Episodic memory, which refers to our ability to encode and recall past events, is essential to our daily lives. Previous research has established that both the entorhinal cortex (EC) and hippocampus (HPC) play a crucial role in the formation and retrieval of episodic memories. However, to understand neural circuit mechanisms behind these processes, it has become necessary to monitor and manipulate the neural activity in a cell‐type‐specific manner with high temporal precision during memory formation, consolidation, and retrieval in the EC‐HPC networks. Recent studies using cell‐type‐specific labeling, monitoring, and manipulation have demonstrated that medial EC (MEC) contains multiple excitatory neurons that have differential molecular markers, physiological properties, and anatomical features. In this review, we will comprehensively examine the complementary roles of superficial layers of neurons (II and III) and the roles of deeper layers (V and VI) in episodic memory formation and recall based on these recent findings.

Distinct computations are performed at multiple brain regions during encoding of the spatial environments. Neural representations in the hippocampal, entorhinal and head direction (HD) networks during spatial navigation have been clearly documented, while the representational properties of the Subicular Complex (SC) network is rather unexplored, even though it has extensive anatomical connections with various brain regions involved in spatial information processing. Here, we report a global cue controlled highly coherent representation of the cue-conflict environment in the SC network, along with strong coupling between HD cells and Spatial cells. We propose that the attractor dynamics in the SC network might play a critical role in orientation of the spatial representations, thus providing a “reference map” of the environment for further processing at other networks.

Distinct computations are performed at multiple brain regions during the encoding of spatial environments. Neural representations in the hippocampal, entorhinal, and head direction (HD) networks during spatial navigation have been clearly documented, while the representational properties of the subicular complex (SC) are relatively underexplored, although it has extensive anatomic connections with various brain regions involved in spatial information processing. We simultaneously recorded single units from different subregions of the SC in male rats while they ran clockwise on a centrally placed textured circular track (four different textures, each covering a quadrant), surrounded by six distal cues. The neural activity was monitored in standard sessions by maintaining the same configuration between the cues, while in cue manipulation sessions, the distal and local cues were either rotated in opposite directions to create a mismatch between them or the distal cues were removed. We report a highly coherent neural representation of the environment and a robust coupling between the HD cells and the spatial cells in the SC, strikingly different from previous reports of coupling between cells from co-recorded sites. Neural representations were (1) originally governed by the distal cues under local-distal cue-conflict conditions, (2) controlled by the local cues in the absence of distal cues, and (3) governed by the cues that are perceived to be stable. We propose that such attractor-like dynamics in the SC might play a critical role in the orientation of spatial representations, thus providing a "reference map" of the environment for further processing by other networks.

Animals predominantly use salient visual cues (landmarks) for efficient navigation. When the relative position of the visual cues is altered, the hippocampal population exhibits heterogeneous responses and constructs context-specific spatial maps. Another critical factor that can strongly modulate spatial representation is the presence of reward. Reward features can drive behavior and are known to bias spatial attention. However, it is unclear whether reward features are used for spatial reference in the presence of distal cues and how the hippocampus population dynamics changes when the association between reward features and distal cues is altered. We systematically investigated these questions by recording place cells from the CA1 in different sets of experiments while the rats ran in an environment with the conflicting association between reward features and distal cues. We report that, when rewards features were only used as local cues, the hippocampal place fields exhibited coherent and dynamical orientation across sessions, suggesting the use of a single coherent spatial map. We found that place cells maintained their spatial offset in the cue conflict conditions, thus showing a robust spatial coupling featuring an attractor-like property in the CA1. These results indicate that reward features may control the place field orientation but may not cause sufficient input difference to create context-specific spatial maps in the CA1.

Hippocampal place cells are functional units of spatial navigation and are present in all subregions: CA1, CA2, CA3, and CA4. Recent studies on CA2 have indicated its role in social and contextual memories, but its contribution to spatial novelty detection and encoding remains largely unknown. The current study aims to uncover how CA2 processes spatial novelty and to distinguish its functional role towards the same from CA1. Accordingly, a novel 3-day paradigm was designed where animals were introduced to a completely new environment on the first day, and on subsequent days, novel segments were inserted into the existing spatial environment while the other segments remained the same, allowing us to compare novel and familiar parts of the same closed-loop track on multiple days. We found that spatial novelty leads to dynamic and complex hippocampal place cell firings at both individual neuron and population levels. Place cells in both CA1 and CA2 had strong responses to novel segments, leading to higher average firing rates and increased pairwise cross correlations across all days. However, CA2 place cells that fired for novel areas had lower spatial information scores than CA1 place cells active in the same areas. At the ensemble level, CA1 only responded to spatial novelty on day 1, when the environment was completely novel, whereas CA2 responded to it on all days, each time novelty was introduced. Therefore, CA2 was more sensitive and responsive to novel spatial features even when introduced in a familiar environment, unlike CA1.