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

基本信息

批准号：
10708806
负责人：
Gergely Turi
金额：
$ 19.99万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
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/10708806
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 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 clinical application conditioned fear data modeling emerging adult experience experimental study fear memory improved innovation juvenile animal memory acquisition memory consolidation mental function neural neuropsychiatric disorder normal aging novel novel strategies optogenetics preclinical study predictive modeling relational memory two-photon young adult

项目摘要

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.

时间结合能力，可以实现不连续刺激和事件的关系关联，随着正常衰老和衰老相关的神经精神疾病而减弱。这一关键心理因素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。全球这种与老龄化相关的损害的经济负担估计超过 1 万亿美元，并且还在以惊人的速度增长。速度惊人。更好地了解神经功能随衰老而发生的变化，从而导致退化时间约束能力可以极大地促进缓解认知和情感的长期目标正常衰老和衰老相关神经精神疾病的损害。然而，电路和随着年龄的增长，网络功能导致时间结合能力减弱的原因仍然未知。这首席研究员最近由 NIH 资助的使用追踪恐惧学习范式的工作已经确定了关键的海马体 CA1 输出区 (HPC) 的神经活动动态支持编码和年轻成人受试者在时间束缚期间情感上显着关联的表征。这框架现在将扩展到揭示老年受试者中改变的过程。当前的项目利用了基于先前未表征的功能的新颖的、概念上创新的时间绑定模型已知的 CA1 径向子层偏向微电路基序，并提出亚群活动的改变网络动态可能是与年龄相关的时间结合能力损伤的基础。根据之前的数据该模型预测，在成年早期，深层 CA1 锥体细胞 (CA1PC) 输出刺激表征跨越时间结合的不连续间隙，而学习相关的尖波纹波（SWR）增加事件发生率有助于巩固行为事件之外的关系关联。老化相关时间结合期间亚层偏向信号的变化和/或巩固期间的SWR动态因此，关系关联可能是衰老过程中时间结合能力减弱的基础。在今后的工作中，任何这里发现的改变将被用来为提高时间结合能力的新策略提供信息随着衰老和减轻记忆中受损的关系组织和情感关联。揭开与衰老相关的神经动力学变化支持时间结合能力，该项目结合了状态- 最先进的技术，包括次电路活动的 2 光子成像、电生理学和光遗传学在清醒、有行为的小鼠中触发网络活动事件。在目标 1 中，CA1 桡动脉的衰老相关变化子层输出调解时间绑定，用于追踪恐惧记忆获取将被识别。在目标 2 中，将揭示与年龄相关的 SWR 活动的变化，以巩固相关的恐惧关联。这拟议的研究与 NIH 的目标一致，并将促进对神经过程的理解时间结合能力随着衰老而下降，这对于改善治疗方法至关重要正常寿命期间以及与衰老相关的疾病中的认知和情感障碍。