DEVELOPMENTAL ACTION OF ESTROGEN ON COGNITIVE SUBSTRATES

雌激素对认知基质的发育作用

• 批准号: 2249060
• 负责人: DOMINIQUE CLAUDE TORAN-ALLERAND
• 金额: $ 19.97万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2249060
• 关键词: DEVELOPMENTAL; ACTION; ESTROGEN; COGNITIVE; SUBSTRATES

This proposal addresses cellular and molecular mechanisms that may underlie the development and regulation of sensitivity of neural substrates of cognitive functions to the gonadal steroid hormone, estrogen, and to three neurotrophins, nerve growth factor (NGF), brain- derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). These studies advance our hypothesis that estrogen action in developing and perhaps injured, diseased or aging target brain regions may involve interactions with the neurotrophins and their receptors. The proposed, interrelated and multidisciplinary experiments exploit novel and unique correlative cell and tissue culture approaches to understanding the distribution, responses and control of three key elements involved in the actions and interaction of estrogen and the neurotrophins in their neural targets: the neurons themselves, the receptor systems (mRNA and protein), and a responsive gene, choline acetyl transferase (ChAT), by looking at the basis of the responses cell-by-cell. These correlative studies are designed to elucidate some cellular and molecular consequences of estrogen and neurotrophin interactions with respect to the potential for developmentally-critical autocrine and synergistic regulatory mechanisms that may be important for the biology of their target neurons. Organotypic cultures of the hippocampus, cerebral cortex and septum/diagonal band, and a neural cell line responsive to estrogen and NGF, PC12, will be studied morphologically in living and fixed preparations by means of neurohistological stains and chemically-specific neuroanatomic techniques: autoradiography, histochemistry, in situ hybridization histochemistry, and immunohistochemistry. Morphological findings will be correlated with functional output, using sensitive quantitative measures of estrogen binding, mRNA expression and neurotrophin receptor content and function. The experiments are designed to investigate in parallel: (a) the interactions of estrogen and the neurotrophins with respect to transcription and translation of the genes for the neurotrophins and their receptors and for estrogen receptors; and (b) the regulatory actions of estrogen and the neurotrophins in developing and regenerating target CNS neurons. These experiments have clinical relevance for understanding the mechanisms underlying the genesis of a wide variety of cognitive disorders of considerable clinical, socio-cultural, and educational importance such as the sexually dimorphic childhood disorders of cognition (learning disabilities, infantile autism, delayed speech acquisition, and stuttering); the cognitive deficits associated with Turner's syndrome, aging, and Alzheimer's disease, and perhaps even schizophrenia. The possibility that estrogen may interact with the neurotrophins and their receptors introduces a potentially major new regulatory influence on neuronal development, survival, plasticity and repair of brain regions underlying learning, memory and other cognitive functions, with relevance not only for disorders of cognition but also for developing therapeutic approaches to them.

该提案解决了可能的细胞和分子机制 神经敏感性的发展和调节的基础 性腺类固醇激素认知功能的底物， 雌激素，以及三种神经营养素、神经生长因子 (NGF)、脑- 衍生神经营养因子 (BDNF) 和神经营养蛋白-3 (NT-3)。 这些 研究推进了我们的假设，即雌激素在发育和发育中的作用 也许受伤、患病或衰老的目标大脑区域可能涉及 与神经营养素及其受体的相互作用。 所提议的， 相互关联和多学科的实验探索新颖和独特的 相关的细胞和组织培养方法来了解 涉及的三个关键要素的分配、响应和控制 雌激素和神经营养素在神经中的作用和相互作用 目标：神经元本身、受体系统（mRNA 和 蛋白）和响应基因胆碱乙酰转移酶（ChAT）， 逐个细胞地查看响应的基础。 这些相关的 研究旨在阐明一些细胞和分子 雌激素和神经营养素相互作用的后果 发育关键的自分泌和协同作用的潜力 对其生物学可能很重要的调节机制 目标神经元。 海马、大脑皮层的器官型培养 和隔膜/对角带，以及对雌激素有反应的神经细胞系 NGF、PC12 将在活体和固定体中进行形态学研究 通过神经组织学染色和化学特异性制备 神经解剖学技术：放射自显影、组织化学、原位 杂交组织化学和免疫组织化学。 形态学 研究结果将与功能输出相关联，使用敏感的 雌激素结合、mRNA 表达的定量测量 神经营养蛋白受体的含量和功能。 实验是这样设计的 并行研究：(a) 雌激素和 神经营养素与基因转录和翻译有关 对于神经营养素及其受体以及雌激素受体；和 (b) 雌激素和神经营养素的调节作用 发育和再生目标中枢神经系统神经元。 这些实验有 理解潜在机制的临床相关性 多种认知障碍的起源 临床、社会文化和教育的重要性，例如性 二态性儿童认知障碍（学习障碍， 婴儿自闭症、言语习得延迟和口吃）；这 与特纳综合征、衰老相关的认知缺陷 阿尔茨海默病，甚至可能是精神分裂症。 可能性 雌激素可能与神经营养素及其受体相互作用 引入了对神经元潜在的重大新调节影响 底层大脑区域的发育、生存、可塑性和修复 学习、记忆和其他认知功能，不仅具有相关性 用于认知障碍，也用于开发治疗方法 给他们。