Mechanisms and functions of temporal coordination in the entorhinal-hippocampal network

PROJECT SUMMARY Episodic memory involves learning and recalling associations between items and their spatio-temporal context. Those memories can be further used to flexibly support different behavioral demands. In this proposal we address the question of how the fine temporal coordination of neuronal activity across entorhinal and

hippocampal areas support learning and memory. Oscillatory synchrony in the theta (~5-9 Hz) and gamma (~30- 100 Hz) frequency bands between hippocampus and entorhinal cortices has been implicated in these processes, although the precise mechanisms are not known. The medial (MEC) and lateral (LEC) entorhinal areas are the

major source of inputs to the hippocampus. Previously, we found that gamma oscillations synchronize population activity in hippocampal-entorhinal circuits during navigation and learning. However, how the gamma-frequency coordination of hippocampal assemblies brought about by distinct entorhinal inputs supports the formation and

reactivation of specialized memory representations in different CA1 subpopulations is not known. In this proposal, we will deploy a novel approach combining multi-region laminar recording and temporally selective optogenetic perturbations to elucidate the circuit mechanisms that support spatial and non-spatial learning in

rats. Previous work suggested that different CA1 pyramidal cell subpopulations are specialized in encoding complementary memory representations, and they receive differential innervation from MEC and LEC. In Aim 1, we will perform simultaneous neural recordings across CA1-2, MEC and LEC while rats navigate mazes to

examine how area and layer-specific gamma synchrony modulates neuronal firing dynamics. This will be enabled by a novel analytical method to isolate different pathway-specific gamma oscillations durign behavior. In Aim 2 we will investigate how functional interactions among neuronal assemblies across these structures are

modulated by behavioral demands, by training rats in different types of learning tasks. We will investigate whether different hippocampal-entorhinal neuronal subpopulations form assemblies and sequences representing behavioral relevant locations during learning. We will also test the causal contribution of entorhinal gamma inputs

to this process with selective optogenetic perturbations. The sequential activation of cell assemblies during behavior is recapitulated during pauses in exploration and sleep, coordinated by SWRs; a process that supports memory consolidation. In Aim 3 we will test if synchronous M/LEC inputs influence which assemblies are

recruited into SWRs, therefore determining which aspects of experience are replayed and consolidated. To do so, we will perform closed-loop optogenetic silencing of CA1 condition on real-time detection of M/LEC inputs during sleep periods following different learning tasks. By combining technical innovations for recording,

analyzing, and manipulating circuit dynamics, this proposal will reveal how entorhinal inputs support hippocampal representations, memory replay and predictive coding. These Aims will also expand our understating of fundamental circuit mechanisms of impaired cognition common to multiple neuropsychiatric diseases.