Hysterectomy and Cognition: A Preclinical Evaluation

项目摘要(摘要) 子宫切除术是最常见的外科手术之一。 在女人身上。这些手术中的大多数都是在平均开始更年期之前完成的。研究 提示在绝经前的女性中，卵巢激素的突然丧失是由于 卵巢切除术(卵巢切除术)可能对认知老化有害。然而， 保留卵巢的子宫切除术不会导致卵巢激素的严重损失 发生在卵巢切除术后。目前，子宫切除术是否对认知老化有独特的影响 未知。人类研究表明，女性患痴呆症的风险可能会增加 年轻时接受过子宫切除术的女性与保留生育能力的女性相比 器官。利用老鼠模型，这项拟议的研究将调查以下几种药物的短期和长期影响 手术绝经类型对认知的影响。在具体目标1中，我将确定以下变化的影响 通过对受试者进行行为组合评估来研究外科绝经对脑老化轨迹的影响 学习和记忆。来自我们实验室的初步数据表明，外科更年期变种有 对认知的独特影响；然而，这些认知变化背后的神经生物学机制仍然存在 难以捉摸。近年来，血清促性腺激素水平的变化，包括黄体生成素(LH)的增加 水平，与绝经后有害的认知影响有关。此外，临床上 与年龄匹配的人相比，阿尔茨海默病(AD)患者往往表现出更高的黄体生成素水平 控制。事实上，一些衰老和阿尔茨海默病的啮齿动物模型已经表明，下调促黄体生成素可以改善 认知表现，与雌激素水平无关。黄体生成素被认为激活了下游的信号级联 它们对学习和记忆至关重要。为此，结合评估的行为结果， 特异性目标1、特异性目标2将评估脑组织中黄体生成素水平和黄体生成素受体表达的变化。 以及手术绝经变异后ERK1/2-CREB信号转导的后续变化。 这项资助的首要目标是确定认知变化的神经生物学机制。 在衰老和更年期期间。为了实现这一点，这项提议结合了一系列行为和 神经生物学技术提供关键数据，帮助解决外科手术的复杂行为影响 绝经和外科绝经对认知老化影响的潜在机制。理解 外科更年期神经认知的复杂性将阐明新的和临床上可翻译的因素， 这将有助于改善妇女一生的健康和福祉。

Project Summary (Abstract) Hysterectomy, or the surgical removal of the uterus, is one of the most common surgical procedures performed in women. The majority of these surgeries are completed prior to the average onset of menopause. Research suggests that in pre-menopausal women, the abrupt loss of circulating ovarian hormones resulting from oophorectomy (the surgical removal of the ovaries) can be detrimental to cognitive aging. However, hysterectomy with ovarian conservation does not result in the same drastic loss of ovarian hormones that occurs with oophorectomy. Whether hysterectomy has a unique impact on cognitive aging is currently unknown. Human research has shown that there may be an increased risk of developing dementia in women who have undergone hysterectomy in young adulthood compared to women who retain their reproductive organs. Using a rat model, the proposed research will investigate the short- and long- term effects of several types of surgical menopause on cognition. In Specific Aim 1, I will determine the impact of variations in surgical menopause on the trajectory of brain aging by evaluating subjects on a behavioral battery assessing learning and memory. Preliminary data from our laboratory suggests that surgical menopause variants have unique effects on cognition; however, neurobiological mechanisms underlying these cognitive changes remain elusive. In recent years, changes in serum gonadotropin levels, including increased luteinizing hormone (LH) levels, have been associated with detrimental cognitive effects after menopause. Furthermore, clinical populations with Alzheimer's disease (AD) tend to exhibit increased LH levels compared to age-matched controls. Indeed, some rodent models of aging and AD have shown that downregulation of LH improves cognitive performance, regardless of estrogen levels. LH is thought to activate signaling cascades downstream that are critical to learning and memory. To this end, in conjunction with the behavior outcomes assessed in Specific Aim 1, Specific Aim 2 will evaluate changes in LH levels and LH receptor expression in the brain, as well as subsequent alterations in ERK1/2-CREB signal transduction, following surgical menopause variations. The overarching goal of this grant is to identify a neurobiological mechanism for the cognitive changes seen during aging and menopause. To accomplish this, this proposal combines a battery of behavioral and neurobiological techniques to provide crucial data helping to resolve the complex behavioral effects of surgical menopause and mechanisms underlying variations in surgical menopause on cognitive aging. Understanding the neurocognitive complexities of surgical menopause will elucidate novel and clinically translatable factors, which will serve to improve women's health and well-being throughout their lifespan.