Lower Urinary Tract Syndrome (LUTS) affects millions of adults with an array of distressing symptoms, from urgency and pain to incontinence, and can lead to progressive debility, depression and isolation. Although brain control of bladder function is likely dysregulated in many of the millions of patients with lower urinary tract symptoms (LUTS), we know surprisingly little of the precise neural circuits involved and the interplay of neural signaling between brain regions. Advances in neural mapping and availability of disease models (e.g. diabetic, Alzheimer's and interstitial cystitis) in mice, combined with functional imaging and brain stimulation modalities in humans, will make it possible in future to diagnose specific neural deficits in patients with LUTS and apply customized, directed neural therapies. Our current P20 is using modern neuroscience techniques such as optogenetics to map, in fine detail, the neural circuits controlling bladder filling and voiding. To link these mapping studies with functional imaging in humans, we must develop methods to perform functional imaging during cystometrograms (CMGs) in mice. In addition, these methods are needed to examine the role of derangements in brain function in LUTS models in mice. The current proposal aims to create approaches to performing functional Magnetic Resonance Imaging (MRI) using Blood Oxygen Level Dependent (BOLD) MRI to monitor the patterns of brain activation during the filling and voiding cycles of the CMG.
Aim 1 will develop methods to perform BOLD MRI during CMG and analyze the results in anesthetized male and female mice of the 3 founder strains of the Collaborative Cross, selected because they show diverse CMG patterns.
This aim will develop the methods and define the variation of brain activation during CMG phases across diverse mouse strains.
Aim 2 will extend these methods to conscious mice undergoing CMG, permitting examination of frontal pathways in regulating and responding to bladder filling and voiding.
Aim 3 will extend the method further to mice undergoing chemogenetic stimulation (causing voiding) or suppression (inhibiting voiding) of specific neurons of the pontine micturition center (PMC) and periaqueductal gray during CMGs, identifying brain regions engaging most closely with these regions defined by fine mapping as essential to the micturition process. Development of CMG/BOLD MRI methods in mice will: 1. Augment fine mapping of neural control circuits in mice. 2. Permit direct comparisons between fMRI in mice and in humans. 3. Permit investigators studying LUTS models in mice to interrogate the role of disturbances in brain function in LUTS in mice. !
| Hill, Warren G; Zeidel, Mark L; Bjorling, Dale E et al. (2018) The void spot assay: Recommendations on the use of a simple micturition assay for mice. Am J Physiol Renal Physiol : |
