Circuit mechanisms of hippocampal replay

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.