CHOLINERGIC DENERVATION AND REINNERVATION IN AGING

描述（研究者摘要）：尽管已经表明， 成年人中枢神经系统能够对 损伤，调节中枢神经系统代偿性发芽的机制 知之甚少，知之甚少。 这种可塑性反应在成年人大脑皮层中的发展及其丧失 随着年龄的增长，仍然缺乏。这个实验室的新初步数据 已经揭示了与年龄相关的胆碱能纤维密度的损失， 以“斑片状”的方式支配大脑皮层。这些数据 表明剩余的胆碱能细胞缺乏代偿性发芽 纤维，这可能有助于注意力的不稳定变化， 和认知能力都是正常的老年人回答 其中一些问题，我将特别寻求了解 神经支配和神经再支配的程度和时间过程 胆碱能纤维，基底前脑胆碱能纤维丢失后 神经元，在年轻的成年和老年大鼠。 细胞特异性病变 基底前脑胆碱能系统导致部分皮质ChAT丢失， 随着时间的推移而恢复，但尚不清楚个体 胆碱能神经轴突在这个时间过程中。 我将检查 轴突损伤，并确定ChAT水平的恢复是否反映 轴突长入，通过量化基底前脑病变的影响 对ChAT和NGFR免疫反应阳性神经支配密度的影响。病变后， 老年大鼠基底前脑胆碱能系统受损， 再生能力;尚不清楚这是否是由于 胆碱能标记物的永久性下调或不能 来产生发芽纤维。提出了两种实验范例： 第一个目的是测量胆碱能ChAT和NGFR， 免疫反应性轴突去神经支配和内嗅皮层发芽， 在HDB中胆碱能细胞的兴奋性毒性损伤之后。第二 范例旨在检查皮质终末野的大小， HDB中的单个神经元，并测量其在 当老鼠的大脑体积增大时，注射不同的 间隔在0.5和2.5 mm之间的彩色荧光示踪剂将 制成不同年龄大鼠的皮层， 将不同时间间隔的双标记细胞绘制为 终端字段大小的度量。因此，我的直接目标是 制作一个大鼠模型来研究胆碱能皮质去神经支配 和神经再生，通过测量影响的时间过程， 胆碱能基底前脑核团的病变对 衰老过程中大脑皮质的胆碱能神经支配 江西篇章我的长期目标是应用这个模型来剖析 可能参与胆碱能的细胞和分子机制 纤维发芽（或老年时缺乏纤维）。

DESCRIPTION (Investigator's Abstract): Although it has been shown that the adult central nervous system is capable of a plastic response to injury, the mechanisms that regulate compensatory sprouting in the CNS are poorly understood, and a great deal of knowledge regarding the development of this plastic response in the adult cortex, and its loss with aging, is still lacking. New preliminary data from this laboratory have revealed an age-related loss of cholinergic fiber density, innervating the cerebral cortex in a "patchy" fashion. These data suggest lack of compensatory sprouting in the remaining cholinergic fibers, that could contribute to the erratic modifications in attention and cognition present in otherwise normal aged individuals. To answer some of these questions, I specifically will seek to understand the extent and time course of denervation and reinnervation of the cholinergic fibers, following loss of the basal forebrain cholinergic neurons, in the young adult and aged rat. Cell specific lesions of the basal forebrain cholinergic system cause partial cortical ChAT loss, which recovers with time, but it is not clear what happens to individual cholinergic axons across this time course. I will examine the extent of axonal injury and determine whether recovery of ChAT levels reflects axonal ingrowth, by quantifying the effects of basal forebrain lesions on ChAT and NGFR immunoreactive innervation density. After lesions of the basal forebrain cholinergic system, aged rats have an impaired capacity for regeneration; it is not clear whether this is due to a permanent down-regulation of the cholinergic markers or to an inability to generate sprouting fibers. Two experimental paradigms are proposed: the first is aimed at measuring the cholinergic ChAT- and NGFR- immunoreactive axonal denervation and sprouting in the entorhinal cortex, after excitotoxic lesions of cholinergic cells in the HDB. The second paradigm is intended to examine the size of cortical terminal fields of individual neurons in the HDB, and to measure its modifications during aging, when the rat brain increases in size. Injections of different colored fluorescent tracers, spaced between 0.5 and 2.5 mm apart, will be made into the cortex of rats at different ages, and the percentage of double-labeled cells at different intervals will be plotted as a measure of terminal field size. My immediate aim is, therefore, to produce a rat model in which to study cholinergic cortical denervation and reinnervation, by measuring the time course of the effects that lesions of the cholinergic basal forebrain nuclei have on the cholinergic innervation of the cerebral cortex, across the aging spectrum. My long term goal is to apply this model to dissect the cellular and molecular mechanisms that may be involved in cholinergic fiber sprouting (or lack thereof in old age.