Layer-specific encoding of working memory in an automated 8-arm radial maze

自动 8 臂径向迷宫中工作记忆的层特定编码

• 批准号: 10428497
• 负责人: Joshua Taliaferro
• 金额: $ 4.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428497
• 关键词: Affect; Area; Attention deficit hyperactivity disorder; Automobile Driving; Behavior; Behavior Control; Behavioral; Brain; Brain region; Calcium; Cells; Classification; Code; Cognitive; Complex; Critical Thinking; Cues; Custom; Dementia; Dependence; Dimensions; Disease; Emerging Technologies; Enterobacteria phage P1 Cre recombinase; Evolution; Functional disorder; Genotype; Grain; Health; Hippocampus (Brain); Home; Human Activities; Image; Implant; Independent Living; Individual; Injections; Investigation; Learning; Life; Location; Machine Learning; Maintenance; Medial; Medial Dorsal Nucleus; Memory impairment; Mental Depression; Metabolic; Mind; Motor; Mus; Neurocognitive; Neurons; Occupations; Operative Surgical Procedures; Opsin; Performance; Phase; Population; Prefrontal Cortex; Primates; Process; Radial; Reproducibility; Research; Resistance; Resolution; Rewards; Rodent; Role; Sampling; Schizophrenia; Sensory; Short-Term Memory; Societies; Supermarket; Task Performances; Technology; Textiles; Thalamic structure; Therapeutic; To specify; Training; Visit; Walking; arm; base; calcium indicator; cellular imaging; cost; empowered; experience; indexing; innovation; lens; long term memory; memory encoding; memory process; microendoscope; new technology; novel; operation; optogenetics; prospective; relating to nervous system; self-directed learning; sensory input; skills; social relationships; theories

PROJECT SUMMARY / ABSTRACT Working memory (WM), the cognitive entity that allows for temporary storage and manipulation of informa- tion, is crucial for much of what gives life subjective meaning, and enables an individual to participate in larger society. This includes following a conversation, finding a supermarket item, planning, driving, learning new skills—most anything that requires holding in mind information from long-term memory and/or sensory input for use requires WM. As a result, WM dysfunction has devastating effects, and regrettably, millions—individuals with schizophrenia, depression, ADHD, dementia, and more—experience varying degrees of WM impairment, which is almost totally treatment resistant. Given its role in neurocognitive health and disease, understanding the mechanisms of WM is imperative. Correspondingly, this project will explore in depth the circuit basis for WM. The prefrontal cortex (PFC) is known to be a primary orchestrator of WM, processing input from other brain regions for WM instantiation. In spatial working memory (SWM), a WM subdomain regularly studied across species, interactions of the PFC with the ventral hippocampus and mediodorsal nucleus of the thalamus (MD) are considered essential, with PFC-MD interactions undergirding neural maintenance of WM content and subsequent action selection. Notably, the PFC is quite heterogeneous, being composed of layers that differ both in their cellular composition and in their connectivity. Yet the possibility that these laminar subregions might uniquely contribute to the multifaceted ways in which the PFC empowers WM is only now being explored: recent studies suggest that superficial PFC layers support WM content maintenance, while deep PFC layers support post-maintenance action selection. This proposal expands upon these studies by using novel technology to explore cellular-resolution laminar representations in WM. Specifically, this proposal examines what WM content is encoded in the activity of individual cells vs. popula- tions in the different PFC layers (Aim 1) and assesses the dependence of these laminar WM representations on input from the MD (Aim 2). To do so, calcium imaging will be performed through microendoscopes in mice genetically and surgically specified to express calcium indicators in particular PFC layers. These mice will perform a trial-based delayed nonmatch to sample WM task in a custom-built, automated 8-armed radial maze, and for Aim 2 will have MD input to the PFC optogenetically silenced during behavior and imaging (to simulate the MD-PFC hypoconnectivity regularly observed in those with WM deficits). Finally, for rigorous mapping of behavior to neural activity, novel machine learning behavioral classification paradigms will be used. WM provides the cognitive building blocks for the very fabric of quotidian life—sustaining social relationships, maintaining a job, living independently, learning new things and more. Given such complexity, detailed interrogation of WM circuit mechanisms is required. Accordingly, this proposal uses emerging technologies to explore circuit mechanisms of both WM function and dysfunction, advancing pursuits of therapeutic innovation.

项目总结/摘要 工作记忆（Working Memory，WM）是一种认知实体，允许暂时存储和处理信息。 它是赋予生命主观意义的重要因素，使个人能够参与更大的社会活动。 社会这包括以下对话，找到一个超市的项目，计划，驾驶，学习新的 技能-大多数需要从长期记忆和/或感官输入中记住信息的东西， 使用需要WM。因此，WM功能障碍具有破坏性的影响，令人遗憾的是， 患有精神分裂症、抑郁症、多动症、痴呆等的患者，会经历不同程度的WM损伤， 这几乎完全是治疗抗性的。鉴于其在神经认知健康和疾病中的作用， 工作记忆的作用机制势在必行。相应地，本项目将深入探讨WM的电路基础。 前额叶皮层（PFC）是工作记忆的主要协调者，负责处理来自其他大脑的输入 用于WM实例化的区域。在空间工作记忆（SWM）中，一个WM子领域经常被研究， 种，PFC与腹侧海马和丘脑背内侧核（MD）的相互作用 被认为是必不可少的，PFC-MD相互作用支持WM内容的神经维持， 后续行动选择。值得注意的是，PFC是非常异构的，由不同的层组成， 在它们的细胞组成和它们的连通性上。然而，这些层流分区可能 为PFC赋予WM的多方面方式做出了独特的贡献，目前正在探索：最近 研究表明，表面PFC层支持WM内容维护，而深层PFC层支持 维修后动作选择。该提案通过使用新技术扩展了这些研究， 探索WM中的细胞分辨率分层表示。 具体来说，这项提案研究了在个体细胞与群体细胞的活动中编码的WM内容， 在不同的PFC层（目标1），并评估这些层流WM表示依赖于 从MD输入（目标2）。为此，将通过小鼠的显微内窥镜进行钙成像 在遗传和手术上被指定为在特别是PFC层中表达钙指示剂。这些老鼠会 在定制的自动化8臂径向迷宫中执行基于试验的延迟非匹配到样品WM任务， 并且对于Aim 2，在行为和成像期间，将具有到PFC的光遗传学沉默的MD输入（以模拟 在WM缺陷的患者中经常观察到MD-PFC连接不足）。最后，为了严格映射 为了将行为与神经活动相结合，将使用新颖的机器学习行为分类范例。 工作记忆为维持生命的社会关系提供了认知的基础， 保持工作，独立生活，学习新事物等等。鉴于这种复杂性，详细 需要询问WM电路机制。因此，本提案使用新兴技术， 探索WM功能和功能障碍的回路机制，推进治疗创新的追求。