The Neglected Subiculum: Decoding and Manipulating Memory Retrieval with Multiphoton Holography

被忽视的下托：用多光子全息术解码和操纵记忆检索

• 批准号: 10755033
• 负责人: Darik Andrew O'Neil
• 金额: $ 4.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755033
• 关键词: Address; Alzheimer' s Disease; Alzheimer’s disease biomarker; Area; Atrophic; Aversive Stimulus; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Calcium; Cells; Code; Computer Analysis; Cues; Development; Disease; Electrophysiology (science); Engineering; Ensure; Functional disorder; Goals; Head; Hippocampal Formation; Hippocampus; Holography; Image; Immediate-Early Genes; Impaired cognition; Knowledge; Laboratories; Learning; Life; Measures; Memory; Memory impairment; Mentorship; Mus; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Output; Pathologic; Phase; Physiological; Play; Positioning Attribute; Postdoctoral Fellow; Protocols documentation; Recording of previous events; Recurrence; Research; Research Personnel; Research Project Grants; Resolution; Retrieval; Role; Slide; Specificity; Stimulus; System; Testing; Training; auditory stimulus; career; clinically significant; computational basis; conditioned fear; design; disadvantaged background; experimental study; fear memory; functional group; in vivo optical imaging; insight; large scale data; light weight; memory recall; memory retrieval; multi-photon; neglect; neural; novel; optogenetics; pre-clinical research; response; skills; two-photon

Memory impairment emerges in diverse, clinically-significant conditions spanning all stages of life. After a memory has been encoded, its retrieval is believed to occur through the reactivation of an engram, the physiological substrate of memory. Engrams are partitioned into neuronal ensembles—small groups of functionally-related neurons—that are dispersed throughout the brain. Direct optogenetic stimulation of engram cells in the hippocampus has proven sufficient to trigger the coordinated reactivation of these dispersed ensembles. The primary output node of the hippocampus, the subiculum, has proven critical to the integrity of memory retrieval and is robustly associated with the memory impairments observed in Alzheimer’s disease. However, despite a rich history of memory research in the hippocampal formation, the subiculum and its role in memory remain critically understudied. Remarkably, recent evidence indicates the integrity of the subiculum may be critical for memory retrieval without being necessary for encoding. Identifying the unique role of the subiculum in memory retrieval is thus a central question in memory research. To address this gap in knowledge, I will leverage large-scale two-photon calcium imaging alongside holographic photostimulation to decode and manipulate subicular activity during memory retrieval in mice. I will test the hypothesis that conjunctive-coding and recurrent-modularity in the subiculum facilitate the coordinated reactivation of neuronal ensembles during memory retrieval. I have constructed an experimental setup in which I am able to simultaneously measure (two-photon calcium imaging) and manipulate neural activity (two- photon holographic optogenetics) in mice during a closed-loop fear conditioning assay. I have found that partially-overlapping neuronal ensembles in the subiculum encode a variety of task-relevant features during retrieval, including the temporal gap between the retrieval cue and the anticipated aversive stimuli. In the F99 phase, I will test the hypothesis that the activation of subsets of the identified neuronal ensembles preferentially drive intra-ensemble activity. To do so, I will be trained in and use two-photon holographic optogenetics to selectively stimulate arbitrary subsets of intra-ensemble and random neurons. Simultaneously, I will record the activity of these neurons using two-photon calcium imaging in order to determine whether stimulation drives persistent activity on an order of magnitude longer than photostimulation duration and whether such activity is specific to ensemble neurons. In the K00 phase, I will investigate the coordination of subicular and cortical activity during memory retrieval, and its perturbation in disease. This proposal will establish a causal understanding of subicular dynamics during memory retrieval, a deeper understanding of the coordination of memory retrieval across brain regions, and nurture the development of an independent researcher from a disadvantaged background at the cutting-edge of memory research.

记忆障碍在潜水员中出现，临床上重要的条件跨越了生命的所有阶段。之后 记忆已经编码，据信它的检索是通过engram的重新激活而发生的 记忆的生理基板。将字符划分为神经元合奏 - 小组的小组 与功能相关的神经元 - 分散在整个大脑中。直接的光遗传刺激 事实证明，海马中的Engram细胞足以触发这些重新激活 分散的合奏。海马的主要输出节点，次花，被证明对 内存检索的完整性，与在 阿尔茨海默氏病。然而，尽管海马形成有丰富的记忆研究历史，但 亚致及其在记忆中的作用仍然批判性地理解。值得注意的是，最近的证据表明 地下的完整性对于记忆检索至关重要，而无需编码。识别 因此，亚图在记忆检索中的独特作用是记忆研究中的一个核心问题。解决 在知识上，我将利用全息图的大规模两光子钙成像 在记忆检索过程中，光刺激以解码和操纵下细胞活性。我将测试 假设在地下中的结合编码和复发性模块化准备了协调的 在记忆检索过程中神经元合奏的重新激活。我已经在 我能够同时测量（两光子钙成像）并操纵神经元活性（两次 - 在闭环恐惧条件测定期间，小鼠的光子全息光遗传学）。我发现 亚致中的部分重叠的神经元合奏编码各种任务与任务相关的功能 检索，包括检索提示与预期的厌恶刺激之间的暂时差距。在F99中 阶段，我将检验以下假设：已识别神经元集合的子集的激活 优先驱动体内活动。为此，我将接受培训并使用两光子全息图 光遗传学以选择性刺激内组和随机神经元的任意子集。同时地， 我将使用两光子钙成像记录这些神经元的活性，以确定是否是否 刺激在比光刺激持续时间长的数量级上驱动持续活动，并且 这种活动是否特定于整体神经元。在K00阶段，我将调查 记忆回收期间的下层和皮质活性及其在疾病中的扰动。该提议将 在记忆检索过程中对下图动态建立因果关系，对 跨大脑区域的记忆检索的协调，并为独立的发展提供护理 在记忆研究前沿的背景下，研究人员的研究人员。