Optogenetic dissection of the functional properties of bladder afferent populations

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DESCRIPTION (provided by applicant): Interstitial cystitis (IC) and overactive bladder (OAB) are chronic urological disorders characterized by urinary urgency and increased micturition frequency. A defining characteristic of IC that distinguishes it from OAB is the presence of pelvic/suprapubic pain that worsens as the disease progresses. Because visceral innervation is unique (organs are innervated by two nerves) and noxious visceral stimuli are unlike noxious cutaneous stimuli, mechanisms of bladder hypersensitivity differ from those of cutaneous hyperalgesia. Mechanical and/or chemical hypersensitivity of the bladder largely underlies the symptoms experienced by both IC and OAB patients. Yet, because the defining combination of symptoms (urgency and frequency with or without pain) for each cohort differs, and because symptoms arise from a common global population of bladder afferents, selective changes in transduction must occur either within afferent subpopulations, or among the central pathways engaged by afferent subpopulations, or both. These phenomena are poorly understood. Heterogeneous bladder neuronal subpopulations with lightly myelinated or unmyelinated peripheral fibers (A? - and C-fibers, respectively) convey information about multiple processes, including homeostatic monitoring (metaboreceptors) and detection of potentially damaging stimuli (nociceptors). Some fibers exhibit chemosensitivity, and most respond to mechanical stimuli, although some may acquire mechanosensitivity only during pathological conditions. We propose to use transgenic mouse lines expressing the light-gated ion channel, channelrhodopsin-2 (ChR2), in specific subsets of bladder afferents to address their respective contributions to the cardinal symptoms of IC and OAB. We hypothesize that subpopulations of bladder afferents contribute uniquely to micturition processes and nociception. We will test this hypothesis by studying afferent subpopulation contributions: 1) using an ex vivo preparation to functionally evaluate intrinsic and mechanical, chemical, and light-evoked response characteristics, 2) to the expression of in vivo micturition and nociceptive reflexes, and 3) to th activation of neurons receiving bladder afferent input in distinct regions of the spinal cord.