Developmental plasticity of micturition reflexes



 DESCRIPTION (provided by applicant): The mechanisms involved in the storage and periodic elimination of urine exhibit marked changes during prenatal and postnatal development. Although the mature micturition reflex becomes functional during the postnatal period, the neural pathways underlying the mature voiding reflex are present at birth but are not active. Injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but suppressed during maturation. There is no model in the literature to explain this developmental switch. We have developed a novel model to be evaluated in this competitive renewal application that focuses on the plasticity (expression, localization, function) of two classes of ion channels in micturition reflex pathways: the transient receptor potential channel vanilloid family (TRPV) and Ca2+- and/or Ca2+ - and voltage-activated K+ channels. Our overall hypothesis is that plasticity in the sensory limb (e.g., urothelium, dorsal root ganglia) of the micturition reflex during the early postnatal period or following spinal cord injury (SCI) involving TRPV4 Ca2+ signaling and Ca2+ - (SKCa) and/or Ca2+ - and voltage-activated K channels (BKCa) underlies micturition reflex maturation and reemergence of primitive voiding function in the adult. We propose a novel paradigm whereby the TRPV4/Ca2+signaling complex acts as a brake to the mature micturition reflex during the early postnatal period and underlies reemergence of primitive voiding following SCI in the adult. Aim 1: We hypothesize that TRPV4 is co- expressed in urothelium and/or bladder sensory neurons with SKCa and/or BKCa during the early postnatal period. Plasticity (tissue/cell distribution, density) in the TRPV4/Ca2+ signaling complex in the urothelium and/or bladder sensory neurons during postnatal maturation determines the pro-inhibitory (brake) or pro- excitatory state of the distention-induced voiding reflex. The tissue/cellular distribution an density of the TRPV4/Ca2+ complex favors the pro-inhibitory (brake) state of the distention-induced voiding reflex during early postnatal development. Aim 2: We hypothesize that TRPV4 functions as a brake to the mature voiding reflex during early postnatal development through interactions with SKCa and/or BKCa in urothelium and/or bladder sensory neurons. The TRPV4/Ca2+ signaling complex elicits hyperpolarization and prevents transmitter (e.g., ATP) release. Aim 3: We hypothesize that SCI-induced plasticity (tissue/cell distribution, density, function) in the TRPV4/Ca2+signaling complex in the urothelium and/or bladder sensory neurons results in the reemergence of the pro-inhibitory (brake) state of the distention-induced voiding reflex and reemergence of primitive voiding reflexes (perineal-to-bladder). These studies will advance our understanding of mechanisms underlying micturition reflex maturation and recapitulation of ontological events following SCI and provide insights into potential lower urinary tract targets to improve voiding function.