The Role of Oriens-Lacunosum Moleculare Interneurons in Sleep-Dependent Memory Consolidation

项目摘要 睡眠和记忆之间的联系已经得到了很好的证实，尽管其中涉及的潜在机制还不清楚。 完全理解睡眠紊乱对健康和认知有许多负面影响， 通常是精神和神经疾病的症状。更全面地了解睡眠的作用 在记忆处理中的作用将进一步加深我们对学习和记忆机制的认识， 潜在的干预领域，以改善疾病状态下的认知功能。这个项目的首要目标是 该项目旨在增加我们对快速眼动（REM）睡眠及其在睡眠依赖性疾病中的作用的理解。 通过阐明定向-腔隙分子（OLM）的必要性和作用来巩固 海马体中的中间神经元。我们的初步数据表明，抑制所有 快速眼动睡眠期间背侧海马中生长抑素表达神经元导致记忆缺陷 巩固在新的物体放置识别（NOPR）和上下文恐惧条件反射（CFC）的任务。我们 假设是OLM中间神经元的活动对于维持进入神经元的信息流的平衡是至关重要的。 海马体的CA 1区域，而在REM睡眠期间改变这些细胞的活动将导致 背景记忆巩固的缺陷本建议中概述的工作将建立在我们初步的 通过使用选择性靶向OLM中间神经元的新型小鼠系获得数据。在目标1中，我们将研究 在REM睡眠期间刺激和抑制OLM细胞的行为效应， 一个依赖于记忆的任务我们将分析REM睡眠期间OLM调制对 NOPR和CFC任务，并使用记录的LFP活动来研究睡眠结构和振荡活动。 目的2将确定在REM睡眠期间调节OLM细胞活性对形成和 维持位置细胞。我们将使用光遗传学结合体内钙成像来识别 位置细胞，并观察OLM细胞调制如何影响位置细胞特性，如视野大小，放电 速率、稳定性和连贯性。这些目标的完成将提供更多关于必要性的信息， 快速眼动睡眠的记忆巩固，并确定OLM细胞在局部海马回路中的作用， 空间记忆处理实验将在睡眠专家吉娜·坡博士的实验室进行， 内存字段。Poe实验室在海马电生理学和啮齿动物睡眠方面的专业知识， 加州大学洛杉矶分校对开发神经技术的浓厚兴趣，使我处于一个有利的位置，使用创新的 方法来调查这些问题。下面介绍的培训计划将强调建立强大的 通过统计和编程课程和讲习班掌握数据分析技能，在切割方面打下坚实的基础- 边缘系统神经科学技术，通过实验和课程提出，并授予写作和 通过在各种场合展示和发表我的研究结果的机会来提高科学沟通能力。

PROJECT SUMMARY The link between sleep and memory is well-established, though the underlying mechanisms involved are not fully understood. Disordered sleep has numerous negative consequences to health and cognition, and is itself often a symptom of psychiatric and neurological illnesses. A more complete understanding of the role of sleep in memory processing will further our knowledge of the mechanisms of learning and memory, as well as point to potential areas for intervention to improve cognitive function in disease states. The overarching goal of this project is to increase our understanding of rapid eye movement (REM) sleep and its role in sleep-dependent consolidation through delineating the necessity and function of oriens-lacunosum moleculare (OLM) interneurons in the hippocampus during this sleep state. Our preliminary data suggest that inhibiting all somatostatin-expressing neurons in the dorsal hippocampus during REM sleep results in deficits in memory consolidation in novel object placement recognition (NOPR) and contextual fear conditioning (CFC) tasks. Our hypothesis is that OLM interneuron activity is crucial for maintaining the balance of information flow into the CA1 region of the hippocampus, and that changing the activity of these cells during REM sleep will result in deficits in contextual memory consolidation. The work outlined in this proposal will build upon our preliminary data through the use of a novel mouse line selectively targeting OLM interneurons. In Aim 1, we will investigate the behavioral effects of both stimulating and inhibiting OLM cells during REM sleep following the acquisition of a hippocampal-dependent memory task. We will analyze the effect of OLM modulation during REM sleep on both NOPR and CFC tasks and use recorded LFP activity to study sleep architecture and oscillatory activity. Aim 2 will determine the effect of modulating OLM cell activity during REM sleep on the formation and maintenance of place cells. We will use optogenetics in combination with in vivo calcium imaging to identify place cells and observe how OLM cell modulation impacts place cell characteristics such as field size, firing rate, stability, and coherence. Completion of these aims will provide more information regarding the necessity of REM sleep for memory consolidation, and define the role of OLM cells in local hippocampal circuits during spatial memory processing. Experiments will take place in the lab of Dr. Gina Poe, an expert in the sleep and memory field. The Poe lab's expertise in hippocampal electrophysiology and rodent sleep, together with UCLA's strong interest in developing neurotechnology, places me in a strong position to use innovative approaches to investigate these questions. The training plan described below will emphasize building strong data analysis skills through courses and workshops in statistics and programming, a solid foundation in cutting- edge systems neuroscience techniques through experiments and courses proposed, and grant-writing and scientific communication abilities through opportunities to present and publish my results in a variety of venues.