Circuit mechanisms of hippocampal replay

我们研究了海马区和相关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区的电路机制感兴趣。 描述过去和未来行为轨迹的序列。这些被称为“回放”的序列很吸引人。 因为它们允许受试者重新体验来自另一个时代的事件的独特方式而受到越来越多的关注 和地点。尽管有这些耐人寻味的功能，但仍有几个问题。我们不知道重播如何影响 其他大脑活动以及它们在行为中扮演的角色。我们也不知道其他赛道外的 海马体参与了回放的生成。在这里，我们将通过录音找到这些问题的答案 以及在海马体和紧密相连的称为内嗅觉皮质的区域操纵神经活动 清醒的，行为自由的老鼠。(目标1)之前扰乱重播的尝试只透露了相对 对行为产生微妙的影响。例如，培训后整合期的中断具有相对 对空间记忆任务的弱影响。在这里，我们提供了初步证据，当老鼠 在探测测试中，学习空间记忆任务中的新目标位置显著影响性能 紧接着表演。我们将使用此效果来确定回放的哪些部分是重要的。为 例如，回放必须连接目标位置和环境中更远的位置 以使以后能够从那些遥远的位置导航到目标。这些假设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。(目的2)内侧内嗅皮层 与空间目标的表征和支持更长的海马区回放有关。 然而，后一种结果仅对MEC活性有部分抑制作用，而在小鼠中， 回放是很难衡量的。我们使用了一种创新的光遗传技术，使用了更具穿透力的 波长的光，以及一种创新的光纤几何形式，以关闭整个 大鼠微血管内皮细胞的长度。我们将利用这一点来寻找对海马体回放的更强影响，以及效果 特定于某些类型的回放，例如朝向目标的回放。此外，我们还可以测试 如目标1所示，MEC对于依赖重放的空间学习是否必要。(目标3)我们还使用 先进的硅探头可以测量MEC沿线数百个单元的活动。因此我们 将寻找MEC本身的重播，以及它与海马体重播的关系。这在以下方面一直存在争议 但随着我们细胞产量的增加，我们将能够解决这个问题，并研究亚类型 MEC单元格，如网格单元格、边框单元格、头部方向单元格等。综合起来，我们的结果将提供 洞察学习和记忆的基本机制，这些机制在疾病中受到影响，例如 阿尔茨海默病、癫痫、中风和正常衰老。

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.