Improving our current therapies for pediatric voiding disorders requires an understanding of the neural events that underlie the maturation of voiding. Working with Dr. W.C. deGroat would assist me in becoming an independent investigator by providing a solid understanding of the neurophysiological approaches used in studying voiding dysfunction. The neonatal rat provides a model of bladder reflex maturation. Between birth and 3 weeks of life, emptying switches from dependence on maternal stimulation of the pudendal nerve to a centrally organized bladder reflex, and the spontaneous activity of the bladder changes from an organized pattern to a chaotic one. Two related hypotheses are proposed: 1. Maturation of central neural control of voiding is influenced by afferent input from the lower urinary tract. 2. The emergence of the mature storage function of bladder smooth muscle is regulated by autonomic nerve activity originating in the central nervous system.
Two Specific Aims are proposed: 1. Determine if alteration of afferent input from the bladder changes maturation of voiding reflexes. 2. Determine if alteration of afferent input, with subsequent changes in the central nervous system, alters maturation of bladder smooth muscle. The timing of voiding reflex changes will be studied in early maternal separation, pudendal nerve transection, and neonatal capsaicin treatment. Early elimination of primitive reflexes and early onset of mature reflexes are anticipated. These preparations and early spinal cord injury will be used to study the maturation of bladder smooth muscle. The pattern of spontaneous bladder activity will be determined using in-vitro optical imaging of calcium and voltage signals. Changes in the site of origination and direction of propagation of spontaneous activity will help determine the relative importance of brain, spinal cord, and peripheral nervous system input on bladder maturation. The long-term goals of this study are to develop new, developmentally appropriate therapies for pediatric voiding dysfunction, and to determine whether bladder overactivity has a developmental origin.
| Ng, Yuen-Keng; de Groat, William C; Wu, Hsi-Yang (2007) Smooth muscle and neural mechanisms contributing to the downregulation of neonatal rat spontaneous bladder contractions during postnatal development. Am J Physiol Regul Integr Comp Physiol 292:R2100-12 |
| Wu, Hsi-Yang; de Groat, William C (2006) Maternal separation uncouples reflex from spontaneous voiding in rat pups. J Urol 175:1148-51 |
| Ng, Yuen-Keng; de Groat, William C; Wu, Hsi-Yang (2006) Muscarinic regulation of neonatal rat bladder spontaneous contractions. Am J Physiol Regul Integr Comp Physiol 291:R1049-59 |
