# Bladder fullness signaling and the neural control of continence

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $385,000

## Abstract

PROJECT SUMMARY
Lower urinary tract symptoms (LUTS) affect millions of people and are especially prevalent in the elderly
population. LUTS are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function.
Despite some progress in our understanding of the circuits that control reflex and voluntary micturition, significant
knowledge gaps remain. An enhanced understanding of how finely tuned and effective neural control over
bladder function is achieved is central to efforts directed at developing newer and more targeted treatments for
LUTS. The objective in this particular application is to understand which neurons detect, relay and process the
bladder distention signal, so that it ultimately becomes integrated into coherent neural control for proper bladder
function. The central hypothesis is that periaqueductal gray (PAG) neurons that receive bladder fullness
information (PAG’sense’) ‘gate’ neurons in the pontine micturition center (PMC) to become activated to initiate
micturition behavior. Successful bladder filling and voiding is directed by PMC neurons that project to spinal cord
motoneurons that, in turn, innervate detrusor and urethral sphincter muscles. Our model predicts that activity in
PMC neurons is likely suppressed until the sensory (bladder distention) signal has been relayed/distributed (from
spinal cord-efferent PAG neurons) to brain regions that exert ‘executive control’ in determining whether a
situation is safe and socially acceptable for voiding. The proper function of both first-pass sensing neurons and
of these inputs, including those from the PAG, that exert inhibitory control over PMC neuron activity are critical
for maintaining continence. Guided by strong preliminary data, we will test our overarching hypothesis by
pursuing three specific aims: 1) identify and map axonal projections of sacral spinal cord-efferent
PAG/PAG’sense’ neurons; 2) using fiber photometry Ca2+ imaging, define neural activity in bladder-afferent-
activity recipient PAG/PAG’sense’ neurons that may function to transform the distention signal to PMC output
action, and determine how inhibitory PMC-afferent neurons, activate or deactivate to allow voiding; and 3) using
optogenetic stimulation define the circuit basis of inhibitory neural control over bladder function, including
identifying neurons that are necessary for maintaining continence. The approach is intellectually and technically
innovative because of its emphasis on sensory-signal-sensing PAG neurons and on inhibitory afferent inputs
(and source cell populations) that regulate PMC activity, and because it employs a novel combination of newly
developed and validated technical approaches. This work is significant because it is one of several key steps in
a continuum of research that is expected to lead to significant improvement of knowledge of our understanding
of the cellular and synaptic circuits that control bladder filling and voiding. Collectively these studi...

## Key facts

- **NIH application ID:** 10032682
- **Project number:** 1R01DK125708-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Anne (Hanneke) Verstegen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2020-06-10 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10032682

## Citation

> US National Institutes of Health, RePORTER application 10032682, Bladder fullness signaling and the neural control of continence (1R01DK125708-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10032682. Licensed CC0.

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