Re-engineering excitation-inhibition connectivity to rejuvenate memory circuits in aging

重新设计兴奋-抑制连接以恢复衰老过程中的记忆电路

• 批准号: 9028637
• 负责人: Amar Sahay
• 金额: $ 202.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028637
• 关键词: Adult; Affect; Age-associated memory impairment; Aging; Alzheimer' s Disease; Behavioral; Biological Assay; Cells; Cellular Compartment Analysis; Cues; Cytoplasmic Granules; Discrimination; Down-Regulation; Engineering; Environment; Episodic memory; Equilibrium; Fluorescent in Situ Hybridization; Fright; Hippocampus (Brain); Human; Immediate-Early Genes; Impairment; Individual; Interneurons; Learning; Link; Medial; Mediating; Memory; Memory impairment; Molecular; Mus; Neurons; Parvalbumins; Pattern; Population; Process; Research; Retrieval; Rodent; Role; Space Perception; Specificity; Staging; Synapses; System; Temporal Lobe; Testing; Up-Regulation; Viral; age related; aged; aging brain; base; cognitive function; dentate gyrus; experience; feeding; hippocampal pyramidal neuron; insight; lentiviral-mediated; memory encoding; memory retrieval; middle age; mild cognitive impairment; mossy fiber; neurobiological mechanism; neurogenesis; novel; overexpression; prevent; public health relevance; research study; restoration; young adult

 DESCRIPTION (provided by applicant): Impairments in episodic memory are a hallmark of aging and early stages of Alzheimer's disease. Episodic memory formation requires a balance of two distinct mnemonic processes, pattern separation and pattern completion in the dentate gyrus (DG)-CA3 circuit of the hippocampus. Whereas, pattern separation in DG is essential to distinguish between similar experiences by minimizing interference, pattern completion in CA3 facilitates the retrieval of memories based on partial cues. Studies in rodents and humans have suggested that pattern separation-completion balance is disrupted in aging and in individuals with mild cognitive impairment. Although structural and functional alterations have been identified within the medial temporal lobe during aging, the neurobiological mechanisms underlying pattern separation-completion imbalance are poorly understood. The proposed research aims to causally link changes in connectivity underlying feed-forward excitation-inhibition (E-I) balance in the DG-CA3 circuit with encoding and memory deficits seen in aging and determine whether molecular restoration of feed-forward E-I balance in DG-CA3 circuitry is sufficient to reverse age-related impairments. Critical to testing these hypotheses is our identification of a novel molecular regulator of connectivity underlying feed-forward E-I balance that does not affect input specificity of mature dentate granule neurons. Using newly developed viral systems to bi-directionally regulate levels of this molecular agency in dentate granule neurons, we will re-engineer connectivity underlying feed-forward excitation and inhibition with unprecedented spatial precision and interrogate its impact on network level pattern separation mechanisms and encoding and memory precision in adulthood and in aging. These studies may generate insights into fundamental mechanisms underlying encoding and memory precision in DG-CA3 circuit in aging and how they may be targeted for reversing age-related cognitive impairments.

 描述（由适用提供）：情节记忆的障碍是老化的标志和阿尔茨海默氏病的早期阶段。情节记忆形成需要在海马的齿状回（DG）-CA3电路中取得两个不同的助记符过程，模式分离和模式完成。而DG中的模式分离对于通过最大程度地减少干扰来区分相似的经验至关重要，而CA3收藏夹中的模式完成基于部分提示的记忆检索。对啮齿动物和人类的研究表明，在衰老和有轻度认知障碍的个体中，模式分离完成平衡受到了破坏。尽管在衰老过程中媒体临时叶中已经确定了结构和功能改变，但对基于模式分离结构失衡的神经生物学机制知之甚少。拟议的研究旨在将DG-CA3电路中的连通性抗兴奋性抑制（E-I）平衡的连通性变化与编码和记忆定义在衰老中所见，并确定DG-CA3电路中的分子E-I平衡是否足以反向年龄降低的障碍。测试这些假设至关重要的是我们鉴定出一种新型的分子调节剂的连通性E-I平衡的连通性调节剂，该连通性E-I平衡不影响成熟的齿状颗粒神经元的输入特异性。使用新开发的病毒系统在齿状颗粒神经元中双向调节该分子代理的水平，我们将重新设计基础的饲料前兴奋和抑制作用，并以空间的精确性进行抑制，并质疑其对网络水平分离机制以及在Adulthod和Aging中的网络水平分离机制以及编码和记忆精确的影响。这些研究可能会深入了解DG-CA3电路中衰老中编码和记忆精度的基本机制，以及如何将它们用于逆转与年龄相关的认知障碍。