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

描述(由申请人提供)：在这一更新中，我们假设更年期类型和相关的激素变化与激素治疗(HT)的认知反应有关。最初的资助使用大鼠评估HTS与外科绝经(OVX)和使用4-乙烯基环己烯二环氧化物(VCD)的过渡性更年期的差异。VCD治疗的大鼠出现卵巢衰竭；卵泡和雌激素耗尽，雄激素变得不受对抗，促性腺激素增加，这一特征类似于过渡的更年期女性。最初拨款的数据为测试有关过渡性更年期与手术更年期的新假设奠定了基础。在女性中，过渡性更年期和手术更年期都与记忆力变化有关。然而，大多数啮齿类动物的研究都测试了OVX后的认知影响。尽管有洞察力的大鼠模型在手术荷尔蒙丢失方面取得了进展，但手术更年期模型&13%的女性。在这里，我们研究不同的更年期类型如何影响认知和大脑老化，并旨在确定绝经过渡和高血压的最佳参数。目的1)我们发现雄烯二酮(Andro)与记忆受损有关。由于Andro直接转化为雌酮，而且我们已经显示雌酮诱导的记忆损伤，我们假设Andro转化为雌酮会损害记忆。Aim 1测试Andro是否转化为雌激素，或雄激素受体刺激，是否导致其认知障碍。目的2)临床研究支持一个关键的窗口，在这一窗口中，羟色胺有助于认知。老鼠研究支持这一点；然而，这些研究使用的是OVX大鼠，只给出了17？-雌二醇(E2)。雌二醇是天然存在于妇女和大鼠体内的，但仅以微量存在于结合马类雌激素(CEE)的羟色胺中。在大鼠中，我们发现CEE增强了手术绝经后的记忆，但在卵泡耗尽后服用会损害过渡期绝经后的记忆。目的2测试不同类型更年期期间和之后的认知变化，以及与E2相比，在卵泡衰竭之前或期间给予CEE是否会损害记忆。目的3)研究发现羟色胺孕激素醋酸甲羟孕酮对去势大鼠的认知功能有损害作用，并使海马区谷氨酸脱羧酶(GAD)蛋白减少，可能是对GABAA受体(GABAAR)刺激的代偿作用。另一种孕激素，醋酸去甲肾上腺素(NETA)，可以增强去卵巢大鼠的记忆。我们假设NetA拮抗GABAAR，减少GABAAR介导的抑制，增强记忆。目标3将确定GABA能系统是否是MPA和NetA诱导的记忆变化的基础。目标4)。这一目标检验了MPA或NetA是否影响CEE或E2的效果。为此，选择了MPA来测试HT Prempro(CEE+MPA)；NETA之所以被选择是因为它有可能成为一种新的组合HT的一部分，因为它被用于避孕并增强了大鼠的认知。在每项研究中，我们将量化GAD和胆碱能标记物，每个标记物之前都被证明与认知有关，在具有认知特征的大鼠的大脑中。多元回归和生长模型将在两种更年期模型中测试GABA能系统、胆碱能系统、激素水平和认知之间的关系。这项工作将深入了解更年期转变的认知影响，更年期类型和HTS的变化，以及相关的机制。

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.