Uncovering Neural Substrates of Diminished Temporal Binding Capacity in Aging

揭示衰老过程中颞结合能力下降的神经基质

• 批准号: 10511354
• 负责人: Gergely Turi
• 金额: $ 23.99万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511354
• 关键词: Address; Affective; Affective Symptoms; Aging; Auditory; Behavioral; Binding; Brain; Cells; Chronic; Clinical; Code; Cognition Disorders; Cognitive; Conditioned Stimulus; Cues; Disease; Economic Burden; Electrophysiology (science); Emotional; Emotional disorder; Event; Foundations; Fright; Funding; Future; Goals; Hippocampus (Brain); Image; Impaired cognition; Impairment; Incidence; Intervention; Knowledge; Learning; Link; Longevity; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Mus; Neurobehavioral Manifestations; Neurons; Neurophysiology - biologic function; Output; Principal Investigator; Process; Pyramidal Cells; Radial; Resolution; Signal Transduction; Stimulus; Techniques; Testing; Therapeutic; Time; Training; Translations; United States National Institutes of Health; Work; age related; aged; awake; base; clinical application; conditioned fear; data modeling; emerging adult; experience; experimental study; fear memory; improved; innovation; juvenile animal; memory acquisition; memory consolidation; mental function; neuropsychiatric disorder; normal aging; novel; novel strategies; optogenetics; preclinical study; predictive modeling; relating to nervous system; relational memory; two-photon; young adult

Temporal binding capacity, which enables the relational association of discontiguous stimuli and events, diminishes with normal aging and aging-associated neuropsychiatric disorders. Decline in this key mental function is a major limiting factor underlying aging-associated cognitive and affective impairment. The global economic burden of such aging-associated impairment is estimated at over $1 trillion and is growing at an alarming pace. An improved understanding of changes in neural functions with aging that contribute to degraded temporal binding capacity could greatly facilitate the long-term objective of alleviating cognitive and affective impairments in normative aging and aging-associated neuropsychiatric disorders. Yet, the changes in circuit and network functioning contributing to diminished temporal binding capacity with aging remain unknown. The Principal Investigator's recent NIH-funded work using trace fear learning paradigms has identified critical neural activity dynamics in the CA1 output region of the hippocampus (HPC) supporting the encoding and representation of emotionally salient associations during temporal binding in young adult subjects. This framework will now be extended to uncovering altered processes in aged subjects. The current project utilizes a novel, conceptually innovative model for temporal binding based upon previously uncharacterized functioning of a known CA1 radial sublayer-biased microcircuit motif and proposes that alterations in subpopulation activity and network dynamics may underlie age-related impairment of temporal binding capacity. Based on prior data the model predicts that, in early adulthood, deep CA1 pyramidal cells (CA1PCs) output stimulus representations across discontiguous gaps for temporal binding, while learning-related increases in sharp-wave ripple (SWR) event incidence facilitate consolidation of relational associations outside of the behavioral episode. Aging-related alterations in sublayer-biased signaling during temporal binding and/or SWR dynamics during consolidation of relational associations may thus underlie diminished temporal binding capacity in aging. In future work, any alterations uncovered here will then be used to inform novel strategies for improving temporal binding capacity with aging and alleviating impaired relational organization and affective associations in memory. To uncover aging-related alterations in neural dynamics supporting temporal binding capacity, the project combines state- of-the-art techniques including 2-photon imaging of subcircuit activity, electrophysiology, and optogenetic triggering of network activity events in awake, behaving mice. In Aim 1, aging-related changes in the CA1 radial sublayer outputs mediating temporal binding for trace fear memory acquisition will be identified. In Aim 2, aging-related alterations in SWR activity for consolidation of relational fear associations will be uncovered. The proposed studies are aligned with NIH objectives and will advance the understanding of the neural processes underlying the decline in temporal binding capacity with aging, which is essential to improving therapeutics for cognitive and affective impairments across the normal lifespan as well as in aging-associated disorders.

时间绑定能力，这使得不连续的刺激和事件能够进行关系关联， 随着正常衰老和衰老相关的神经精神障碍而减少。在这一关键心理上的下降 功能是与衰老相关的认知和情感障碍的主要限制因素。《环球报》 这种与老龄化相关的减值造成的经济负担估计超过1万亿美元，而且还在以 惊人的速度。更好地理解神经功能随年龄的变化而导致的退化 时间约束能力可以极大地促进缓解认知和情感障碍的长期目标 正常衰老和与衰老相关的神经精神障碍的损害。然而，电路和电路上的变化 随着年龄的增长，导致时间结合能力减弱的网络功能仍不清楚。这个 首席调查员最近在NIH资助的使用痕迹恐惧学习范式的工作中发现了关键的 海马区CA1输出区(HPC)的神经活动动力学 青壮年受试者在时间捆绑过程中情绪显著联系的表征。这 框架现在将扩展到揭示老年受试者的改变过程。当前项目使用一个 基于先前未描述的功能的新颖的、概念上创新的时间绑定模型 已知的CA1径向亚层偏置微电路基元的变化，并提出亚布居活性的变化 而网络动力学可能是与年龄相关的时间结合能力受损的基础。基于先前的数据 该模型预测，在成年早期，深CA1锥体细胞(CA1PC)输出刺激表征 跨越不连续的间隙进行时间绑定，同时与学习相关的尖锐波纹(SWR)增加 事件的发生有助于巩固行为事件之外的关系关联。与老龄化相关的 在时间结合和/或SWR动态过程中的亚层偏向信号的变化 因此，关系关联可能是衰老过程中时间绑定能力减弱的基础。在今后的工作中，任何 这里发现的改变将被用来提供改进时间结合能力的新策略 随着年龄的增长，减轻记忆中受损的关系组织和情感联系。揭开真相 支持时间结合能力的神经动力学中与衰老相关的改变，该项目结合了状态- 最先进的技术，包括亚电路活动的双光子成像、电生理学和光遗传学 在清醒、行为正常的小鼠中触发网络活动事件。在目标1中，与衰老相关的CA1放射状改变 将识别调解痕迹恐惧记忆获得的时间绑定的子层输出。在目标2中， 与年龄相关的SWR活动的变化将被揭示出来，以巩固关系恐惧联系。这个 建议的研究与美国国立卫生研究院的目标一致，并将促进对神经过程的理解 随着年龄的增长，时间结合能力的下降是潜在的，这对改进治疗方法是必不可少的 正常寿命内的认知和情感障碍以及与衰老相关的障碍。