Dissertation
The neural control of micturition: from animal models to circuitry
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.006898
Abstract
Urinary urge incontinence is a debilitating condition, effecting millions, without a known cure. Urge incontinence can occur after strokes or other lesions to the frontal cortex or hypothalamus and is also a stereotypical symptom in patients with normal pressure hydrocephalus. In NPH, it is believed that the expanding ventricles damage the surrounding white matter, leading to symptomology. Despite the need for better treatments for those with urge incontinence, who often end up in diapers or nursing homes, our knowledge of the neural circuits responsible for maintaining continence is lacking. Here, we present a detailed investigation of micturition in mice and uncover an inhibitory disynaptic pathway from the frontal cortex to the brainstem that is important for inhibiting urination. We first developed a novel, non-invasive assay to measure micturition in awake mice, using thermal imaging to record voids. We then developed a mouse model of incontinence by inducing hydrocephalus in mice. In addition to becoming frequent and incontinent, hydrocephalic mice had normal intracranial pressure and exhibited the other two stereotypical symptoms of NPH: gait impairment and cognitive dysfunction. Finally, we discovered a pathway from the prefrontal cortex to Barrington’s nucleus via neurotensin expressing neurons in the preoptic area of the hypothalamus. We found that ablating the medial prefrontal cortex or deleting inhibitory neuron from the preoptic area increases voiding. These experiments identify a critical pathway for normal bladder function and open the door for further cell-type and pathway-specific manipulation in this animal model of incontinence.
Details
- Title: Subtitle
- The neural control of micturition: from animal models to circuitry
- Creators
- Margaret Michelle Tish
- Contributors
- Joel Geerling (Advisor)Matthew Howard (Committee Member)Karl J Kreder (Committee Member)Marco Hefti (Committee Member)Krystal Parker (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Summer 2023
- DOI
- 10.25820/etd.006898
- Publisher
- University of Iowa
- Number of pages
- xiv, 174 pages
- Copyright
- Copyright 2023 Margaret Michelle Tish
- Language
- English
- Date submitted
- 07/11/2023
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 155-174).
- Public Abstract (ETD)
Urinary urge incontinence, the sudden urge to empty one’s bladder with the inability to overcome this urge, is a disabling condition that affects millions of individuals. It often occurs after brain damage and does not have a cure, often requiring the use of adult diapers. Patients with normal pressure hydrocephalus (NPH) are especially likely to develop urge incontinence. We do not understand how the brain normally maintains continence, and this hinders the development of treatments for those with incontinence.
In this dissertation, I first describe a novel way to measure micturition events in mice. I then use this assay in the development of a mouse model for NPH. Along with the other symptoms of NPH (gait and cognitive impairments), these mice develop urinary frequency and incontinence. Finally, I uncover a brain pathway that goes from the frontal cortex, through the hypothalamus, and then to the brainstem, and show that this novel pathway is necessary for regulating the bladder-emptying reflex. This pathway inhibits neurons in the brainstem, that activate the bladder, potentially contributing to our ability to overcome this reflex and maintain continence. Supporting this possibility, when we damaged different parts of this pathway, mice voided more frequently and occasionally became incontinent.
This project paves the way for a deeper understanding of the neural control of micturition and maintenance of continence, which may lead to better treatments for individuals with urge incontinence.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984454435402771
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