Voiding dysfunction in the elderly ranges from urinary incontinence to retention and causes significant morbidity. Even so, the current literature contains few data on the changes inflicted by age on the bladder and its function. Pharmacological, physiological, and regional histochemical studies of the aged rat bladder have revealed conflicting results. Ultrastructural and histological analyses of the aged human bladder have disclosed several changes that were associated with voiding dysfunction, but the clinical significance of these findings is yet to be determined. Autonomic innervation to various organ systems changes with aging. However, alterations in innervation to the aging bladder have not been studied. Voiding symptoms related to bladder outlet obstruction and diabetes are similar to those associated with aging. In these conditions, symptoms may arise from altered innervation of the bladder in response to changes in nerve growth factor (NGF) production. The focus of this project is to determine if similar neuroplasticity of the aging bladder occurs in a senescent rat. The Fisher 344 aging rat demonstrated changes in micturition similar to that seen in elderly humans. The first hypothesis is that age-related changes occur in the innervation of the bladder. Total innervation of the aged bladder will be quantitated using Western blot analyses for the neuronal markers PGP9.5 and synaptophysin. Histological changes in the afferent and efferent pathways to the aged bladder will be assessed using retrograde neuronal labeling and immunohistochemistry. The second hypothesis is that the function of the bladder and electrophysiologic properties of bladder nerves are thereby changed. CMGs will be measured to assess bladder function. Conduction velocities will be measured in the afferent and efferent nerves. Relative contributions of the supraspinal and spinal micturition reflexes to voiding by the aged rats will be determined. The third hypothesis is that the mechanism of neuroplasticity in the aging bladder is due to altered trophic factor (NGF) production by the target organ. ELISA for NGF, RT- PCR and in-situ hybridization for NGF mRNA will be used to quantitate NGF production in the aged bladder. Retrograde transport of 125/I-NGF by the aged neurons will be assessed and compared to young controls. Changes in trkA and p75 NGF receptors will be assessed immunohistochemically. Aged rats will be administered exogenous NGF or immunized to NGF to ascertain if reversal of documented changes in bladder innervation is possible; this will further confirm the central role of NGF in neuroplasticity of the aged bladder. Finally, response of the aged rat bladder to """"""""stress"""""""" will be assessed by quantitating changes in NGF production and reinnervation after denervation. By initially focusing on neuroanatomic and neurophysiologic changes, subsequent mechanisms can be elucidated to explain the fundamental process of aging in the bladder. These experiments are necessary to further the understanding in an area which is underserved by basic research and the results may allow future novel treatments in the area of geriatric voiding dysfunction which afflicts a significant number of individuals.
