Variations in Hormone Therapy: Effects on Cognition and Markers of Brain Aging

描述（由申请人提供）：本申请的总体目标是确定哪些变量影响激素治疗是作为认知功能和脑衰老的保护因素还是风险因素。更年期导致的卵巢激素减少与认知能力下降和患阿尔茨海默病的风险增加有关。虽然有证据表明激素替代会减少这种影响，但最近的临床试验没有发现积极的影响，有些还发现了有害的影响。然而，大量的基础科学证据表明，雌激素对认知和与记忆有关的神经生物学变量有有益的影响。因此，尽管在一些临床试验中发现无效或负面的结果，但大量的动物和临床研究显示激素治疗的积极作用，这就引出了一个问题，即是什么因素决定了激素治疗是脑功能和脑衰老的保护剂还是危险因素。我们将使用大鼠模型系统地评估当前激素疗法的变化，测试它们对认知、神经营养因子和突触可塑性标志物是有益还是有害。根据先前的研究，哪些因素可能影响雌激素替代的结果？1. 雌激素的剂量和类型。特异性目的1比较了三种雌激素制剂的剂量特异性效应：动物研究中最常用的雌激素（雌二醇），临床中最常用的雌激素治疗（Premarin，或共轭马雌激素），以及一种对更年期症状有积极作用的有前景的雌激素治疗（雌三醇）。普雷马林和雌三醇都没有对啮齿动物的认知效果进行测试。2. 无对照对照雌激素治疗。我们最近发现，单独服用黄体酮对空间记忆有害，而补剂雌二醇可增强老年大鼠的记忆，并改变大脑认知区域的神经营养素。当黄体酮加入雌二醇治疗时，雌二醇引起的认知和神经营养改变完全逆转。特异性目标2测试了临床上最常用的三种黄体酮单独服用时是否会改变认知和大脑，以及作为联合激素治疗的一部分服用时是否会抵消雌激素引起的改变。此外，我们还将测试黄体酮对认知的影响机制。孕酮的一些代谢物对GABAA受体有影响。我们假设黄体酮通过增加GABAA刺激来损害记忆，进而导致更大的海马抑制，从而损害记忆。通过使用GABAA拮抗剂和激动剂以及介导GABAA对GABAA受体作用的孕酮代谢物，Specific Aim 3将测试单独或与雌二醇同时给予孕酮对认知的负面影响是否由于GABAA系统介导的作用。在每项研究中，将对大鼠进行一系列空间和非空间工作和参考记忆测试，然后评估神经营养素水平和认知脑区域突触可塑性标志物。这些研究将有助于阐明激素治疗的哪些变化会减弱或加剧认知和大脑中与年龄相关的变化，以及黄体酮单独或与雌激素联合使用时的作用机制。

DESCRIPTION (provided by applicant): The broad goal of this application is to determine which variables influence whether hormone therapy acts as a protectant or a risk factor for cognitive functioning and brain aging. Ovarian hormone loss due to menopause has been linked with cognitive decline and increased risk of Alzheimer's disease. While there is evidence that hormone replacement decreases such effects, recent clinical trials failed to find positive effects, and some found detrimental effects. However, abundant basic science evidence suggests that estrogens exert beneficial effects on cognition and neurobiological variables related to memory. Hence, despite the null and negative findings in some clinical trials, the numerous animal and clinical studies showing positive effects of hormone treatment begs the question of what factors determine whether hormone therapy acts as a protectant or a risk factor for brain functioning and brain aging. We will use the rat model to systematically evaluate variations in current hormone therapies, testing whether they are beneficial or detrimental to cognition, neurotrophins, and markers of synaptic plasticity. Based on prior research, what factors might influence the outcome of estrogen replacement? 1. Dose and type of estrogen. Specific Aim I compares the dose-specific effects of three estrogen preparations: the most commonly used estrogen in animal studies (estradiol), the most commonly used estrogen therapy in the clinic (Premarin, or conjugated equine estrogens), and a promising estrogen therapy that has positive effects on menopausal symptoms (estriol). Neither Premarin nor estriol have been tested for cognitive effects in the rodent. 2. Unopposed vs. opposed estrogen treatment. We recently found that progesterone, given alone, is detrimental to spatial memory, and that tonic estradiol replacement enhances memory and alters neurotrophins in cognitive brain regions in aged rats. When progesterone was added to estradiol treatment, the cognitive and neurotrophin alterations due to estradiol were completely reversed. Specific Aim 2 tests whether the three most common clinically-used progestins alter cognition and the brain when given alone, and counteract estrogen-induced alterations when given as part of combination hormone therapy. Further, we will also test a mechanism of progesterone's effects on cognition. Some metabolites of progesterone have effects on the GABAA receptor. We hypothesize that progesterone is impairing memory by increasing GABAA stimulation, in turn resulting in greater hippocampal inhibition thereby impairing memory. By using GABAA antagonists and agonists as well as metabolites of progesterone that mediate the actions of GAB A on the GABAA receptor, Specific Aim 3 will test whether progesterone's negative effects on cognition, when given alone and concurrently with estradiol, are due to effects mediated by the GABAA system. In each study, rats will be tested on a battery of spatial and non-spatial working and reference memory tests, followed by evaluations of neurotrophin levels and markers of synaptic plasticity in cognitive brain regions. These studies will help elucidate which variations in hormone therapy attenuate or exacerbate age-related changes in cognition and the brain, as well as the mechanism of progesterone's effects when given alone and with estrogen.