ESTROGEN AND CHOLINERGIC SYSTEM INTERACTIONS IN AGING

描述：(逐字摘自申请人的摘要)在这些研究中，我们 建议检查雌激素刺激代偿能力的能力。 胆碱能系统在第一个和最多的区域的萌发反应 在阿尔茨海默病(AD)中深受影响的是内嗅皮层(EC)。 一些报道已经描述了突触发芽增加作为对 雌激素，并暗示这种激素与胆碱能上调有关。 在基底前脑中的功能。基于这些研究和我们自己的结果， 我们假设雌激素可能诱导胆碱能萌发和反应。 对细胞丢失的突触发生，并可能带来某种程度的 功能恢复。拟议试验的基本前提是 雌激素具有恢复和延长功能的神经保护作用。 受损的基底前脑胆碱能神经元。男、女渔民344 幼年(3月龄)和老年(24月龄)大鼠，切除性腺和 完好无损，将会收到类似皮质胆碱能神经丧失的损伤 在公元后。单侧损害(允许对侧起作用 内部控制)将在大脑的水平支核产生 192 Ig G-皂苷免疫毒素复合体的Broca斜带(HDB) 放大镜工具。这种免疫毒素专门针对胆碱能神经元。 雌激素或安慰剂治疗将在皮损后四周开始，当 已经发生了最大程度的EC去神经。对于特定目标1，我们将使用标准 免疫组织化学技术测量病变诱导的变化 雌激素治疗导致的EC中胆碱能萌发。在……里面 具体目标2我们将采用改进的Fonnum方法进行检测 胆碱乙酰转移酶(ChAT)活性在同一EC区。以特定的目标 3我们将检查雌激素对存活的基础的再生作用。 半定量RT/PCR分析前脑胆碱能神经元的变化 在两个胆碱能标志物的mRNA表达中，合成酶ChAT 和囊泡乙酰胆碱转运体(Vacht)。最后，在具体目标4 我们将检验雌激素可以改善病变的假设--以及 与年龄相关的行为障碍。实验动物将接受测试 在雌激素治疗前后使用气味识别任务，即 对EC损伤敏感。由此产生的行为测量将是相关的 随着皮质纤维的发芽和胆碱能活动的水平 大脑皮层和基底前脑。

DESCRIPTION: (Verbatim from the Applicant's Abstract) In these studies we propose to examine the ability of estrogen to stimulate the compensatory sprouting response of the cholinergic system in an area that is first and most profoundly affected in Alzheimer's disease (AD), the entorhinal cortex (EC). Several reports have described increased synaptic sprouting in response to estrogen, and have implicated this hormone in the upregulation of cholinergic function in the basal forebrain. Based on these studies and on our own results, we hypothesize that estrogen may induce cholinergic sprouting and reactive synaptogenesis in response to cell loss, and perhaps bring about some degree of functional recovery. The basic premise of the proposed experimentation is that estrogen has a neuroprotective effect that restores and prolongs the function of damaged basal forebrain cholinergic neurons. Male and female Fisher 344 rats, young (3 months old) and aged (24 months old), both gonadectomized and intact, will receive a lesion that mimics the cortical cholinergic denervation in AD. Unilateral lesions (allowing for the contralateral side to act as an internal control) will be produced in the nucleus of the horizontal limb of the diagonal band of Broca (HDB) using 192 IgG-saporin immunotoxin complex as the lesioning tool. This immunotoxin specifically targets cholinergic neurons. Treatment with estrogen or placebo will begin four weeks after lesioning, when maximal EC denervation has occurred. For specific aim 1 we will use standard immunohistochemical techniques to measure the change in lesion-induced cholinergic sprouting in the EC that results from estrogen treatment. In specific aim 2 we will employ a modification of the Fonnum method to assay choline acetyltransferase (ChAT) activity in the same EC area. In specific aim 3 we will examine the regenerative effects of estrogen on surviving basal forebrain cholinergic neurons by semi-quantitative RT/PCR analysis of changes in the mRNA expression of two cholinergic markers, the synthetic enzyme ChAT and the vesicular acetylcholine transporter (VAChT). Finally, in specific aim 4 we will test the hypothesis that estrogen can ameliorate lesion- and age-dependent behavioral impairments. Experimental animals will be tested before and after estrogen treatment using an odor discrimination task that is sensitive to EC damage. The resulting measures of behavior will be correlated with cortical fiber sprouting and with levels of cholinergic activity in the cortex and basal forebrain.