Circuit mechanisms of hippocampal replay

我们研究了海马体和相连区域的神经活动如何介导它们在学习中的作用， 记忆我们感兴趣的是负责激活海马单位的电路机制， 描述过去和未来行为轨迹的序列。这些被称为“重播”的序列， 由于它们允许主体重新体验另一个时间的事件的独特方式， 和地点。尽管有这些有趣的特征，但仍存在一些问题。我们不知道回放会如何影响 其他大脑活动以及它们在行为中扮演的角色。我们也不知道其他电路以外的 海马体参与产生重放。在这里，我们将通过记录这些问题的答案， 在海马体和一个紧密相连的叫做内嗅皮层的区域， 清醒且行为自由的大鼠。(Aim 1）以前试图破坏重播只显示相对 对行为的微妙影响。例如，培训后巩固期的中断相对 对空间记忆任务的影响很弱。在这里，我们提出了初步的证据，破坏重放，而一只老鼠， 在空间记忆任务中学习一个新的目标位置会极大地影响探测测试中的表现 之后立即执行。我们将使用此效果来确定重播的哪些部分是重要的。为 例如，可能是重放必须将目标位置和环境中更远的位置连接起来 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 系统地揭示了重放如何有助于空间学习。(Aim 2）内侧内嗅皮层（MEC） 与空间目标的表征有关，并支持更长的海马重放。 然而，发现后一结果对MEC活性仅具有部分抑制作用，并且在小鼠中， 重播很难衡量。我们使用了一种创新的光遗传学技术， 光的波长，以及光纤几何形状的创新形式，以关闭整个沿着的活动 大鼠MEC的长度。我们将利用这一点来寻找对海马重放的更强影响， 特定于某些类型的重放，例如那些向目标行进的重放。此外，我们可以测试 MEC对于目标1中所示的重放依赖空间学习是否是必要的。(Aim（3）使用 先进的硅探针，以测量活动从数百个单位沿着长度的MEC。因此我们 将在MEC本身中寻找重放，以及它与海马重放的关系。这一点一直存在争议， 但是随着我们细胞产量的增加，我们将能够解决这一问题，并检查 MEC细胞，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，这些机制在疾病中受到影响， 老年痴呆症，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.