Circuit mechanisms of hippocampal replay

海马重放的回路机制

• 批准号: 10402402
• 负责人: David J Foster
• 金额: $ 47.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402402
• 关键词: Address; Affect; Alzheimer' s Disease; Area; Attention; Behavior; Behavioral; Brain; Cells; Data; Disease; Distant; Environment; Epilepsy; Event; Exhibits; Fire - disasters; Future; Generations; Geometry; Goals; Head; Hippocampus (Brain); Imagination; Individual; Learning; Length; Light; Link; Literature; Location; Measurement; Measures; Medial; Mediating; Memory; Methodology; Modeling; Mus; Neurosciences; Pattern; Penetration; Performance; Play; Process; Rattus; Reporting; Rest; Retrieval; Rewards; Role; Schizophrenia; Signal Transduction; Silicon; Speed; Stroke; Suggestion; System; Techniques; Testing; Thinking; Time; Training; Travel; Work; autism spectrum disorder; awake; brain cell; cell cortex; cell type; design; entorhinal cortex; experience; follow-up; hippocampal subregions; innovation; insight; interest; memory process; normal aging; optical fiber; optogenetics; prevent; public health relevance; recruit; relating to nervous system; spatial memory

We study how neural activity in the hippocampus and connected areas mediates their roles in learning and memory. We are interested in circuit mechanisms responsible for activation of hippocampal units in precise sequences that depict past and future behavioral trajectories. These sequences, called "replays", are attracting increasing attention because of the unique way they allow a subject to re-experience events from another time and place. Despite these intriguing features, several questions remain. We do not know how replays impact other brain activity and what role they play in behavior. We also do not know how other circuits outside of the hippocampus are involved in generating replays. Here, we will find answers to these questions, by recording and manipulating neural activity, in hippocampus and in a closely connected area called entorhinal cortex, in awake and freely behaving rats. (Aim 1) Previous attempts to disrupt replay have only revealed relatively subtle effects on behavior. For example, disruption during a post-training consolidation period has relatively weak effects on a spatial memory task. Here we present preliminary evidence that disrupting replay while a rat learns a new goal location in a spatial memory task dramatically affects performance during a probe test performed immediately afterward. We will use this effect to determine which parts of replays are important. For example, it could be that replays must join up the goal location and more distant locations in the environment to enable later navigation to the goal from those distant locations. These and other hypotheses will be tested systematically to reveal how replay contributes to spatial learning. (Aim 2) The medial entorhinal cortex (MEC) has been implicated in the representation of spatial goals, and in supporting longer hippocampal replays. However, this latter result was found with only a partial suppressive effect on MEC activity, and in mice, where replay is difficult to measure. We use an innovative new optogenetic technique using more penetrative wavelengths of light, and an innovative form of optical fiber geometry, to shut down activity along the entire length of the MEC in the rat. We will use this to look for stronger effects on hippocampal replay, and for effects that are specific to certain types of replay, such as those that travel toward the goal. Further, we can test whether MEC is necessary for replay-dependent spatial learning as shown in Aim 1. (Aim 3) We also use advanced silicon probes to measure activity from hundreds of units along the length of the MEC. Therefore we will look for replay within MEC itself, and how it relates to hippocampal replay. This has been controversial in the literature, but with our increased cell yield we will be able to resolve this, and also examine sub-types of MEC cell such as grid cells, border cells, head direction cells etc. Taken together, our results will provide insight into fundamental mechanisms of learning and memory, that are affected in diseases such as Alzheimer's disease, epilepsy, stroke and normal aging.

我们研究海马体和连接区域的神经活动如何调节它们在学习和学习中的作用 记忆。我们对负责精确激活海马单位的电路机制感兴趣 描述过去和未来行为轨迹的序列。这些被称为“重播”的序列很吸引人 由于它们以独特的方式让受试者重新体验另一个时间的事件而受到越来越多的关注 和地点。尽管有这些有趣的功能，但仍然存在一些问题。我们不知道重播有何影响 其他大脑活动以及它们在行为中发挥的作用。我们也不知道除此之外的其他电路如何 海马体参与生成重播。在这里，我们将通过记录来寻找这些问题的答案 并操纵海马体和称为内嗅皮层的紧密连接区域的神经活动 清醒且行为自由的老鼠。 （目标 1）之前破坏重播的尝试仅揭示了相对 对行为产生微妙的影响。例如，培训后巩固期间的干扰相对 对空间记忆任务的影响较弱。在这里，我们提供了初步证据表明，当老鼠 在空间记忆任务中学习新的目标位置会极大地影响探测测试期间的性能 之后立即执行。我们将使用此效果来确定重播的哪些部分很重要。为了 例如，重播可能必须将目标位置和环境中更远的位置连接起来 以便以后能够从那些遥远的位置导航到目标。这些和其他假设将得到检验 系统地揭示重播如何有助于空间学习。 （目标 2）内侧内嗅皮层 (MEC) 与空间目标的表示以及支持更长的海马体重放有关。 然而，后一个结果仅对 MEC 活性有部分抑制作用，并且在小鼠中， 重播很难衡量。我们使用一种创新的光遗传学技术，利用更具渗透性的 光的波长和光纤几何形状的创新形式，可以关闭整个区域的活动 大鼠 MEC 的长度。我们将用它来寻找对海马重放的更强影响，以及效果 特定于某些类型的重播，例如朝着目标前进的重播。进一步，我们可以测试 MEC 是否对于依赖重放的空间学习是必要的，如目标 1 所示。（目标 3）我们还使用 先进的硅探针可测量沿 MEC 长度的数百个单元的活动。因此我们 将寻找 MEC 本身的重播，以及它与海马重播的关系。这在业内曾引起争议 文献中，但随着细胞产量的增加，我们将能够解决这个问题，并检查 MEC 细胞，例如网格细胞、边界细胞、头部方向细胞等。综合起来，我们的结果将提供 深入了解学习和记忆的基本机制，这些机制受到疾病的影响，例如 阿尔茨海默病、癫痫、中风和正常衰老。