Najjar, Sarah A.
(2020)
The Role of the Colon Epithelium in Visceral Nociception and Gut Motility.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Visceral pain and dysmotility are major symptoms of common gastrointestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Both of these symptoms arise from changes in sensory signaling in the colon; visceral pain results from increased excitability of colon extrinsic primary afferent neurons (ExPANs) and disordered motility involves changes in neurons of the enteric nervous system (ENS), including the intrinsic primary afferent neurons (IPANs) that initiate peristalsis. The colon epithelium is at the forefront of these sensory cascades, as it is the first to interact with all luminal contents and contains the machinery to detect and send sensory information. However, it is unclear exactly how epithelial cell activity influences surrounding afferent neurons in normal and pathological conditions, and this intercellular signaling has been difficult to study because of the close association between epithelial and afferent nerve endings. Therefore, the goal of my studies was to investigate how selective activation and inhibition of colon epithelial cells influences these processes. Using optogenetic tools, I demonstrated that specific activation of the colon epithelium initiates action potential firing in ExPANs in an ATP-dependent manner. Epithelial-induced ExPAN activation resulted in nociceptive behavioral responses. I then showed that inhibition of the epithelium could attenuate nociceptive signaling and reduce visceral hypersensitivity in a mouse model of IBD. Lastly, I showed that selective activation of the epithelium initiated Ca2+ activity in ENS neurons and initiated local colon contractions, which was also dependent on ATP signaling. Additionally, these experiments showed that epithelial activation influenced the frequency of neuronally-mediated rhythmic contractions in the colon. Together these results demonstrate for the first time how epithelial stimulation, in the absence of any other mechanical or chemical stimuli, initiates nociceptive signaling and gut motility. The ability of epithelial inhibition to reduce visceral hypersensitivity reveals the potential of targeting the colon epithelium for treatments of pain. Understanding the biology of this epithelial-neuronal interface and how it changes in pathological conditions will provide valuable insight into why visceral pain is often co-morbid with dysmotility.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
18 August 2020 |
| Date Type: |
Publication |
| Defense Date: |
8 May 2020 |
| Approval Date: |
18 August 2020 |
| Submission Date: |
9 June 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
151 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
primary afferent neurons, colon epithelium, optogenetics, visceral pain, gut motility |
| Date Deposited: |
18 Aug 2020 23:08 |
| Last Modified: |
18 Aug 2020 23:08 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39221 |
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