Interactive effects of short-term estrogen replacement and long-term exercise on the aging brain and cognition in a rodent model of menopause

女性在自然绝经或手术绝经后，由于永久性绝经，认知能力下降的风险增加 卵巢激素的丢失。激素替代疗法，这是通常为更年期开的处方 与更年期相关的症状，也可以提供一些认知方面的好处。然而，不利的一面 长期治疗的效果会阻止其长期使用。到目前为止，很少有研究关注停止治疗后激素替代的长期影响。我们已经开发出一种短期雌激素替代疗法的中年啮齿动物模型，它与长期、持续的 改善空间工作记忆的治疗。它还诱导其同源基因α-持续上调- 海马体中的受体，是大脑中空间工作记忆所需的区域。而海马区 功能可以从雌激素治疗中受益，其他认知领域可能受到不利影响或仍然存在 不受影响。因此，我们建议检验我们的模型在保护前额叶皮质功能方面的实用性，这是 在高级衰老过程中特别容易恶化，可能不受影响，或者更糟糕的是， 长期接触雌激素。鉴于雌激素治疗可能在特定的大脑区域产生相反的效果 考虑到长期使用的方式和风险，我们必须开发佐剂或替代品 治疗策略。有氧运动是一个明显的选择，因为它具有一般的健康和认知能力。 有益，在衰老过程中具有神经保护作用，是一种免费的非药物干预措施。我们的Main 因此，我们的目标是证明这两种疗法联合使用的能力 促进绝经后健康衰老。我们预计联合治疗将最大限度地有利于 生理和大脑健康。此外，单独评估这两种策略对大脑可塑性的影响 结合在一起，将提供有价值的洞察其基础的分歧和重叠 行动机制。

Women are at an increased risk for cognitive decline after natural or surgical menopause due to the permanent loss of ovarian hormones. Hormone replacement therapy, which is typically prescribed for climacteric symptoms associated with menopause, can also provide some cognitive benefits. However, the adverse side effects of long-term treatment prevent its prolonged use. Few investigations to date have looked at the long-term impact of hormone replacement after treatment has been discontinued. We have developed a middle-aged rodent model of short-term estrogen replacement therapy which is as effective as long-term, continuous treatment at improving spatial working memory. It also induces sustained upregulation of its cognate alpha- receptor, in the hippocampus, a region of the brain required for spatial working memory. While hippocampal function can benefit from estrogen treatment, other cognitive domains may be adversely affected or remain unaffected. Thus, we propose to examine the utility of our model in protecting prefrontal cortical function, which is particularly susceptible to deterioration during advanced aging and can be unaffected or worse, impaired, by prolonged estrogen exposure. Given that estrogen therapy can have opposing effects in a brain region-specific manner and the risks associated with extended use, it is imperative that we develop adjuvant or alternative therapeutic strategies. Aerobic exercise is an obvious candidate because it has general health and cognitive benefits, is neuroprotective during aging, and is a cost-free nonpharmacological intervention. Our main objective, therefore, is to demonstrate the capacity for these two therapies to be used in combination to promote healthy aging post menopause. We expect combination therapy to be maximally beneficial for physiological and brain health. Moreover, evaluating the effects of the two strategies on brain plasticity, alone and in combination, will provide valuable insight into the divergence and overlap in their underlying mechanisms of action.