Developmental plasticity of micturation reflexes

项目摘要/摘要 有许多儿童排尿功能障碍可能是由出生后异常引起的。 排尿反射成熟。最近的研究表明，童年和儿童之间存在很强的相关性 下尿路(LUT)功能障碍和成人膀胱过度活动。因此，了解这些因素 调节出生后排尿功能的神经控制可能为深入了解 儿童和成人排尿功能障碍。此外，成人神经性损伤或疾病 系统可能导致原始功能的重新出现，这些功能在开发早期就很突出 但随后在神经成熟时被抑制。因此，排尿的发育研究 反射通路可能为神经源性的机制提供关键的见解。 成人膀胱功能障碍。这项提议的中心假设是 中枢神经系统(CNS)和外周神经系统(PNS)驱动力的变化 排尿反射成熟。排尿功能的神经控制发生显著变化 在出生后早期发育过程中，可能受多种因素的调节，包括 成熟的脊髓上机制(促肾上腺皮质激素释放因子、CRF/CRF受体系统)和 神经元和靶器官(节后神经元和膀胱)相互作用的变化。在这 竞争性续订申请，我们提出的目标将提供进一步的机械性洞察 多学科研究对排尿反射神经控制的发育诱导改变 涉及大鼠模型和一种新的慢性过度表达神经生长的实验方法 因子(NGF)小鼠系(UPII-NGFv2)。这项建议的目的是：(1)描述 腰骶髓内CRF/CRF受体系统及其功能的研究 受体系统在LUT通路中作为发育的功能；(2)确定其机制 UPII-NGFv2小鼠成熟排尿功能加速发育的基础；(3)确定 大鼠盆大神经节内膀胱节后细胞的功能特性 发展，基础通道属性，有助于电生理的多样性 成人的特性以及膀胱NGF对这些特性的贡献。

Project Summary/Abstract There are a number of childhood voiding dysfunctions that may be attributable to abnormal postnatal maturation of voiding reflexes. Recent studies have shown a strong correlation between childhood lower urinary tract (LUT) dysfunction and adult overactive bladder. Thus, understanding the factors that regulate the neural control of voiding function during the postnatal period may provide insight into childhood and adult voiding dysfunction. Furthermore, injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but then were suppressed during neural maturation. Therefore, developmental studies of micturition reflex pathways are likely to provide key insights into the mechanisms underlying neurogenic disorders of urinary bladder function in adults. The central hypothesis of this proposal is that changes in both the central nervous system (CNS) and peripheral nervous system (PNS) drive micturition reflex maturation. Marked changes in the neural control of voiding function that occur during early postnatal development may be mediated by multiple factors, including upregulation of mature supraspinal mechanisms (corticotropin releasing factor, CRF/CRF receptor system) and changes in neuron and target organ (postganglionic neuron¿urinary bladder) interactions. In this competitive renewal application, we propose aims that will provide further mechanistic insight into developmental-induced changes in the neural control of micturition reflexes using a multidisciplinary experimental approach involving a rat model as well as a novel, chronic overexpressing nerve growth factor (NGF) mouse line (UPII-NGFv2). The aims of this proposal are: (1) to characterize the CRF/CRF receptor system in the lumbosacral spinal cord and to define the function of the CRF/CRF receptor system in LUT pathways as a function of development; (2) to determine the mechanisms underlying an accelerated development of mature voiding function in UPII-NGFv2 mice; (3) to define the functional properties of bladder postganglionic cells in the major pelvic ganglion (MPG) during development, the underlying channel properties that contribute to the diversity of electrophysiological properties in the adult and the contribution of urinary bladder NGF to these properties.