Urothelial Cells and Sensory Signaling

PROJECT SUMMARY Urothelial cells play an active role in bladder physiology by responding to physical/chemical stimuli and signaling to sensory neurons and other cell types in the bladder. Numerous bladder diseases affecting millions of people, including overactive bladder, pain related to recurrent bladder infection, chemotherapeutic cystitis, and bladder pain syndrome, have been suspected to disrupt urothelial sensory signaling, leading to pathological changes to sensory signaling, including pain. While it has been accepted that urothelial cells play a role in bladder sensory function, it is unclear how these cells contribute to the sensation of filling and how it is altered under painful conditions. To unravel the role of urothelial cells in bladder nociception and sensory dysfunction, we have developed a novel mouse model that allows for direct stimulation of urothelial cells using optogenetics. We will functionally and molecularly identify the population of sensory neurons responding to direct urothelial stimulation of sensory nerve activity in normal and inflammatory conditions. Identifying these neurons may lead to more targeted therapies for treating visceral pain and sensory disorders associated with epithelial dysfunction. We will also assess which brain areas increase activity with optogenetic urothelial stimulation using functional magnetic resonance imaging and compare it to noxious and non-noxious distension to understand better the sensory information relayed by urothelial cells to the central nervous system. The results from these studies will allow us to understand better how urothelial cells contribute to bladder interoception and nociception and under what conditions. Finally, we will examine the impact of urothelial stimulation on voiding and nociceptive behaviors in freely moving mice before and after induction of cystitis using wireless light delivery devices. These experiments will give us insight into the role of urothelial sensory signals behaviorally. The project's overall goal is to evaluate and identify components of the communication between urothelial cells, sensory neurons, and the brain. Further, we will investigate how this signaling is changed under altered urothelial function. The results from this proposal will aid in furthering our understanding of urothelial sensory neuron signaling in aspects of pain. Hopefully, this improved understanding will lead to better therapeutic targets for bladder pain and other painful visceral disorders.