Egocentric coding of external items in the lateral entorhinal cortex.

Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations.

Conflicts between local and global spatial frameworks dissociate neural representations of the lateral and medial entorhinal cortex.

Manipulation of spatial reference frames is a common experimental tool to investigate the nature of hippocampal information coding and to investigate high-order processes, such as cognitive coordination. However, it is unknown how the hippocampus afferents represent the local and global reference frames of an environment. To address these issues, single units were recorded in freely moving rats with multi-tetrode arrays targeting the superficial layers of the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two primary cortical inputs to the hippocampus. Rats ran clockwise laps around a circular track partitioned into quadrants covered by different textures (the local reference frame). The track was centered in a circular environment with distinct landmarks on the walls (the global reference frame). Here we demonstrate a novel dissociation between MEC and LEC in that the global frame controlled the MEC representation and the local frame controlled the LEC representation when the reference frames were rotated in equal, but opposite, directions. Consideration of the functional anatomy of the hippocampal circuit and popular models of attractor dynamics in CA3 suggests a mechanistic explanation of previous data showing a dissociation between the CA3 and CA1 regions in their responses to this local-global conflict. Furthermore, these results are consistent with a model of the LEC providing the hippocampus with the external sensory content of an experience and the MEC providing the spatial context, which combine to form conjunctive codes in the hippocampus that form the basis of episodic memory.

Lateral entorhinal neurons are not spatially selective in cue-rich environments.

The hippocampus is a brain region that is critical for spatial learning, context-dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral EC (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue-deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus-an internal, path-integration system and an external, landmark-based system-it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue-rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions.

Theta modulation in the medial and the lateral entorhinal cortices.

Hippocampal neurons show a strong modulation by theta frequency oscillations. This modulation is thought to be important not only for temporal encoding and decoding of information in the hippocampal system, but also for temporal ordering of neuronal activities on timescales at which physiological mechanisms of synaptic plasticity operate. The medial entorhinal cortex (MEC), one of the two major cortical inputs to the hippocampus, is known to show theta modulation. Here, we show that the local field potentials (LFPs) in the other major cortical input to the hippocampus, the lateral entorhinal cortex (LEC), show weaker theta oscillations than those shown in the MEC. Neurons in LEC also show weaker theta modulation than that of neurons in MEC. These findings suggest that LEC inputs are integrated into hippocampal representations in a qualitatively different manner than the MEC inputs. Furthermore, MEC grid cells increase the scale of their periodic spatial firing patterns along the dorsoventral axis, corresponding to the increasing size of place fields along the septotemporal axis of the hippocampus. We show here a corresponding gradient in the tendency of MEC neural firing to skip alternate theta cycles. We propose a simple model based on interference of delta oscillations with theta oscillations to explain this behavior.

Influence of boundary removal on the spatial representations of the medial entorhinal cortex.

The medial entorhinal cortex (MEC) is thought to create and update a dynamical representation of the animal's spatial location. Most suggestive of this process are grid cells, whose firing locations occur periodically in space. Prior studies in small environments were ambiguous as to whether all spatially modulated cells in MEC were variants of grid cells or whether a subset resembled classic place cells of the hippocampus. Recordings from the dorsal and ventral MEC were performed as four rats foraged in a small square box centered inside a larger one. After 6 min, without removing the rat from the enclosure, the walls of the small box were quickly removed, leaving the rat free to continue foraging in the whole area enclosed by the larger box. The rate-responses of most recorded cells (70 out of 93 cells, including 15 of 16 putative interneurons) were considered spatially modulated based on information-theoretic analysis. A number of cells that resembled classic hippocampal place cells in the small box were revealed to be grid cells in the larger box. In contrast, other cells that fired along the boundaries or corners of the small box did not show grid-cell firing in the large box, but instead fired along the corresponding locations of the large box. Remapping of the spatial response in the area corresponding to the small box after the removal of its walls was prominent in most spatially modulated cells. These results show that manipulation of local boundaries can exert a powerful influence on the spatial firing patterns of MEC cells even when the manipulations leave global cues unchanged and allow uninterrupted, self-motion-based localization. Further, they suggest the presence of landmark-related information in MEC, which might prevent cumulative drift of the spatial representation or might reset it to a previously learned configuration in a familiar environment.

Anticipation in the rodent head direction system can be explained by an interaction of head movements and vestibular firing properties.

The rodent head-direction (HD) system, which codes for the animal's head direction in the horizontal plane, is thought to be critically involved in spatial navigation. Electrophysiological recording studies have shown that HD cells can anticipate the animal's HD by up to 75-80 ms. The origin of this anticipation is poorly understood. In this modeling study, we provide a novel explanation for HD anticipation that relies on the firing properties of neurons afferent to the HD system. By incorporating spike rate adaptation and postinhibitory rebound as observed in medial vestibular nucleus neurons, our model produces realistic anticipation on a large corpus of rat movement data. In addition, HD anticipation varies between recording sessions of the same cell, between active and passive movement, and between different studies. Such differences do not appear to be correlated with behavioral variables and cannot be accounted for using earlier models. In the present model, anticipation depends on the power spectrum of the head movements. By direct comparison with recording data, we show that the model explains 60-80% of the observed anticipation variability. We conclude that HD afferent dynamics and the statistics of rat head movements are important in generating HD anticipation. This result contributes to understanding the functional circuitry of the HD system and has methodological implications for studies of HD anticipation.

Cohesiveness of spatial and directional representations recorded from neural ensembles in the anterior thalamus, parasubiculum, medial entorhinal cortex, and hippocampus.

Anatomical and physiological evidence suggests that hippocampal place cells derive their spatial firing properties from the medial entorhinal cortex (MEC) and other parahippocampal areas that send spatial and directional input to the MEC. MEC neurons fire in a precise, geometric pattern, forming a hexagonal grid that tessellates the surface of environments. Similar to place cells and head direction cells, the orientation of grid cell firing patterns can be controlled by visual landmarks, but the cells maintain their firing patterns even in the dark. Place cells and head direction cells can also completely decouple from external landmarks in the light, but it is not known whether the MEC and parahippocampal regions exhibit similar properties or are more explicitly tied to external landmarks. We recorded neurons in the MEC, parasubiculum, and CA1 and head direction cells of the anterior thalamus as the rat's internal direction sense was pitted against a salient visual landmark by slowly rotating the rat in a covered bucket while counter-rotating the visual cue. In different sessions, spatial firing rate maps and head direction tuning curves either rotated their preferred firing locations/directions by the same amount as the bucket rotation or maintained their preferences in the external laboratory framework. In few cases, the firing preferences rotated with the cue card. When cells from different regions were recorded simultaneously, the dominant response in one area almost always matched the response of the other areas. Although dominant responses were consistent throughout the recording regions, CA1 ensembles exhibited a greater degree of response heterogeneity than other regions, which nearly all exhibited internally consistent responses. Thus, the parahippocampal and MEC input to the hippocampus can be controlled by the animal's internal direction sense (presumably reflected in the firing of head direction cells) and become completely decoupled from external sensory input, yet maintain internal coherence with each other and in general with the place cell system of the hippocampus.

Backward shift of head direction tuning curves of the anterior thalamus: comparison with CA1 place fields.

The head direction cell system is composed of multiple regions associated with the hippocampal formation. The dynamics of head direction tuning curves (HDTCs) were compared with those of hippocampal place fields. In both familiar and cue-altered environments, as a rat ran an increasing number of laps on a track, the center of mass (COM) of the HDTC tended to shift backward, similar to shifting observed in place cells. However, important differences existed between these cells in terms of the shift patterns relative to the cue-altered conditions, the proportion of backward versus forward shifts, and the time course of shift resetting. The demonstration of backward COM shifts in head direction cells and place cells suggests that similar plasticity mechanisms (such as temporally asymmetric LTP induction or spike timing-dependent plasticity) may be at work in both brain systems, and these processes may reflect a general mechanism for storing learned sequences of neural activity patterns.

Head direction cell representations maintain internal coherence during conflicting proximal and distal cue rotations: comparison with hippocampal place cells.

Place cells of the hippocampal formation encode a spatial representation of the environment, and the orientation of this representation is apparently governed by the head direction cell system. The representation of a well explored environment by CA1 place cells can be split when there is conflicting information from salient proximal and distal cues, because some place fields rotate to follow the distal cues, whereas others rotate to follow the proximal cues (Knierim, 2002a). In contrast, the CA3 representation is more coherent than CA1, because the place fields in CA3 tend to rotate in the same direction (Lee et al., 2004). The present study tests whether the head direction cell network produces a split representation or remains coherent under these conditions by simultaneously recording both CA1 place cells and head direction cells from the thalamus. In agreement with previous studies, split representations of the environment were observed in ensembles of CA1 place cells in approximately 75% of the mismatch sessions, in which some fields followed the counterclockwise rotation of proximal cues and other fields followed the clockwise rotation of distal cues. However, of 225 recording sessions, there was not a single instance of the head direction cell ensembles revealing a split representation of head direction. Instead, in most of the mismatch sessions, the head direction cell tuning curves rotated as an ensemble clockwise (94%) and in a few sessions rotated counterclockwise (6%). The findings support the notion that the head direction cells may be part of an attractor network bound more strongly to distal landmarks than proximal landmarks, even under conditions in which the CA1 place representation loses its coherence.

Coupling between place cells and head direction cells during relative translations and rotations of distal landmarks.

Hippocampal place cells are selectively active when a rat occupies restricted locations in an environment, and head direction cells fire selectively when the rat's head is pointed in a particular direction in allocentric space. Both place cells and head direction cells are usually coupled, and they are controlled by a complex interaction between external landmarks and idiothetic cues. Most studies have investigated this interaction by rotating the landmarks in the environment. In contrast, a recent study translated the apparatus relative to the landmarks in an environment and found that most place cells maintained the same preferred location on the apparatus regardless of the location of the apparatus in the room. Because head direction cells are insensitive to the rat's location in an environment, the distal landmarks may influence the place field firing locations primarily by controlling the bearing of the head direction cell system. To address this question, ensembles of CA1 place cells and head direction cells of the anterior thalamus were recorded simultaneously, as a rectangular or circular track was moved to different locations in a room with distinct visual landmarks. Most place cells maintained their firing fields relative to the track when the track was translated, and head direction cells maintained the same preferred firing direction. When the distal landmarks were rotated around the track, the firing fields of place cells and the preferred directions of head direction cells rotated with the cues. These results suggest that the precise firing locations of place cells are controlled by an interaction between local and idiothetic cues, and the orientation of the CA1 ensemble representation relative to the distal landmarks may be controlled indirectly by the distal landmarks' influence over the bearing of the head direction cell system.

Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3.

The hippocampus, a critical brain structure for navigation, context-dependent learning and episodic memory, is composed of anatomically heterogeneous subregions. These regions differ in their anatomical inputs as well as in their internal circuitry. A major feature of the CA3 region is its recurrent collateral circuitry, by which the CA3 pyramidal cells make excitatory synaptic contacts on each other. In contrast, pyramidal cells in the CA1 region are not extensively interconnected. Although these differences have inspired numerous theoretical models of differential processing capacities of these two regions, there have been few reports of robust differences in the firing properties of CA1 and CA3 neurons in behaving animals. The most extensively studied of these properties is the spatially selective firing of hippocampal 'place cells'. Here we report that in a dynamically changing environment, in which familiar landmarks on the behavioural track and along the wall are rotated relative to each other, the population representation of the environment is more coherent between the original and cue-altered environments in CA3 than in CA1. These results demonstrate a functional heterogeneity between the place cells of CA3 and CA1 at the level of neural population representations.

Amelioration of fornix lesion induced learning deficits by self-stimulation rewarding experience.

Intracranial self-stimulation (ICSS) rewarding experience is known to modulate learning and memory and induce morphological and neurochemical changes in hippocampus. Therefore, we studied the effect of ICSS on the hippocampus-dependent operant and the spatial learning tasks in rats with bilateral electrolytic lesioning of fornix. Bilateral lesioning of fornix induced deficits in acquisition and performance of both the tasks, whereas exposure to 10 days of ICSS experience from ventral tegmental area reversed these behavioural deficits. Hence, we propose that the ICSS experience ameliorates the fornix lesion induced behavioural deficits, by inducing neuronal plasticity in the hippocampus which may act as a compensatory mechanism for the deficits produced by the lesioning of fornix.

Facilitation of acquisition and performance of operant and spatial learning tasks in self-stimulation experienced rats.

Adult male Wistar rats were implanted bilateraly with bipolar electrodes in substantia nigra-ventral tegmental area (SN-VTA) to experience intracranial self-stimulation (ICSS) for 15 min per day over a period of 10 days. These rats were then assessed for the acquisition and performance of the operant and the spatial learning tasks. ICSS experienced rats showed rapid acquisition of both the operant and the spatial learning tasks. Both the lever press performance for 7 sessions in the operant learning task and mean number of alternations per session in the spatial learning task were significantly higher (p < .001) in ICSS experienced rats compared with controls. The results suggest that prior ICSS experience facilitates the acquisition and performance in both the operant and the spatial learning tasks, which may be due to the structural and neurochemical alterations in the hippocampus induced by ICSS experience.