Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging

描述（由申请人提供）：在本次更新中，我们假设更年期类型和相关激素变化与激素治疗（HT）的认知反应性有关。最初的拨款使用大鼠来评估手术绝经（Ovx）和过渡绝经（4-乙烯基环己烯二氧化物（VCD））时HTs的变化。vcd处理的大鼠出现卵巢衰竭；卵泡和雌激素的消耗，雄激素变得不对抗，促性腺激素增加，类似于过渡绝经妇女的轮廓。最初拨款的数据为测试过渡性绝经和手术性绝经的新假设奠定了基础。在女性中，过渡性和手术性更年期都与记忆变化有关。然而，大多数啮齿动物研究都测试了Ovx后的认知影响。尽管洞见大鼠模型在手术激素损失方面的产量，手术绝经模型的女性<13%。在这里，我们研究了不同的更年期类型如何影响认知和大脑衰老，并旨在确定更年期过渡和激素治疗的最佳参数。在大鼠实验中，我们提出了四个目的：目的1)我们发现雄烯二酮（Andro）与记忆损伤有关。因为安德罗直接转化为雌酮，而且我们已经证明了雌酮引起的记忆障碍，我们假设安德罗转化为雌酮会损害记忆。目的1测试安德罗向雌激素的转化，或雄激素受体刺激，是否导致其认知损害。目的2)临床研究支持HT有利于认知的关键窗口期。对大鼠的研究支持了这一点；然而，这些研究使用的是Ovx大鼠，并且只给17¿-雌二醇（E2）。E2在女性和大鼠中自然产生，但仅在结合马雌激素（CEE） HT中存在微量。在大鼠中，我们发现CEE增强了手术绝经后的记忆，但在卵泡去除后给予CEE会损害过渡性绝经后的记忆。目的2测试不同类型绝经期间和之后的认知变化，以及与E2相比，在卵泡清除之前或期间给予CEE是否会损害记忆。目的3)我们发现羟孕酮醋酸甲孕酮（MPA）对Ovx大鼠的认知功能有损害，海马谷氨酸脱羧酶（GAD）蛋白水平降低，可能是对GABAA受体（GABAAR）刺激的补偿。另一种黄体酮醋酸去甲稀酮（NETA）增强了Ovx大鼠的记忆。我们假设NETA拮抗GABAAR，减少GABAAR介导的抑制，增强记忆。目的3将确定gaba能系统是否在MPA和neta诱导的记忆变化中起作用。目标4)。目的是测试MPA或NETA是否会影响CEE或E2的效果。为此选择MPA对HT Prempro （CEE+MPA）进行测试；之所以选择NETA，是因为它有可能成为一种新型HT组合的一部分，因为它用于避孕药，并增强了大鼠的认知能力。在每一项研究中，我们将量化GAD和胆碱能标记物，这两种标记物之前都被证明与认知有关，在认知特征大鼠的大脑中。多元回归和生长模型将检验gaba能系统、胆碱能系统、激素水平和认知在两种绝经模型中的关系。这项工作将有助于深入了解更年期过渡的认知影响，更年期类型和HTs的变化及其相关机制。

DESCRIPTION (provided by applicant): In this renewal, we hypothesize that type of menopause and associated hormone changes relate to cognitive responsiveness to hormone therapy (HT). The initial grant used rats to assess variations in HTs with surgical menopause (Ovx), and transitional menopause using 4-vinylcyclohexene diepoxide (VCD). VCD-treated rats undergo ovarian failure; follicles and estrogens deplete, androgens become unopposed, and gonadotropins increase, a profile resembling transitionally menopausal women. Data from the initial grant lay the foundation for testing new hypotheses regarding transitional versus surgical menopause. In women, both transitional and surgical menopause have been related to memory changes. However, most rodent studies have tested cognitive effects after Ovx. Despite insight rat models yield regarding surgical hormone loss, surgical menopause models <13% of women. Here, we examine how different menopause types impact cognitive and brain aging, and aim to determine optimal parameters for the menopause transition and HT. Four aims are proposed, using rats: Aim 1) We found that androstenedione (Andro) relates to impaired memory. Since Andro is directly converted to estrone, and we have shown estrone-induced memory impairments, we hypothesize that Andro's conversion to estrone impairs memory. Aim 1 tests whether Andro's conversion to estrogens, or androgen receptor stimulation, underlies its cognitive detriments. Aim 2) Clinical studies support a critical window during which HT benefits cognition. Rat studies support this; however, these studies used Ovx rats, and gave only 17¿-estradiol (E2). E2 is naturally-occurring in women and rats, but is present only in trace amounts in conjugated equine estrogens (CEE) HT. In rats, we found that CEE enhanced memory after surgical menopause, but impaired memory after transitional menopause when given after follicle depletion. Aim 2 tests cognitive change during and after different types of menopause, and whether giving CEE before or during follicular depletion impairs memory, as compared to E2. Aim 3) We found that the HT progestin medroxyprogesterone acetate (MPA) impaired cognition in Ovx rats, and decreased hippocampal glutamic acid decarboxylase (GAD) protein, possibly compensating for GABAA receptor (GABAAR) stimulation. Another progestin, norethindrone acetate (NETA), enhanced memory in Ovx rats. We hypothesize that NETA antagonizes the GABAAR, reducing GABAAR-mediated inhibition, enhancing memory. Aim 3 will determine whether the GABAergic system underlies MPA- and NETA-induced memory changes. Aim 4). This aim tests whether MPA or NETA impacts the effects of CEE or E2. MPA was chosen for this aim to test the HT Prempro (CEE+MPA); NETA was chosen due to its potential to be part of a novel combination HT, as it is used in contraceptives and it enhanced rat cognition. In each study, we will quantify GAD and cholinergic markers, each previously shown to relate to cognition, in brains of cognitively characterized rats. Multiple regression and growth modeling will test relations between the GABAergic system, cholinergic system, hormone levels, and cognition in both menopause models. This work will yield insight into cognitive effects of the menopause transition, variations in menopause type and HTs, and related mechanisms.