# Mapping brainstem control of continence

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $389,250

## Abstract

PROJECT SUMMARY: Disorders of urinary storage and voiding, including incontinence, overactive bladder
and lower urinary tract symptoms (LUTS) afflict millions of people and engender enormous medical cost, and our
lack of understanding of LUTS mechanisms hampers treatment. Because successful bladder filling and voiding
requires finely tuned and effective neural control, effective LUTS treatment will require understanding how this
neural control is achieved and how it is deranged in different patient populations.
 Prior studies identify brain/spinal cord regions involved in controlling bladder function, but do not
resolve neuronal subpopulations or their connections. We lack and seek to develop in mice a complete circuit map
of the control of bladder filling/voiding. Prior work and our own data identified the Pontine Micturition Center
(PMC) and its many corticotropin releasing hormone (CRH) neurons (PMCCRH) as major drivers of voiding.
 The brain coordinates pelvic afferents (signaling bladder filling) to periaqueductal gray (PAG) and other
sites, and cues from the external environment (processed in loci like the lateral preoptic area (LPOA) and lateral
hypothalamic area (LHA)) to “decide” when to void. To define how the brain integrates these two major inputs to
control PMCCRH neurons, we will combine state of the art neuroscience methods with careful studies of bladder
function to determine the roles of non CRH PMC region neurons in voiding and to define the
anatomic/functional interfaces between PMCCRH and neurons of the vlPAG, LPOA and LHA.
 Aim #1 will define neural populations in the PMC region critical to control of bladder function. Although
PMCCRH neurons appear to be the major group driving voiding, locus coeruleus neurons which express tyrosine
hydroxylase (LCTH) and GABA-ergic neurons of the pontine central gray (PCGGABA) may also play a role. We will
selectively activate or ablate PMCCRH, LCTH or PCGGABA neurons and examine effects on bladder function.
 Aim 2 will focus on the PAG portion of the afferent control pathway. We will define how vlPAG GLUT
or GABA neurons (vlPAGGLUT or vlPAGGABA) connect to and control PMCCRH neurons by exploiting preliminary
data showing axonal projections from vlPAG to PMC, as well as evidence that direct stimulation of these neurons
can stimulate (vlPAGGLUT) or inhibit (vlPAGGABA) voiding. These results will permit us and others in future to
unravel the detailed “switch” circuit in the PAG integrating sacral afferent information to regulate voiding. via
PMCCRH neurons.
 Aim 3 will focus on hypothalamic regions which help coordinate bladder function with events in the
external environment. We will define functional and anatomic connections between LPOA and LHA neuron
populations and PMCCRH neurons. These studies will set the stage for discovery of the rostral inputs helping
control activity of hypothalamic neurons which, in turn regulate PMCCRH neurons, and permit the animal to
control voiding in the cont...

## Key facts

- **NIH application ID:** 10128435
- **Project number:** 5R01DK113030-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Mark L. Zeidel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,250
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128435

## Citation

> US National Institutes of Health, RePORTER application 10128435, Mapping brainstem control of continence (5R01DK113030-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10128435. Licensed CC0.

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