The hippocampus is a key component of the medial temporal lobe memory system that is essential for the formation of new, autobiographical memories. Work in our laboratory attempts to understand the flow of information through the hippocampal formation and the computations performed by the various subfields of the hippocampus and its input structures. To address these issues, we use multi-electrode arrays to record the extracellular action potentials from scores of well-isolated hippocampal neurons in freely moving rats. These neurons have the fascinating property of being selectively active when the rat occupies restricted locations in its environment. They are termed “place cells,” and it has been suggested that these cells form a cognitive map of the environment (O’Keefe and Nadel, The hippocampus as a cognitive map, 1978). The animal uses this map to navigate efficiently in its environment and to learn and remember important locations. It is hypothesized that these cells play a major role in the formation of episodic (autobiographical) memories, perhaps by providing an internal, spatial framework used to organize and store the different components of a particular experience. The spatial framework is hypothesized to come from special neurons called “grid cells” in the medial entorhinal cortex. External sensory information is hypothesized to come from high-order sensory neurons in the lateral entorhinal cortex. Place cells are hypothesized to combine the “where” information from the medial entorhinal cortex with the “what” information from the lateral entorhinal cortex to create context-specific, conjunctive representations of “what happened where.” This neural system constitutes a tremendous opportunity to investigate the mechanisms by which the brain transforms sensory input into an internal, cognitive representation of the world “out there” and then uses this representation as the framework that organizes and stores memories of past events.
Hippocampal place cells fire selectively when a rat occupies a particular location. Shown below are pictures of a rat foraging for food inside a box and on a circular track. Three examples of place fields recorded in each environment are shown to the right of the pictures. Warmer colors in the place-field firing rate maps indicate levels of higher neuronal activity with red being the highest. Blue indicates no firing. Thus, in the box, the first cell illustrated fires selectively when the rat is near the North wall (by the white cue); the second cell fires selectively when the rat is near the center of the box; and the third cell fires selectively when the rat is at the Southeast corner of the box. The examples at the bottom show cells that fire selectively at different locations on the track. These place fields are controlled by a complex interaction among local cues, global landmarks, and self-motion cues (e.g., vestibular senses).
Our laboratory performs experiments in which we manipulate the various cues that control place fields and record how the various components of the hippocampus respond to these manipulations. From these results, we attempt to deduce the neural representations and computations performed by each region. One experimental paradigm we use is the double rotation protocol, in which the rats are trained to run clockwise for food reward on a circular track composed of quadrants of different textures. In addition to these local cues, there are distal cues at the periphery of the visible environment. On the experimental day, we run the rat in the standard cue configuration, followed by a session in which the local cues are rotated counterclockwise and the distal cues are rotated clockwise an equal amount. This “mismatch” of local and distal cues elicits complex responses from populations of place cells in the hippocampus, as some place cells follow the local cues by rotating counter-clockwise while others follow the distal cues by rotating clockwise. A subset of cells respond ambiguously with no clear relationship to either the local or distal cues and other place cells turn on or shut off.
Although place cells have been studied for over 30 years, we are still in the initial stages of exploring and understanding these cells. Although the hippocampus is composed of anatomically heterogeneous subregions, until recently, place field studies have overwhelmingly focused on only a small portion of the hippocampus, the CA1 subfield. Using high-density recording techniques, our lab records simultaneously from multiple subfields of the hippocampal formation, or from portions of the hippocampus in concert with input structures such as the entorhinal cortex.
The CA1 and CA3 subfields of the hippocampus differ in their anatomical inputs as well as in their internal circuitry. CA3 pyramidal cells project to CA1, but a significant number of connections are made within CA3 itself. These “recurrent collaterals” are hypothesized to endow CA3 place cells with different properties than those of CA1 place cells. For many years, investigators were unable to find major differences between the properties of CA1 and CA3 place fields. In 2004, using the double rotation protocol, our laboratory published the first two papers demonstrating robust, functional differences between CA3 and CA1 place fields (Lee et al., PDF Document: 2004a, PDF Document: 2004b). In accordance with attractor neural network theories, we predicted that the recurrent circuitry in CA3 would generate a coherent response from the population of CA3 place cells when the local-global cue mismatch was detected. In contrast, we predicted a heterogeneous pattern of responses from CA1, which lacks the recurrent circuitry of CA1. The following figure demonstrates that these predictions were verified (Lee et al., PDF Document: 2004b). Each matrix shows the correlation between the firing of a population of CA1 (left) or CA3 (right) cells in a standard (STD) session and in a double-rotation mismatch (MIS) session. When the mismatch was only 45°, place field maps were similar between the STD and MIS sessions for both CA1 and CA3 populations (indicated by the high band of correlation [red] along the diagonal of the matrix). When the mismatch was 90° or more, the correlation structure broke down in CA1. However, the high band of correlation was maintained in CA3 (although shifted from the diagonal, indicating that the CA3 map was controlled by the local cues on the track). These results indicated that the CA3 population responded more coherently to the manipulation than did the CA1 population, as predicted by computational theories of attractor networks and pattern completion/generalization.
We also discovered in these large datasets other intriguing differences between CA1 and CA3. For example, it was previously known that when a rat repeatedly runs through a place field on a linear track, CA1 place fields shift backwards lap-by-lap. This result is believed to reflect the encoding and storage of memories of learned sequences. Our lab discovered that this phenomenon is differentially expressed in CA3 and CA1 (Lee et al., PDF Document: 2004a). Whereas CA1 expressed the backward shift in every standard and mismatch session except the very first mismatch session, CA3 expressed the shift only in the rat’s first experience in the novel mismatch session. Based on an analysis of the shape of the place fields, we concluded that the sequence memory is stored rapidly and enduringly within CA3 (perhaps in the recurrent collaterals), whereas the memories are only temporarily stored in CA1. This difference is consistent with longstanding ideas that CA1 may act as a comparator between representations about the current state of the world from the entorhinal cortex and representations of stored memories from CA3.
Current projects in the lab involve extending this work to include recordings from the dentate gyrus and entorhinal cortex. The properties of place cells in the dentate gyrus are strikingly different than in other hippocampal areas as the proportion of granule cells with place fields in a given environment is much smaller than in CA1 or CA3. A number of investigators have hypothesized that the function of the dentate gyrus may be to perform pattern separation, the transformation of similar representations into highly dissimilar, nonoverlapping representations. We are using the double rotation paradigm to test this theory by recording from hippocampal inputs of the entorhinal cortex (see next section) and from the dentate gyrus to determine if the dentate representations of the standard and mismatch environments are less correlated than their input representations.
Hippocampal Inputs: Lateral vs. Medial Entorhinal Cortex
One underlying principle of research in our lab is that the computations performed in the hippocampus cannot be understood without first understanding the nature of the hippocampal input representations. The hippocampus has two major inputs: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC)
The remarkable discovery of grid cells in (MEC) has received enormous attention in the field (Hafting et al., 2005). Grid cells fire in multiple places in the environment, in an exquisitely crystalline, repeated hexagonal pattern. The grid cells of dorsal MEC display a fine-scale grid pattern, with multiple vertices within a recording chamber. In contrast, the grid cells of progressively more ventral MEC display more coarse-scale grids (see figure). Our laboratory published the first report that showed that some MEC cells also responded to the boundaries of an environment (Savelli et al., PDF Document: 2008). This signal may be important for binding the grid cells to the boundaries, thereby stabilizing the MEC internal spatial representation relative to the external world.
The other major cortical input to the hippocampus originates in the LEC. Our lab discovered a major dissociation between LEC and MEC in that lateral entorhinal cortical (LEC) does not show any robust spatial firing properties (neither grid cells or place cells) under standard recording conditions (Hargreaves et al., PDF Document: 2005). The firing rate maps below show strong spatial tuning of MEC cells but very weak spatial firing in LEC.
We have shown recently that cells in the superficial layer of lateral entorhinal cortex fire when the rat is investigating objects. This is consistent with the notion that LEC is sending predominantly non-spatial information to the hippocampus. Multi-electrode recording in LEC has allowed us to document a number of response types in this region such as firing to familiar objects, memory of object location as indicated by the cell continuing to fire in the location even after the object has been moved, and recognition of a novel object in the environment.
The convergence of LEC non-spatial information and MEC spatial information in the hippocampus lends support to the idea that episodic memory, the memory for “what happened”, “where it happened”, and “when it happened” is constructed in the hippocampus. Current experiments in our lab are further characterizing the spatial input from medial entorhinal cortex and the non-spatial input from the lateral entorhinal cortex.
Our lab also engages in computational modeling of various phenomena seen in the neurophysiological data we have collected from the hippocampus and entorhinal cortex. For example, one model describes how the multi-peaked firing of grid cells may be transformed into the single-peaked firing of hippocampal place cells. The model theorizes how inputs from grid cells onto place cells may be selected and how place fields may develop in a novel environment as a result of plasticity in the network. (Savelli et al., PDF Document: 2010).
Another computational project, in collaboration with Kechen Zhang of the Dept. of Biomedical Engineering, seeks to explain the changes in place field firing or “remapping” seen when the animal is exposed to novel spatial configurations as in the double rotation protocol. Place fields in the hippocampus consist of both a firing-rate component and a temporal component defined by spike-phase precession relative to the local theta rhythm. Previous models based on oscillatory phase interference can account for phase precession, but not for the remapping that can occur when an animal is exposed to novel spatial information. A novel room may elicit complete remapping, in which the population spatial code becomes statistically independent, but subtler cue manipulations can induce partial remapping in which some degree of coherence with previous representations is retained. We constructed and are analyzing a model of spatial coding based on spatial envelopes created by interfering oscillators that explains graded remapping as well as all-or-none complete remapping.