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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：情节记忆中的障碍是老化的标志和阿尔茨海默氏症的早期阶段在CA3中，基于部分提示的记忆是在衰老期间的较小认知障碍的人。向前激发（E-I）（E-I）在衰老中看到的编码和记忆缺陷的DG-CA3电路，并确定DG-CA3电路中的馈电E-I平衡是否足以反向年龄相关的障碍。我们鉴定了一个新型的摩尔分子调节因子的连通性E-I平衡，该馈电E-I平衡不影响成熟的齿状颗粒神经元的输入指定，我们将在牙齿颗粒神经元中重新使用齿状颗粒神经元。精确和询问对成年和衰老中的网络水平分离机制和记忆精度的影响。