CHOLINERGIC DENERVATION AND REINNERVATION IN AGING

描述(调查人员摘要)：尽管已经表明 成人中枢神经系统能够对 损伤--调节中枢神经系统代偿性萌发的机制 人们对此知之甚少，而且关于 这种可塑性反应在成人大脑皮质中的发展及其丢失 随着年龄的增长，仍然缺乏。来自这个实验室的新的初步数据 揭示了与年龄相关的胆碱能纤维密度的丧失， 以“零星”的方式支配大脑皮层。这些数据 提示剩余的胆碱能缺乏代偿性萌发 纤维，这可能会导致注意力的不稳定变化 而认知存在于其他正常的老年人身上。回答 对于这些问题中的一些，我会特别寻求理解 去神经和再神经支配的程度和时间进程 基底前脑胆碱能丧失后的胆碱能纤维 幼年大鼠和老年大鼠的神经元。细胞特异型病变 基底前脑胆碱能系统导致部分皮质Chat丢失， 它会随着时间的推移而恢复，但还不清楚个人会发生什么 胆碱能轴突穿过这个时间进程。我会检查一下 轴突损伤并确定ChAT水平的恢复是否反映 通过量化基底前脑损伤的影响，轴突生长 ChAT和NGFR免疫反应神经分布密度。在损伤后 基底前脑胆碱能系统，衰老大鼠有受损 再生能力；尚不清楚这是否归因于 胆碱能标志物永久性下调或丧失能力 以产生发芽的纤维。提出了两种实验范式： 第一个目的是测量胆碱能Chat-和NGFR- 免疫反应阳性的轴突在内嗅皮层失神经和发芽， 在HDB胆碱能细胞的兴奋性毒性损伤后。第二 范式旨在检查大脑皮质终末野的大小 HDB中的单个神经元，并测量其在 衰老，当大鼠的大脑增大时。不同种类的注射剂 彩色荧光示踪剂，间隔在0.5到2.5毫米之间，将 取不同日龄大鼠的大脑皮质，并计算其百分率。 不同间隔的双标记单元格将绘制为 终端字段大小的度量。因此，我的直接目标是 建立一种研究胆碱能皮质神经支配的大鼠模型 和神经再支配，通过测量影响的时间进程 胆碱能前脑基底核团的损害 大脑皮层的胆碱能神经支配 频谱。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(或在年老时缺乏)。

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.