DEVELOPMENTAL ACTION OF ESTROGEN ON COGNITIVE SUBSTRATES

这项建议涉及的细胞和分子机制可能 神经敏感度的发展与调节 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)和神经营养因子-3(NT-3)。这些 研究提出了我们的假设，即雌激素在发育和发育中的作用 也许受伤、患病或老化的目标脑区可能涉及 与神经营养因子及其受体的相互作用。建议的、 相互关联的多学科实验开发了新颖和独特的 相关细胞和组织培养方法研究 三个关键要素的分布、反应和控制 雌激素和神经营养因子在其神经中的作用和相互作用 靶标：神经元本身、受体系统(信使核糖核酸和 蛋白质)和一个反应基因，胆碱乙酰转移酶(ChAT)，通过 逐个细胞地观察反应的基础。这些关联 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与 发展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 以神经元为目标。海马体、大脑皮层器官培养 和隔膜/斜角带，以及对雌激素有反应的神经细胞系 而NGF，PC12，将在活体和固定状态下进行形态研究 通过神经组织学染色和化学特异性的方法进行准备 神经解剖技术：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 研究结果将与功能输出相关联，使用SENSIVE 雌激素结合、mRNA表达和雌激素水平的定量测定 神经营养素受体的含量和功能。实验是设计的 并行研究：(A)雌激素与 神经营养因子与基因转录和翻译 神经营养因子及其受体和雌激素受体；以及 (B)雌激素和神经营养素的调节作用 发育和再生靶向中枢神经系统神经元。这些实验已经 临床意义的理解机制背后的基础 相当多种类的认知障碍的发生 临床、社会文化和教育的重要性，如性 儿童二态认知障碍(学习障碍， 婴儿自闭症、言语习得延迟和口吃)； 认知缺陷与特纳综合征、衰老和 阿尔茨海默氏症，甚至精神分裂症。这种可能性 雌激素可能与神经营养因子及其受体相互作用 引入了对神经元的潜在重大新调节影响 大脑潜在区域的发育、生存、可塑性和修复 学习、记忆和其他认知功能，不仅与 不仅用于认知障碍，而且还用于开发治疗方法 敬他们。

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.