Sex differences in factors influencing cognitive aging

描述（由申请人提供）： 越来越多的证据表明，行为和激素因素改变了衰老和阿尔茨海默病（AD）的进展。这些知识对预防认知能力下降的策略具有重要意义。啮齿动物模型将被用于评估人类研究表明改变年龄和疾病相关变化的两个因素：先前的认知经验和高脂肪饮食。1)先前的认知经验：使用它可以防止你失去它吗？保持精神活跃的人表现出较少的与年龄相关的认知衰退。动物研究解决了这一问题，只使用男性，和认知实践的局限性还没有详细说明。一组男性和一组女性将不接受迷宫测试，而另一组将只接受测试的程序部分。其他雄性和雌性大鼠将在一生中接受工作记忆或参考记忆认知练习，然后在它们变老时进行空间和非空间工作记忆和参考记忆测试，以评估是否发生记忆转移效应。此外，我们最近发现认知测试和衰老都会改变神经营养因子。我们假设这些认知测试的改变可以防止与年龄相关的记忆力下降。具体目标1测试的假设，即记忆的认知实践的要求影响是否认知实践程序衰减年龄相关的神经营养因子和认知变化。2)高脂肪/胆固醇（HF/HQ饮食）：数据表明HF/HC饮食是衰老和AD认知能力下降的风险因素。我们发现HF/HC饮食损害中年雄性大鼠的记忆，睾酮治疗改善老年雄性大鼠的记忆。由于人类研究发现，睾酮治疗改善了老年男性的认知和血脂水平，我们质疑睾酮是否逆转了HF/HC饮食的不利影响。所有测试高脂肪饮食影响的动物研究均使用年轻或中年男性。由于数据表明男性对不良饮食条件更敏感，我们将评估HF/HC饮食对中年男性与女性的影响。在女性中，数据表明绝经状态影响心血管风险因素，如血脂。中年雌性大鼠可分为“更年期”状态（estropause），这为我们提供了评估生殖衰老、HF/HC饮食和认知之间相互作用的机会。我们将切除一组中年女性的卵巢，并将完整的女性分为雌激素暂停状态，以确定卵巢激素去除或生殖衰老是否影响HF/HC饮食的认知结果。具体目标2测试的假设，中年女性，像男性一样，表现出认知障碍，由于HF/HC饮食取决于状态的雌激素暂停，和睾酮减弱的不利影响HF/HC饮食在中年男性。在迷宫组合之后，将在认知脑区域中测定来自两项研究的大鼠的神经营养因子水平。

DESCRIPTION (provided by applicant): There is increasing evidence that behavioral and hormonal factors alter progression of aging and Alzheimer's Disease (AD). Such knowledge has great implications for strategies to prevent cognitive decline. The rodent model will be used to evaluate two factors that human research suggests alter age- and disease- related changes: prior cognitive experience and a high fat diet. 1) Prior cognitive experience: Does using it prevent you from losing it? People who stay mentally active show less age-related cognitive decline. Animal work addressing this has only used males, and the limitations of cognitive practice have not been detailed. One male and one female group will receive no maze testing, while another will receive only procedural components of testing. The other male and female rats will receive either working or reference memory cognitive practice throughout life, and then spatial and non-spatial working and reference memory testing when they become aged to evaluate whether memory transfer effects occur. Also, we recently found that both-cognitive testing and aging altered neurotrophins. We hypothesize that these alterations due to cognitive testing protect against age-related memory decline. Specific Aim 1 tests the hypothesis that the mnemonic demands of cognitive practice affect whether cognitive practice procedures attenuate age-related neurotrophin and cognitive changes. 2) High fat/cholesterol (HF/HQ diet: Data suggest that a HF/HC diet is a risk factor for cognitive decline in aging and AD. We found that a HF/HC diet impaired memory in middle-aged male rats, and that testosterone treatment improved memory in aged male rats. Since human work found that testosterone treatment improved cognition and lipid profiles in older men, we question whether testosterone reverses the detrimental effects of a HF/HC diet. All animal studies testing effects of a high fat diet used young or middle-aged males. Since data suggest that males are more sensitive to adverse dietary conditions, we will evaluate the effects of a HF/HC diet in middle-aged males vs. females. In women, data suggest that menopause status affects cardiovascular risk factors such as lipid profiles. Middle-aged female rats can be grouped into state of "menopause" (estropause), which affords us the opportunity to evaluate interactions between reproductive senescence, HF/HC diet, and cognition. We will ovariectomize one group of middle-aged females, and divide intact females into estropause state to determine if ovarian hormone removal or reproductive senescence influences cognitive outcome of a HF/HC diet. Specific Aim 2 tests the hypotheses that middle-aged females, like males, show cognitive impairment due to a HF/HC diet depending on state of estropause, and that testosterone attenuates the detrimental effects of a HF/HC diet in middle-aged males. After the maze battery, rats from both studies will have neurotrophin levels assayed in cognitive brain regions.