Dissecting the role of the dentate gyrus microcircuit to improve cognitive discrimination in aging and Alzheimer's Disease

剖析齿状回微电路在改善衰老和阿尔茨海默氏病认知辨别中的作用

• 批准号: 10592865
• 负责人: Stefano Fusi
• 金额: $ 246.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592865
• 关键词: Adult; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Brain region; Cell Survival; Code; Cognitive; Cognitive deficits; Computer Models; Computer Simulation; Discrimination; Disease; Environment; Exercise; Genetic; Grant; Hippocampus; Image; Interneurons; Intervention; Knowledge; Lateral; Learning; Life; Mammals; Maps; Mediating; Memory; Modeling; Molecular Target; Mus; Neurons; Optics; Pattern; Physiological; Play; Population; Process; Proliferating; Regulation; Role; Supporting Cell; Testing; Therapeutic; age related; age related cognitive disorder; aged; antagonist; density; dentate gyrus; experience; experimental study; granule cell; improved; in vivo; insight; memory encoding; mild cognitive impairment; mouse model; nerve stem cell; neural; neural circuit; neurogenesis; normal aging; optogenetics; pharmacologic; targeted treatment; translational potential; two-photon; virtual reality environment

The dentate gyrus subregion of the hippocampus (DG) has been proposed to play a critical role in ‘pattern separation’, a computational process by which similar experiences are transformed into discrete non- overlapping neural representations. Deficits in pattern separation are found in normal aging as well as in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). The dentate gyrus is one of only two brain regions where new neurons are produced throughout life in mammals, a phenomenon termed adult hippocampal neurogenesis (AHN). AHN has been shown to decrease markedly both in normal aging and in AD. We have shown that AHN in mice is required for ‘cognitive discrimination’, a form of learning that may involve pattern separation. In addition, our preliminary results show that a genetic and a pharmacological manipulation that significantly increase AHN (iBax mice and Bax antagonist) rescues cognitive discrimination in aged mice. However, due to technical limitations, our knowledge about the specific role of AHN in the regulation of memory functions and how these processes are altered during age-related cognitive decline remain extremely limited. We will leverage unprecedented genetic access to AHN in combination with recent technical breakthroughs for neural recordings and manipulations to uncover the impact of AHN in aged mice. We will test the hypotheses that abGCs support sparse memory encoding enabling effective pattern separation and that increasing AHN can rescue age-related deficits in cognitive discrimination through improved pattern separation. In addition to unraveling the function of AHN we will also explore whether this process can be harnessed pharmacologically to rescue cognitive deficits associated with aging. We will test this in mouse models of aging by leveraging the complementary expertise of the Hen lab in targeted molecular and pharmacological manipulations of AHN in behaving mice, the expertise of the Losonczy lab with in vivo large- scale optical recordings, and the expertise of the Fusi lab in computational modeling approaches. At the end of the grant period, our experiments will have provided transformative new insights into the function of abGCs and into the therapeutic potential of targeting AHN to alleviate age-related cognitive deficits in normal aging and possibly in age-related disorders such as MCI and AD.

海马齿状回亚区（DG）在脑电活动中起着重要的作用， 分离是一个计算过程，通过这个过程，类似的经验被转化为离散的非 重叠的神经表征在正常老化和轻度老化中发现了模式分离的缺陷。 认知障碍（MCI）和阿尔茨海默病（AD）。齿状回是仅有的两个大脑区域之一 在哺乳动物的整个生命过程中，新的神经元都在产生，这种现象被称为成年海马 神经发生（AHN）。AHN在正常衰老和AD中均显示出显著降低。我们有 表明小鼠的AHN是“认知辨别”所必需的，这是一种可能涉及模式的学习形式， 分居此外，我们的初步结果表明，遗传和药理学操作， 显著增加AHN（iBax小鼠和Bax拮抗剂）挽救了老年小鼠的认知辨别。 然而，由于技术上的限制，我们对AHN在调节 记忆功能以及这些过程在与年龄相关的认知衰退期间如何改变仍然非常重要。 有限公司我们将利用前所未有的基因接入AHN结合最近的技术 在神经记录和操纵方面取得突破，以揭示AHN对老年小鼠的影响。我们将 测试以下假设：abGC支持稀疏存储器编码，从而实现有效的模式分离，以及 增加AHN可以通过改善模式来挽救与年龄相关的认知歧视缺陷， 分居除了解开AHN的功能，我们还将探讨这一过程是否可以被 利用脑电波来挽救与衰老相关的认知缺陷。我们将在小鼠中进行测试 通过利用母鸡实验室在靶向分子和 在行为小鼠中AHN的药理学操作，Losonczy实验室的专业知识， 规模的光学记录，以及Fusi实验室在计算建模方法方面的专业知识。结束时 在资助期间，我们的实验将为abGCs的功能提供变革性的新见解 以及靶向AHN以减轻正常衰老中与年龄相关的认知缺陷的治疗潜力 并且可能在年龄相关的疾病如MCI和AD中。