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 context of its external environment.

Public Health Relevance

Many patients suffer from incontinence and overactive bladder, often because the nerves controlling bladder filling and voiding fail to function. The proposed studies will use state of the art neural mapping methods, coupled with careful measurements of bladder function in awake and anesthetized mice, to define how the brain integrates signals from the bladder and the external environment to control bladder filling and voiding. These studies should help us to develop a clear understanding of why bladder symptoms occur, and how to treat them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK113030-02
Application #
9431201
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hoshizaki, Deborah K
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Verstegen, Anne M J; Vanderhorst, Veronique; Gray, Paul A et al. (2017) Barrington's nucleus: Neuroanatomic landscape of the mouse ""pontine micturition center"". J Comp Neurol 525:2287-2309