Developmental plasticity of micturation reflexes

描述（由申请人提供）：有许多儿童排尿功能障碍可能归因于出生后排尿反射的异常成熟。最近的研究表明，儿童下尿路功能障碍与成人膀胱过度活动有很强的相关性。因此，了解在产后时期调节排尿功能的神经控制的因素可能有助于了解儿童和成人排尿功能障碍。此外，成人神经系统的损伤或疾病可导致原始功能的重新出现，这些功能在发育早期突出，但在神经成熟过程中被抑制。因此，排尿反射通路的发育研究可能为成人膀胱功能神经源性疾病的机制提供关键见解。该建议的中心假设是中枢神经系统（CNS）和外周神经系统（PNS）的变化驱动排尿反射成熟。在出生后早期发育过程中，排尿功能的神经控制发生显著变化，可能是由多种因素介导的，包括成熟的椎管上机制（促肾上腺皮质激素释放因子、CRF/CRF受体系统）的上调以及神经元与靶器官（神经节后神经元-膀胱）相互作用的改变。在这个竞争性更新应用中，我们提出的目标是通过多学科实验方法，包括大鼠模型以及一种新型的慢性过表达神经生长因子（NGF）小鼠系（UPII-NGFv2），为排尿反射神经控制的发育诱导变化提供进一步的机制见解。本提案的目的是：(1)表征腰骶脊髓中的CRF/CRF受体系统，并确定CRF/CRF受体系统在LUT通路中的功能，作为发育的功能；(2)确定UPII-NGFv2小鼠成熟排尿功能加速发展的机制；(3)明确大盆腔神经节（MPG）膀胱神经节后细胞在发育过程中的功能特性、导致成人电生理特性多样性的潜在通道特性以及膀胱NGF对这些特性的贡献。

DESCRIPTION (provided by applicant): 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 neuronyenurinary 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. PUBLIC HEALTH RELEVANCE: Project Narrative 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 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. These studies will focus on the development of the prominent neurotransmitter/receptor system in descending spinal pathways and changes and mechanisms involved in neuron and target organ (i.e., postganglionic neuronyenurinary bladder) interactions that underlie maturation of voiding function. It is anticipated that these studies will provide insights into potential targets and therapeutic interventions for childhood and adult voiding dysfunctions.