscerofugal neurons. This work was published in 2016 and represents the fifth paper on these intriguing neurons that Tim has studied in so much detail.

Rochelle Peterson (nee Bowley) started a PhD in the laboratory in 2015 after being awarded an Australian Postgraduate Award scholarship. She has been applying methods developed for our studies of visceral organs to characterise sensory innervation of striated muscle preparations in vitro. She has developed a thin, flat sheet preparation of mouse abdominal muscles and combined extracellular recording of sensory firing with rapid anterograde transport of biotinamide. This has allowed her to correlate the morphology and sensitivity of a class of Group III muscle afferents for the first time. These neurons appear to comprise a discrete class of metaboreceptors and the work has been submitted for publication. She has followed this up with novel studies of the chemosensitivity of these sensory fibres, identifying novel mechanisms by which their firing is modulated by metabolites.

We have been keen to extend our range of techniques to characterise sensory neurons, and especially nociceptors, in a range of preparations. In collaboration with Dr Christine Barry, we have set up a preparation of isolated mouse dura. This thin sheet contains numerous peptidergic axons of trigeminal nociceptors which, in humans, are known to contribute to the mysterious processes of headache. We have carried out both close electrophysiological recordings from the axons and filled them with biotinamide to characterise them physiologically and morphologically. To date it has not proved possible to combine these approaches, but this is still being attempted. The preparation also contains large numbers of mast cells, providing an ideal setup to study mast-cell/nociceptor interactions under highly controlled conditions in vitro. This work will form part of a request for funding.

Selected Publications

Hibberd TJ, Costa M, Travis L, Brookes SJH, Wattchow DA, Feng J, Hu H, Spencer NJ (2017) Neurogenic and myogenic patterns of electrical activity in isolated intact mouse colon. Neurogastroenterol Motil. [Epub ahead of print]

 

Costa M, Wiklendt L, Keightley L, Brookes SJH, Dinning PG, Spencer NJ (2017) New insights into neurogenic cyclic motor activity in the isolated guinea-pig colon. Neurogastroenterol Motil. [Epub ahead of print]

 

Nicholas S, Yuan SY, Brookes SJ, Spencer NJ, Zagorodnyuk VP (2017) Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder. Br J Pharmacol, 174(2):126-138

 

Brookes S, Chen N, Humenick A, Spencer NJ, Costa M (2016) Extrinsic Sensory Innervation of the Gut: Structure and Function. Adv Exp Med Biol, 891:63-9

 

Chen BN, Olsson C, Sharrad DF, Brookes SJH (2016) Sensory innervation of the guinea pig colon and rectum compared using retrograde tracing and immune-histochemistry. Neurogastroenterol Motil, 28(9):1306-16

 

Palmer G, Hibberd TH, Roose T, Brookes SJH* and Taylor M (2016) Measurement of strains experienced by viscerofugal nerve cell bodies during mechanosensitive firing using Digital Image Correlation. Am J Physiol Gastrointest Liver Physiol, 311(5):G869-G879. *Corresponding author.

 

Arkwright JW, Underhill ID, Dodds KD, Brookes SJ, Costa M, Spencer NJ, Dinning PG (2016) A composite fibre optic catheter for monitoring peristaltic transit of intra-luminal content. J Biomedical Optics, 9(3):305-10

 

Arkwright JW, Underhill ID, Dodds KN, Brookes SJH, Costa M, Spencer NJ & Dinning PG (2016) A composite fibre optic catheter for monitoring peristaltic transit of an intra-luminal bead. J Biophotonics, 9(3):305-10

 

Carbone SE, Jovanovska V, Brookes SJH & Nurgali K (2016) Electrophysiological and morphological changes in colonic myenteric neurons from chemotherapy-treated patients; a pilot study. Neurogastroenterol Motil, 28(7):975-84

 

Dinning PG, Sia TC, Kumar R, Mohd Rosli R, Kyloh M, Wattchow DA, Wiklendt L, Brookes SJ, Costa M, Spencer NJ (2016) High-resolution colonic motility recordings in vivo compared with ex vivo recordings after colectomy, in patients with slow transit constipation. Neurogastroenterol Motil, 28(12):1824-1835

 

Hibberd TJ, Kestell GR, Kyloh MA, Brookes SJH Wattchow DA & Spencer NJ (2016) Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse. Am J Physiol Gastrointest Liver Physiol, 310(8):G561-73

 

Ng KS, Brookes SJH, Montes-Adrian N, Mahns MA and Gladman MA (2016) Electrophysiology of Human Rectal Afferents. Am J Physiol Gastrointest Liver Physiol, 311(6):G1047-G1055

 

Rahman AA, Robinson AM, Brookes SJH, Eri R and Nurgali K (2016) Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum. Cell Tiss Res, 366(2):285-299

 

Spencer NJ, Zagorodnyuk V, Brookes SJ, Hibberd T (2016) Spinal afferent nerve endings in visceral organs: recent advances. Am J Physiol Gastrointest Liver Physiol, 311:G1056-G1063

 

Spencer NJ, Kyloh M, Beckett EA, Brookes S, Hibberd T (2016) Different types of spinal afferent nerve endings in stomach and esophagus identified by anterograde tracing from dorsal root ganglia. J Comp Neurol, 524(15):3064-3083

 

Spencer NJ, Dinning PG, Brookes SJH and Costa M (2016) Insights into the mechanisms underlying colonic motor patterns. J Physiol (Lond), 594(15):4099-4116

 

Chen BN, Sharrad D, Hibberd TJ, Zagorodnyuk VP, Costa M and Brookes SJH (2015) Neurochemical characterisation of extrinsic nerves in myenteric ganglia of the guinea-pig distal colon. Journal of Comparative Neurology, 523(5):742-56

 

Kuizenga MH, Tiong CS, Dodds KN, Wiklendt L, Arkwright JW, Brookes SJH, Spencer NJ, Wattchow DA, Dinning PG and Costa M (2015) Neurally-mediated propagating Discrete Clustered Contractions superimposed on myogenic ripples in ex vivo segments of human ileum. American Journal of Physiology, 308(1):G1-G11

 

Sharrad DF, Hibberd TJ, Kyloh MA, Brookes SJH and Spencer NJ (2015) Quantitative immunohistochemcial co-localisation of TrpV1 and CGRP in varicose axons of the murine oesophagus, stomach and colorectum. Neuroscience Letters, 599:164-171

 

Humenick A, Chen BN, Wiklendt L, Spencer NJ, Zagorodnyuk VP, Dinning PG, Costa M & Brookes SJH (2015) Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. Journal of Physiology, 15;593(16):3693-3709

 

Spencer NJ, Sia TC, Brookes SJH, Costa M (2015) CrossTalk opposing view: 5-HTis not necessary for peristalsis. Journal of Physiology, 593(15):3229-3231

 

Costa M, Wiklendt L, Simpson P, Spencer NJ, Brookes SJ, Dinning PG (2015) Neuromechanical factors involved in the formation and propulsion of fecal pellets in the guinea-pig colon. Neurogastroenterology & Motility, 27(10):1466-77

 

Nicholas S, Keightley L, Brookes SJH, Costa M, Gibbins IL, Zagorodnyuk VP (2015) Conscious voiding during bladder obstruction in guinea pigs correlates with contractile activity of isolated bladders. Autonomic Neuroscience: Basic & Clinical, 194:74-83

 

Dinning PG, Costa M and Brookes SJH (2015) Chapter 100. Sensory and Motor Function of the Colon. In: Feldman M, Friedman LS, and Brandt LJ, Eds. Sleisenger & Fordtrans’ Gastrointestinal & Liver Disease 10th Edition, Philadelphia: Saunders; 2015pp 1696-1712

 

Hibberd TJ, Spencer NJ, Zagorodnyuk VP, Chen BN, Brookes SJH (2014) Targeted electrophysiological analysis of viscerofugal neurons in the myenteric plexus of guinea-pig colon. Neuroscience, 275C:272-284

 

Carbone SE, Jovanovska V, Nurgali K, Brookes SJH (2014) Human enteric neurons: morphological, electrophysiological and neurochemical identification. Neurogastroenterology & Motility, 26(12):1812-6

 

Sharrad DF, De Vries E, Brookes SJH (2013) Selective expression of α-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea-pig rectum and human colon. Journal of Comparative Neurology, 521(3):657-676

 

Sharrad DF, Gai WP, Brookes SJH (2013) Selective co-expression of synaptic proteins, α-synuclein, cysteine string protein-α, synaptophysin, synaptotagmin-1, and synaptobrevin-2 in vesicular acetylcholine transporter-immunoreactive axons in the guinea-pig ileum. Journal of Comparative Neurology, 521(11):2523-37

 

Carbone SE, Dinning PG, Costa M, Spencer NJ, Brookes SJH and Wattchow DA (2013) Ascending excitatory neural pathways modulate slow phasic myogenic contractions in the isolated human colon. Neurogastroenterology and Motility, 25(8) 670-676

 

Brookes SJH, Spencer NJ, Costa M and Zagorodnyuk VP (2013) Extrinsic primary afferent signalling in the gut. Nature Reviews Gastroenterology & Hepatology, 10(5):286-96

 


Investigators

  • Simon JH Brookes, BSc(Hons), PhD

  • Marcello Costa, MD, FAA, Matthew Flinders Distinguished Professor and Professor of Neurophysiology

  • David A Wattchow, PhD, FRACS, Consultant Surgeon

Support Staff

  • Bao Nan Chen, BMed, MSc, Research Assistant

  • Adam Humenick, BSc(Hons), Research Assistant

Students

  • Rochelle Peterson (nee Bowley), PhD Student

  • Alan Quek, PhD Student

  • Joseph Hearnden, Honours Student

  • Amanda Weragoda, Honours Student


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