How is Fullness Sensed in the Urinary Bladder?

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SUMMARY In normal day-to-day life, the sense of urinary bladder fullness is conveyed to the central nervous system such that voiding of urine is not too frequent, and retaining urine is not too painful. Much attention has focused on attempting to treat urinary bladder dysfunctions however, to understand any disorder of the lower urinary tract an essential physiological question must be addressed, and that is: How is bladder fullness sensed? Amazingly, the basic physiological mechanisms for sensing bladder fullness remain elusive. Exploring this fundamental question will be the focus of the current proposal, which should deepen our understanding of this process, providing important insights into the fundamental mechanisms involved in translating bladder fullness into afferent information. We propose the novel overarching concept that local changes in mechanical properties of the urinary bladder wall during filling are what drives sensory outflow. Importantly, pressure, per se, does not drive afferent nerve activity. Rather, it is the local deformation of the bladder wall that is the stimulus for afferent nerve activity. During filling, local excitation of detrusor smooth muscle (DSM) spreads spatially to cause small transient contractions of the bladder wall, called micromotions. Micromotions lead to angular distortions and localized changes in wall tension of the bladder wall. It is this localized change in wall tension that we believe triggers afferent nerve activity to sense bladder filling. This proposal gets at the heart of determining how fullness is sensed in the urinary bladder, without speculating about cell types involved in signaling (urothelial cells, interstitial cells, fibroblasts, etc). This project utilizes numerous novel techniques and approaches, such as our pentaplanar reflected image macroscopy platform that enables real-time monitoring of micromotions on the entire surface of the bladder. We have devleoped cutting edge imaging methodologies and signal processing algorithms to quantify bladder motility and Ca2+ signaling dynamcis. In Aim 1, we will determine the basis for local excitation of DSM during bladder filling. We will use imaging techniques on mice expessing genetically encoded Ca2+ indicators to study how the excitatiliby of the DSM affects the spatial spread of Ca2+ signals. Aim 2 explores spatial-temporal relationships between excitation and the rate/extent of angular distortions, and afferent nerve activity during filling. We will use simultaneous recordings of DSM Ca2+ activity, bladder pressure and afferent nerve activity. Finally, in Aim 3, we will investigate the basis for mechano-sensing by afferent nerves in the urinary bladder and the role of Piezo1 and Piezo2 stretch-sensitive cation channels. Importantly, we will characterize bladder function in Piezo2 knockout mice in vivo. Through completion of this project, we will gain fundamental insights into the mechanisms whereby physical forces during filling are sensed by the urinary bladder. Once we gain a full understanding of these processeses, we will be better suited to model, study, and treat bladder dysfunctions.