Impact of Reproductive Aging on the Functional and Structural Architecture of the Human Brain

项目摘要 尽管女性在阿尔茨海默病人群中的比例过高，但性别和性别对阿尔茨海默病的影响 类固醇激素对大脑老化的影响还没有得到充分的研究。在过去的四分之一世纪里， 的脑成像研究已经研究了65岁成年人与年龄相关的认知能力下降的神经基础， 老了这种惯例忽视了女性生活中最重要的神经内分泌变化之一-- 过渡到绝经期-并在我们对关键的中年时期大脑老化的理解中留下了空白 年绝经过渡期的特点是性生活质量的全面下降， 90%的情况下，17 β-雌二醇和孕酮。对于许多女性来说，这种内分泌变化伴随着 通过自我报告的记忆力和注意力的下降，或“更年期雾”。动物研究提供了强大的 有证据表明雌二醇和孕酮在易受脑损伤的脑区起神经保护作用。 神经变性，包括前额叶皮层和内侧颞叶。女性在多大程度上 生殖老化导致人类大脑宏观结构形态、内在脑网络 连接，以及高阶认知背后的神经回路代表了一个显着的知识差距 这一点还有待充分研究。这个项目将探讨生殖老化对大脑的影响， 健康中年妇女（N=90，年龄45-55），调查神经和认知老化的内分泌基础， 中年充分表征的样品被富集以包括前、后和后的平衡分布。 绝经期妇女在有限的年龄范围内，以隔离生殖老化的影响， 时间老化该项目将建立在现有的更年期文学应用国家的最先进的 计算技术，以扩大我们目前的理解相当粗糙的地区差异， 大脑活动和形态的变化。在目标1中，我将确定性激素的消耗 在中年改变大规模的功能性大脑网络使用静息态功能磁共振成像和计算方法 复杂系统分析。在目标2中，我将使用海马体的高分辨率解剖成像， 以确定性激素的消耗是否影响特定的 海马亚区（CA 1 -3、齿状回、下托）和内嗅、嗅周和海马旁 皮质，富含性激素受体的区域。在目标3中，我将确定生殖老化的影响 选择性注意的神经机制，包括抑制神经处理无关信息的能力。 信息，其目的是阐明常见的认知投诉的神经基础， 绝经这个项目将阐明与年龄相关的神经和认知变化的内分泌基础， 这是认知神经科学中未充分研究的领域，对女性健康有明显的影响。

Project Summary Despite the over-representation of women in the Alzheimer’s disease population, the influence that sex and sex steroid hormones have on the aging brain remains understudied. Over the last quarter century, the vast majority of brain imaging studies have studied the neural basis of age-related cognitive decline in adults aged 65 and older. This convention overlooks one of the most significant neuroendocrine changes in a woman’s life—the transition to menopause—and leaves a gap in our understanding of the aging brain during the critical midlife years. The menopausal transition is marked by a sweeping decline in the production of sex hormones—up to 90% in the case of 17-estradiol and progesterone. For many women, this endocrine change is accompanied by self-reported decrements in memory and attention, or “menopause fog”. Animal studies provide powerful evidence that estradiol and progesterone play a neuroprotective role in brain regions vulnerable to neurodegeneration, including the prefrontal cortex and medial temporal lobes. The degree to which female reproductive aging leads to changes in human macrostructural brain morphology, intrinsic brain network connectivity, and the neural circuits underlying higher-order cognition represents a significant knowledge gap that has yet to be adequately examined. This project will probe the effects of reproductive aging on the brain in healthy midlife women (N=90, ages 45–55), investigating the endocrine basis of neural and cognitive aging in midlife. The well-characterized sample is enriched to include a balanced distribution of pre, peri-, and post- menopausal women across a limited age range in order to isolate the effects of reproductive aging from chronological aging. This project will build on the existing menopause literature by applying state-of-the-art computational techniques to extend beyond our current understanding of fairly coarse regional differences in brain activity and morphology by menopause status. In Aim 1, I will determine how the depletion of sex hormones in midlife alters large-scale functional brain networks using resting-state fMRI and computational approaches from complex systems analysis. In Aim 2, I will use high-resolution anatomical imaging of the hippocampus and surrounding medial temporal lobe to determine whether the depletion of sex hormones impacts specific hippocampal subfields (CA1-3, dentate gyrus, subiculum) and entorhinal, perirhinal, and parahippocampal cortices, regions enriched with sex hormone receptors. In Aim 3, I will determine the effects of reproductive aging on neural mechanisms of selective attention, including the ability to suppress neural processing of irrelevant information, with the goal of elucidating the neural underpinnings of common cognitive complaints during menopause. This project will clarify the endocrine basis of age-related neural and cognitive changes, a severely understudied area in cognitive neuroscience with clear implications for women’s health.