Resveratrol for Enriching Neurogenesis & Memory in the Aged

描述（由申请人提供）：海马神经发生在老年时下降。由于新增加的神经元参与海马依赖性学习和记忆功能，因此认为神经发生的年龄相关性减少有助于在老年人中观察到的认知功能障碍。虽然衰老不会减少推定的海马神经干/祖细胞（NSC）的数量或损害神经元分化和新生细胞的存活，但在老年海马中静止NSC的百分比增加。在这种情况下，鉴定能够刺激静止的NSC在老年海马体中产生新神经元的安全膳食补充剂对于促进老年人认知功能的改善具有巨大价值。白藜芦醇是一种在红葡萄皮中发现的植物抗毒素，具有有效的抗氧化和抗炎特性，由于衰老过程中NSC可塑性降低与活性氧和炎症增加之间的联系，白藜芦醇作为一种潜在的膳食补充剂用于改善老年海马体中的神经发生。此外，在意识到含白藜芦醇的红葡萄酒消费者的心脏风险降低后，白藜芦醇正在被推广为改善心血管健康的膳食补充剂。然而，其对NSC和神经发生的影响尚不清楚。我们假设老年人服用白藜芦醇可以促进海马神经干细胞的增殖和神经发生，从而改善认知功能。我们建议通过以下两个具体目标的高度定量实验来解决这一假设。在具体目标1中，我们将量化老年大鼠长期（28天）给予不同剂量白藜芦醇刺激NSC增殖和增加海马神经发生程度的疗效。在具体目标2中，我们将确定长期给予白藜芦醇是否会改善表现出认知功能障碍的老年大鼠的学习和记忆功能。我们还将确定白藜芦醇治疗后这些受损大鼠的认知功能增强是否与新生神经元纳入海马记忆回路的增加以及神经发生相关基因表达的增加有关。这些研究与开发膳食补充剂策略高度相关，这些策略可缓解老年人或患有早期阿尔茨海默病的老年患者中与阿尔茨海默病相关的认知障碍。 公共卫生相关性：该项目将测试长期给予认知受损的老年大鼠白藜芦醇刺激神经干细胞增殖和改善海马神经发生和认知功能的功效。这些研究与开发膳食补充剂疗法有关，该疗法可减轻老年人或患有早期阿尔茨海默病的老年患者的认知障碍。

DESCRIPTION (provided by applicant): Hippocampal neurogenesis declines in old age. As newly added neurons participate in hippocampal- dependent learning and memory functions, age-related decrease in neurogenesis is believed to contribute to cognitive dysfunction observed in the elderly. While aging does not reduce the numbers of putative hippocampal neural stem/progenitor cells (NSCs) or impair neuronal differentiation and survival of newly born cells, the percentage of quiescent NSCs increases in the aged hippocampus. In this context, identification of safe dietary supplements that have the ability to stimulate the quiescent NSCs to produce new neurons in the aged hippocampus has immense value for promoting improved cognitive function in the elderly. Resveratrol, a phytoalexin found in the skin of red grapes with potent antioxidant and anti- inflammatory properties, strikes as a potential dietary supplement for improving neurogenesis in the aged hippocampus because of the perceived link between reductions in NSC plasticity and increases in reactive oxygen species and inflammation during aging. Moreover, after the awareness of reduced cardiac risk in the consumers of Resveratrol-containing red wine, Resveratrol is being promoted as a dietary supplement for improving cardiovascular health. However, its effects on NSCs and neurogenesis are unknown. We hypothesize that Resveratrol administration in old age promotes hippocampal NSC proliferation and neurogenesis, which in turn leads to improved cognitive function. We propose to address this hypothesis through highly quantitative experiments in the following two specific aims. In Specific Aim 1, we will quantify the efficacy of long-term (28 days) administration of different doses of Resveratrol in aged rats for stimulating the proliferation of NSCs and increasing the extent of hippocampal neurogenesis. In Specific Aim 2, we will ascertain whether long-term administration of Resveratrol would improve learning and memory function in aged rats displaying cognitive dysfunction. We will also determine whether the enhanced cognitive function after Resveratrol treatment in these impaired rats is associated with increased incorporation of newly born neurons into the hippocampal memory circuitry and increased expression of neurogenesis-related genes. These studies are highly relevant towards developing dietary supplement strategies that ease hippocampal-related cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This project will test the efficacy of long-term administration of Resveratrol in cognitively impaired aged rats for stimulating neural stem cell proliferation and improving hippocampal neurogenesis and cognitive function. These studies are relevant towards developing dietary supplement therapies that alleviate cognitive impairments in the elderly or in elderly patients with early stage of Alzheimer's disease.