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（由申请人提供）：情景记忆受损是衰老和阿尔茨海默病早期阶段的标志。情景记忆的形成需要海马齿状回 (DG)-CA3 回路中两种不同记忆过程、模式分离和模式完成的平衡。然而，DG 中的模式分离对于通过最大限度地减少干扰来区分相似的经历至关重要，而 CA3 中的模式完成则有助于根据部分线索检索记忆。对啮齿动物和人类的研究表明，在衰老过程中和患有轻度认知障碍的个体中，模式分离-完成平衡会被破坏。尽管在衰老过程中内侧颞叶发生了结构和功能改变，但模式分离-完成失衡背后的神经生物学机制仍知之甚少。拟议的研究旨在将 DG-CA3 回路中前馈兴奋抑制 (E-I) 平衡的连通性变化与衰老过程中出现的编码和记忆缺陷联系起来，并确定 DG-CA3 回路中前馈 E-I 平衡的分子恢复是否足以逆转与年龄相关的损伤。检验这些假设的关键是我们鉴定出一种新型的连接性分子调节剂，该调节剂是前馈 E-I 平衡的基础，该调节剂不会影响成熟齿状颗粒神经元的输入特异性。使用新开发的病毒系统来双向调节齿状颗粒神经元中这种分子机构的水平，我们将以前所未有的空间精度重新设计前馈兴奋和抑制的连接性，并探讨其对成年和衰老过程中网络水平模式分离机制以及编码和记忆精度的影响。这些研究可能会深入了解衰老过程中 DG-CA3 回路的编码和记忆精确度的基本机制，以及它们如何能够逆转与年龄相关的认知障碍。