AGING, HYPERTENSION AND ESTROGEN NEUROPROTECTION

绝经后，许多女性会经历进行性认知障碍，患痴呆的风险明显更高。虽然导致这些进行性认知缺陷的机制尚不清楚，但雌激素的丧失似乎是一个主要的潜在因素。绝经期雌激素的减少也与高血压的风险增加有关，高血压会导致认知障碍。我们实验室之前的研究表明，雄性自发性高血压大鼠（SHR）表现出与年龄相关的学习和记忆障碍，这与脾后皮层的神经元重塑有关，脾后皮层是大鼠和人类空间学习的重要区域。虽然这些缺陷通常在老年（2岁）雄性Sprague-Dawley大鼠中变得明显，但它们首次在雄性SHR中被发现时，年龄要小得多（1岁）。慢性降压治疗（卡托普利）显著延缓SHR的认知障碍和神经元重塑，表明高血压有助于这些改变。很少有研究检查高血压和雌激素丧失对认知功能的影响。我们首次证实，消除内源性雌激素（卵巢切除）和外源性雌激素（饮食中的植物雌激素）对雌性SHR的动脉压控制有显著影响，即，雌性SHR在喂食高NaCl饮食时通常不会表现出动脉压的增加，但在消除内源性和外源性雌激素后，它们对高NaCl饮食的反应是动脉压的大幅增加（60毫米汞柱）。这提供了一个具有挑战性的模型，用来验证雌激素和高血压的丧失都可以加速女性SHR中认知能力和神经元稳定性的年龄相关下降的假设。提出的研究验证了以下假设：雌激素耗竭会加速认知障碍和脾后皮层的神经元重塑，而雌激素替代可以防止这些变化。具体目标2。雌激素耗竭会减少女性SHR的脑血流量，而雌激素替代会逆转这种减少。具体目标3。雌激素耗竭会损害血管反应性，导致女性SHR的小动脉肥大，而雌激素替代可以逆转这些影响。

Following menopause many women experience progressive cognitive impairment and have a significantly higher risk of dementia. While the mechanisms which contribute to these progressive cognitive deficits are unknown, the loss of estrogen appears to be a major underlying factor. The loss of estrogen at menopause is also associated with an increased risk of hypertension which contributes to cognitive impairment. Previous work from our laboratory has shown that male spontaneously hypertensive rats (SHR) display age-related learning and memory impairments that are associated with neuronal remodeling in the retrosplenial cortex, an area that is important for spatial learning in rats and humans. While these deficits normally become apparent in aged (2 year-old) male Sprague-Dawley rats, they are first identifiable in male SHR at a significantly younger age (1 year-old). Chronic anti-hypertensive therapy (captopril) significantly delays both cognitive impairment and neuronal remodeling in SHR, suggesting that hypertension contributes to these changes. Few studies have examined the effects of hypertension and estrogen loss on cognitive function. We have established for the first time that elimination of both endogenous estrogen (ovariectomy) and exogenous estrogens (plant phytoestrogens in the diet) has a dramatic effect on arterial pressure control in female SHR, i.e., female SHR normally do not show an increase in arterial pressure when fed a high NaCl diet, but following elimination of both endogenous and exogenous estrogen, they respond to a high NaCl diet with a very large increase in arterial pressure (> 60 mm Hg). This provides a provocative model with which to test the hypothesis that both the loss of estrogen and hypertension can accelerate the age-related decline in cognitive ability and neuronal stability in female SHR. The proposed studies test the hypotheses that: Specific Aim 1. Estrogen depletion accelerates cognitive impairment and neuronal remodeling in the retrosplenial cortex, and that estrogen replacement protects against these changes. Specific Aim 2. Estrogen-depletion reduces cerebral blood flow in female SHR and estrogen replacement reverses these decreases. Specific Aim 3. Estrogen-depletion impairs vascular reactivity and causes arteriolar hypertrophy in female SHR, and that estrogen replacement reverses these effects.