Estrogenic-cholinergic interactions in memory modulation

记忆调节中的雌激素-胆碱能相互作用

基本信息

批准号：
6574123
负责人：
Karyn M Frick
金额：
$ 7.44万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-01 至 2004-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6574123
关键词：
acetylcholine behavior test choline acetyltransferase enzyme activity estrogen receptors estrogens female genetically modified animals hippocampus hormone regulation /control mechanism immunotoxicity injection /infusion laboratory mouse memory neocortex ovariectomy prosencephalon scopolamine

项目摘要

DESCRIPTION (provided by applicant): The main objective of the proposed research is to understand the mechanisms by which estrogenic modulation of the cholinergic system facilitates spatial memory. The proposed studies uniquely address these issues in a series of three experiments using drug injections, a recently developed mouse cholinergic immunotoxin, and a knockout mouse lacking estrogen receptor alpha (ERa). The specific aims are as follows: 1) To determine whether estrogen facilitates spatial memory retention in mice through modulation of cholinergic function, 2) To examine whether destruction of basal forebrain cholinergic afferents to neocortex and hippocampus by a new mouse immunotoxin affects estrogenic modulation of spatial memory, and 3) To investigate whether estrogen modulates cholinergic function and spatial memory via activation of the ERa receptor. Ovariectomized female mice will receive one session of training in a spatial water maze task requiring them to use extramaze cues to locate a hidden escape platform. Immediately afterward, they wilt be injected with estrogen, scopolamine, or a combination of both. Twenty-four hours later, mice will receive a retention test. One week later, the mice will again be injected with estrogen and scopolamine and then sacraficed 24 hours later for analysis of choline acetyltransferase (CHAT) activity in the hippocampus and frontoparietal cortex. In Experiment 1, we will examine the ability of post-training estrogen injections to enhance spatial memory and augment cholinergic function in the presence of the cholinergic antagonist scopolamine. Because we hypothesize that the locus of estrogenic-cholinergic interaction is the basal forebrain, Experiment 2 will test the ability of estrogen to enhance memory using mice in whom basal forebrain cholinergic neurons were selectively destroyed using the toxin saporin, which is linked to antibodies raised against the mouse low-affinity nerve growth factor receptor, p75. Finally, in Experiment 3 we will examine whether estrogen modulates spatial memory and cholinergic function via activation of the ERa receptor. Findings from the proposed studies will lay a foundation to elucidate the mechanisms by which estrogen influences cholinergic modulation of memory. If estrogen improves memory by modulating basal forebrain cholinergic function, then this work may have significant implications for the treatment of Alzheimer's disease, for which anticholinesterases are largely ineffective.

描述（由申请人提供）：所提议研究的主要目的是了解胆碱能系统的雌激素调节促进空间记忆的机制。拟议的研究在一系列三项实验中独特地解决了这些问题，这些实验使用药物注射、最近开发的小鼠胆碱能免疫毒素和缺乏雌激素受体α（ERa）的基因敲除小鼠。具体目标如下：1）确定雌激素是否通过调节胆碱能功能促进小鼠的空间记忆保留，2）检查一种新的小鼠免疫毒素对新皮质和海马的基底前脑胆碱能传入的破坏是否会影响雌激素对空间记忆的调节。记忆，3) 研究雌激素是否通过激活 ERa 受体来调节胆碱能功能和空间记忆。切除卵巢的雌性小鼠将接受一次空间水迷宫任务训练，要求它们使用迷宫外线索来找到隐藏的逃生平台。随后，他们将立即注射雌激素、东莨菪碱或两者的组合。二十四小时后，小鼠将接受保留测试。一周后，再次给小鼠注射雌激素和东莨菪碱，24小时后处死小鼠，分析海马和额顶叶皮层的胆碱乙酰转移酶（CHAT）活性。在实验1中，我们将检查训练后注射雌激素在胆碱能拮抗剂东莨菪碱存在下增强空间记忆和增强胆碱能功能的能力。因为我们假设雌激素-胆碱能相互作用的部位是基底前脑，实验 2 将使用毒素皂草素选择性破坏基底前脑胆碱能神经元的小鼠来测试雌激素增强记忆的能力，皂草素与针对小鼠低亲和力神经生长因子受体 p75。最后，在实验 3 中，我们将检查雌激素是否通过激活 ERa 受体来调节空间记忆和胆碱能功能。拟议研究的结果将为阐明雌激素影响胆碱能记忆调节的机制奠定基础。如果雌激素通过调节基础前脑胆碱能功能来改善记忆，那么这项工作可能对阿尔茨海默病的治疗具有重大意义，而抗胆碱酯酶对此病基本上无效。