Hormonal Influences on Cognition

描述(申请人提供)：性腺类固醇现在被广泛接受。 在关键发育时期和成年后通过组织和 重组神经内分泌和行为功能所涉及的回路。最近，雌二醇也被证明作用于神经内分泌轴以外的区域，并对神经元发挥神经保护和神经营养作用。这些影响在绝经后妇女中尤其明显，因为激素替代可以改善认知能力下降，降低发病率，并推迟几种神经退行性疾病的发生。妇女健康倡议研究表明，目前的性腺激素替代方案会导致不良反应，并取消一个主要的治疗方案，因此，了解雌激素如何在大脑(和其他组织)发挥积极作用并设计更好的激素替代方案变得至关重要。拟议的实验将利用大鼠和小鼠的模型来研究雌激素和雄激素对识别记忆(视觉和位置)的增强。激素和药物将被用来确定哪些雌激素受体介导物体识别(视觉记忆)和物体放置(空间记忆)的短期(非基因组)和长期(基因组效应)增强。缺乏雌激素特定受体的老鼠也将接受这些记忆任务的检查。介导雌激素依赖性记忆增强的机制将通过使用高尔基体技术来确定激素对皮质和海马神经元树突形态和棘密度的影响，这是已知对记忆至关重要的。性腺激素是否 对男性记忆功能的贡献也将通过相同的行为和解剖学技术进行检测。由于战后婴儿潮一代的老龄化，美国与年龄和疾病相关的痴呆症正在增长，因此拟议的研究具有巨大的健康相关性。拟议的实验应能更好地了解性腺激素的作用机制，从而为设计新的激素/药物以预防和治疗与年龄和神经退行性疾病相关的记忆障碍提供见解。

DESCRIPTION (provided by applicant): It is now well accepted that gonadal steroids exert potent influences in the brain during critical developmental periods and into adulthood by organizing and reorganizing the circuitry involved in neuroendocrine and behavioral functions. More recently, estradiol has also been shown to act in regions outside the neuroendocrine axis and to exert neuroprotective and neurotrophic actions on neurons. These effects are especially prominent in postmenopausal women where hormonal replacement ameliorates cognitive decline and decreases the incidence and delays the onset of several neurodegenerative diseases. With the demonstration by the Women's Health Initiative Study that current gonadal hormone replacement regimens lead to adverse effects and cancellation of one major treatment arm, it has become critical to understand how estrogen exerts its positive actions in the brain (and other tissues) and to design better hormone replacement regimens. Proposed experiments will utilize rat and mice models to investigate enhancement of recognition memory (visual and place) by estrogens and androgens. Hormones and drugs will be utilized to determine which estrogen receptors mediate the short term (non-genomic) and long term (genomic effects) enhancements of object recognition (visual memory) and object placement (spatial memory). Mice lacking specific receptors for estrogen will also be examined with these memory tasks. Mechanisms mediating estrogen-dependent enhancements in memory will be determined by use of Golgi techniques to determine hormonal effects on dendritic morphology and spine density in cortical and hippocampal neurons which are known to be important for memory. Whether gonadal hormones contribute to memory function in males will also be examined by the same behavioral and anatomical techniques. Proposed studies have enormous health relevance since age and disease related dementia is growing in the U.S. due to the aging of post war "baby boom" generations. Proposed experiments should provide better understanding of the mechanisms for gonadal hormone action and thereby provide insights for designing new hormones/drugs for the prevention and treatment of age and neurodegenerative disease related memory impairments.