The role of the medial entorhinal cortex in spatial and temporal coding

The hippocampus (HIPP) is the core of a memory system crucial for the formation of new episodic (unique event) memories in humans and episodic-like memories (for what, where and when) in rodents. Its prevalent role in the formation of memories is thought to rely on a variety of specialized neural network computations: It is for example believed that hippocampal networks associate information about different aspects of an experience (such as a particular event and the place at which the event occurred) into a coherent memory trace. In order to prevent interference between memories that are similar (such as two different experiences within the same place) each memory is assigned a neural code that is highly distinct from those for previously acquired memories. Finally, hippocampal networks are thought to fuse memories for individual fragments of an experience into a temporally structured sequence which represent an episode. Information about different aspects of an experience reaches the HIPP via the entorhinal cortex (EC), which is its major cortical input structure. Electrophysiological single-unit recordings in behaving rodents revealed that in particular the medial division of the EC (MEC) contains a variety of cell types that are specialized in the representation of spatial and self-motion information. It is therefore believed that input from the MEC supports the spatial component of memory processing in the HIPP. Here, we tested the long-standing hypothesis that hippocampal spatial coding relies on input from the MEC. This was achieved by performing extensive, bilateral excitotoxic lesions of the MEC and placing electrode arrays into the CA1 pyramidal cell layer of the HIPP. Hippocampal neural computations were assessed by recording extracellular action potentials (APs) from individual neurons as rats explored open field environments. The firing patterns of hippocampal neurons are known to correlate with the rat’s behavior, in that each cell fires APs at restricted proportions of the environment, forming spatial receptive fields (so-called place fields). The spatial precision and organization of those place fields was examined in control and MEC-lesioned rats. We found that hippocampal neurons retained their spatial selectivity after MEC lesions, even though the precision and stability of the hippocampal spatial code were reduced. The ability to form distinct spatial representation for different environments was entirely intact in MEC-lesioned rats. Contrary to most contemporary theories of hippocampo-entorhinal function, our findings suggest that the MEC is not the only determinant of hippocampal spatial computations and that sources lacking sophisticated spatial firing, such as the lateral division of the entorhinal cortex (LEC) and local hippocampal network computations are sufficient to support this function. Following the finding that spatial firing was partly preserved in MEC-lesioned rats, we tested whether the MEC is necessary for the temporal organization of spike timing within the place field. Hippocampal place cells that are activated along the rat’s trajectory through space are thought to be linked into synaptically connected neuronal sequences via a mechanisms referred to as hippocampal theta phase precession (hTPP). Theta phase precession reflects the temporal distribution of APs within each place field with reference to the local field potential (LFP) oscillation at theta frequency (4 to 10 Hz). We found that hTPP was strongly disrupted in MEC-lesioned rats, demonstrating that the MEC is necessary for the temporal organization of hippocampal spatial firing. Cognitive functions that rely on sequentially activated place cells are thus likely to rely on the MEC. In summary, the presented data demonstrate that the contribution of the MEC to hippocampal spatial coding is less predominant than postulated by contemporary theories of hippocampo-entorhinal function. In addition, the findings suggest that the MEC, which is widely considered a spatial processing center of the brain, supports memory through the temporal organization of hippocampal spatial firing

Hippocampal Global Remapping Can Occur without Input from the Medial Entorhinal Cortex.

The high storage capacity of the episodic memory system relies on distinct representations for events that are separated in time and space. The spatial component of these computations includes the formation of independent maps by hippocampal place cells across environments, referred to as global remapping. Such remapping is thought to emerge by the switching of input patterns from specialized spatially selective cells in medial entorhinal cortex (mEC), such as grid and border cells. Although it has been shown that acute manipulations of mEC firing patterns are sufficient for inducing hippocampal remapping, it remains unknown whether specialized spatial mEC inputs are necessary for the reorganization of hippocampal spatial representations. Here, we examined remapping in rats without mEC input to the hippocampus and found that highly distinct spatial maps emerged rapidly in every individual rat. Our data suggest that hippocampal spatial computations do not depend on inputs from specialized cell types in mEC

The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity.

The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC

Lateral entorhinal cortex is critical for novel object-context recognition

Episodic memory incorporates information about specific events or occasions including spatial locations and the contextual features of the environment in which the event took place. It has been modeled in rats using spontaneous exploration of novel configurations of objects, their locations, and the contexts in which they are presented. While we have a detailed understanding of how spatial location is processed in the brain relatively little is known about where the nonspatial contextual components of episodic memory are processed. Initial experiments measured c-fos expression during an object-context recognition (OCR) task to examine which networks within the brain process contextual features of an event. Increased c-fos expression was found in the lateral entorhinal cortex (LEC; a major hippocampal afferent) during OCR relative to control conditions. In a subsequent experiment it was demonstrated that rats with lesions of LEC were unable to recognize object-context associations yet showed normal object recognition and normal context recognition. These data suggest that contextual features of the environment are integrated with object identity in LEC and demonstrate that recognition of such object-context associations requires the LEC. This is consistent with the suggestion that contextual features of an event are processed in LEC and that this information is combined with spatial information from medial entorhinal cortex to form episodic memory in the hippocampus. © 2013 Wiley Periodicals, Inc.Publisher PDFPeer reviewe

Hippocampal Global Remapping Can Occur without Input from the Medial Entorhinal Cortex

Summary: The high storage capacity of the episodic memory system relies on distinct representations for events that are separated in time and space. The spatial component of these computations includes the formation of independent maps by hippocampal place cells across environments, referred to as global remapping. Such remapping is thought to emerge by the switching of input patterns from specialized spatially selective cells in medial entorhinal cortex (mEC), such as grid and border cells. Although it has been shown that acute manipulations of mEC firing patterns are sufficient for inducing hippocampal remapping, it remains unknown whether specialized spatial mEC inputs are necessary for the reorganization of hippocampal spatial representations. Here, we examined remapping in rats without mEC input to the hippocampus and found that highly distinct spatial maps emerged rapidly in every individual rat. Our data suggest that hippocampal spatial computations do not depend on inputs from specialized cell types in mEC. : Schlesiger et al. find that specialized spatial cells in mEC are not required for generating distinct hippocampal maps across environments. Inputs to the hippocampus, therefore, do not need to be specialized for spatial coding to support hippocampal spatial computations. Keywords: episodic memory, medial entorhinal cortex, hippocampus, place cells, grid cells, border cells, global remapping, hippocampal map

Medial Entorhinal Cortex Lesions Only Partially Disrupt Hippocampal Place Cells and Hippocampus-Dependent Place Memory

The entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC) cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired in the water maze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory, but it is necessary for the normal acquisition of place memory

The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity

The superficial layers of the medial entorhinal cortex (MEC) are the major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that the MEC inputs to the hippocampus are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To therefore determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Strikingly, theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences within the hippocampal theta cycle are particularly dependent on the MEC. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research