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Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle

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Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Systems/Circuits Identification of a rhythmic firing pattern in the enteric nervous system that generates rhythmic electrical activity in smooth muscle Nick J Spencer1, Timothy J Hibberd1, Lee Travis1, Lukasz Wiklendt1, Marcello Costa1, Hongzhen Hu2, Simon J Brookes1, David A Wattchow3, Phil G Dinning1,3, Damien J Keating1 and Julian Sorensen4 1College of Medicine and Public Health & Centre for Neuroscience, Flinders University, Adelaide, Australia 2Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA 3Discipline of Surgery and Gastroenterology, Flinders Medical Centre, South Australia. 4Cyber Sensing and Shaping, Cyber & Electronic Warfare Division, Defence, Science & Technology Group, Edinburgh, South Australia, Australia. DOI: 10.1523/JNEUROSCI.3489-17.2018 Received: 7 December 2017 Revised: 30 April 2018 Accepted: 9 May 2018 Published: 28 May 2018 Author contributions: N.J.S., M.C., and H.H. designed research; N.J.S. wrote the first draft of the paper; N.J.S., S.J.B., D.A.W., P.D., D.J.K., and J.S. edited the paper; N.J.S., T.H., M.C., H.H., and J.S. wrote the paper; T.H. and L.T. performed research; T.H. contributed unpublished reagents/analytic tools; T.H., L.T., L.W., and J.S. analyzed data. Conflict of Interest: The authors declare no competing financial interests. The experiments carried out in this study were funded by grants to NJS (grant # 1067317 & 1127140) from the National Health and Medical Research Council (NH & MRC) of Australia. NJS, TJH, MC, SJB designed research, LT, RG & TJH performed research, JS & LW analyzed data, NJS, DJK, DAW & HZ wrote the paper. The authors declare no competing financial interests. Corresponding author: College of Medicine and Public Health & Centre for Neuroscience, Flinders University, GPO Box 2100, Adelaide, South Australia, [email protected], Tel: +61 8 8204 4241, Fax: +61 8 8204 5768 Cite as: J. Neurosci ; 10.1523/JNEUROSCI.3489-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors Page | 1 1 2 3 4 5 6 Identification of a rhythmic firing pattern in the enteric nervous system that 7 generates rhythmic electrical activity in smooth muscle 8 9 10 Abbreviated Title: 11 12 Novel enteric firing pattern 13 14 15 Nick J Spencer*†1, Timothy J Hibberd†1, Lee Travis1, Lukasz Wiklendt1, Marcello Costa1, 16 Hongzhen Hu2, Simon J Brookes1, David A Wattchow3, Phil G Dinning1,3, Damien J Keating1 & 17 Julian Sorensen4 18 19 20 1. College of Medicine and Public Health & Centre for Neuroscience, Flinders University, 21 Adelaide, Australia, 2. Department of Anesthesiology, The Center for the Study of Itch, 22 Washington University School of Medicine, St. Louis, MO, USA 3. Discipline of Surgery and 23 Gastroenterology, Flinders Medical Centre, South Australia. 4. Cyber Sensing and Shaping, 24 Cyber & Electronic Warfare Division, Defence, Science & Technology Group, Edinburgh, South 25 Australia, Australia. 26 27 28 † Equal first author 29 *Corresponding author: 30 College of Medicine and Public Health & Centre for Neuroscience 31 Flinders University 32 GPO Box 2100 33 Adelaide, South Australia 34 [email protected] 35 Tel: +61 8 8204 4241 36 Fax: +61 8 8204 5768 37 38 9 Figures, 4 Tables, 7 Extended figures, 4 movie files 39 250 words in Abstract, 650 words in Introduction 40 1316 words in Discussion 41 42 Acknowledgements: 43 The experiments carried out in this study were funded by grants to NJS (grant # 1067317 & 1127140) 44 from the National Health and Medical Research Council (NH & MRC) of Australia. NJS, TJH, MC, SJB 45 designed research, LT, RG & TJH performed research, JS & LW analyzed data, NJS, DJK, DAW & HZ wrote 46 the paper. The authors declare no competing financial interests. 47 1 Page | 2 48 49 Abstract 50 51 The enteric nervous system (ENS) contains millions of neurons essential for organization of 52 motor behaviour of the intestine. It is well established the large intestine requires ENS activity to 53 drive propulsive motor behaviours. However, the firing pattern of the ENS underlying 54 propagating neurogenic contractions of the large intestine remains unknown. To identify this, we 55 used high resolution neuronal imaging with electrophysiology from neighbouring smooth muscle. 56 Myoelectric activity underlying propagating neurogenic contractions along murine large intestine 57 (referred to as colonic migrating motor complexes, CMMCs) consisted of prolonged bursts of 58 rhythmic depolarizations at a frequency of ~2 Hz. Temporal coordination of this activity in the 59 smooth muscle over large spatial fields (~7mm, longitudinally) was dependent on the ENS. 60 During quiescent periods between neurogenic contractions, recordings from large populations of 61 enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic 62 contractions was characterized by the emergence of temporally synchronized activity across large 63 populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and 64 temporally synchronized across large numbers of ganglia at ~2 Hz. ENS activation preceded 65 smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were 66 controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing 67 of large populations of enteric neurons represents a unique neural motor pattern outside the 68 central nervous system. This is the first direct observation of rhythmic firing in the ENS 69 underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity 70 we identified underlies the generation of CMMCs. 71 72 73 Significance statement 74 How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in 75 the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known 76 that myogenic pacemaker cells exist in the GI-tract (called Interstitial cells of Cajal, ICC) that 77 generate rhythmic myogenic contractions. However, the mechanisms underlying the generation 78 of rhythmic neurogenic contractions of smooth muscle in the GI-tract remains unknown. We 79 developed a high resolution neuronal imaging method with electrophysiology to address this 80 issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the 81 ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate 82 rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI-tract. 83 84 85 86 Key Words: pacemaker, pattern generator, electrical rhythmicity, slow wave, depolarization, 87 peristalsis, enteric nervous system, neurogenic, colon, colonic migrating motor complex, 88 CMMC. 2 Page | 3 89 INTRODUCTION 90 91 The gastrointestinal (GI) tract contains its own nervous system, known as the enteric nervous 92 system (ENS). A unique feature of the ENS is that it contains entire neural circuits comprising 93 sensory neurons, interneurons and motor neurons which can be studied more readily than in the 94 central nervous system (CNS). Another unique feature of the ENS is that isolated segments of 95 intestine can independently coordinate propulsive movements and propel content without any 96 neural connections to the brain or spinal cord (Brann and Wood, 1976; Costa and Furness, 1976; 97 Brookes et al., 1999; Wood, 2012; Costa et al., 2015; Spencer et al., 2016a). 98 99 The ENS consists of millions of neurons that are contained within interconnected micro ganglia 100 that form two distinct plexuses, known as the myenteric and submucosal plexuses (Furness, 101 2006; Wood, 2012). Much has been learnt about the different types of neurons within the ENS 102 (Costa et al., 1996; Furness, 2006), particularly in guinea pig ileum (Costa and Brookes, 1994), 103 including their neuronal projections and synaptic inputs and outputs (Bornstein et al., 1994; 104 Furness et al., 1998; Furness, 2006; Mazzuoli and Schemann, 2012; Wood, 2012; Mazzuoli- 105 Weber and Schemann, 2015). In mammals, the neurons responsible for coordinating motor 106 behavior along the intestine are located in the myenteric plexus and include inhibitory and 107 excitatory motor neurons, ascending and descending interneurons, and a unique population of 108 intrinsic sensory neurons only found in the GI-tract (Furness et al., 1998; Mazzuoli and 109 Schemann, 2009, 2012; Mazzuoli-Weber and Schemann, 2015). Despite a detailed knowledge of 110 these neurons, a major unresolved mystery is how such a large population of neurons behave 111 during the neurogenic motor behaviors that propel content along the bowel (Wood, 2008, 2016; 112 Hu and Spencer, 2018). 113 114 It is well known that non-neuronal pacemaker cells exist in the GI-tract (known as Interstitial 115 Cells of Cajal, ICC) that generate and control the frequency of myogenic depolarizations in GI- 116 smooth muscle cells, known as slow waves (Huizinga et al., 1995; Dickens et al., 1999; Huizinga 117 et al., 2014). However, rhythmic neurogenic contractions
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