Mark P. Brandon

Reduction of Theta Rhythm Dissociates Grid Cell Spatial Periodicity from Directional Tuning

Inhibition of neuronal activity in the medial septum stops grid cells in the medial entorhinal cortex from firing in a grid. Grid cells recorded in the medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4 to 11 hertz). We analyzed grid cell spatial coding during reduction of network theta rhythm oscillations caused by medial septum (MS) inactivation with muscimol. During MS inactivation, grid cells lost their spatial periodicity, whereas head-direction cells maintained their selectivity. Conjunctive grid–by–head-direction cells lost grid cell spatial periodicity but retained head-direction specificity. All cells showed reduced rhythmicity in autocorrelations and cross-correlations. This supports the hypothesis that spatial coding by grid cells requires theta oscillations, and dissociates the mechanisms underlying the generation of entorhinal grid cell periodicity and head-direction selectivity.

New and Distinct Hippocampal Place Codes Are Generated in a New Environment during Septal Inactivation

The hippocampus generates distinct neural codes to disambiguate similar experiences, a process thought to underlie episodic memory function. Entorhinal grid cells provide a prominent spatial signal to hippocampus, and changes in their firing pattern could thus generate a distinct spatial code in each context. We examined whether we would preclude the emergence of new spatial representations in a novel environment during muscimol inactivation of the medial septal area, a manipulation known to disrupt theta oscillations and grid cell firing. We found that new, highly distinct configurations of place fields emerged immediately and remained stable during the septal inactivation. The new place code persisted when theta oscillations had recovered. Theta rhythmicity and feedforward input from grid cell networks were thus not required to generate new spatial representations in the hippocampus.

During running in place, grid cells integrate elapsed time and distance run

The spatial scale of grid cells may be provided by self-generated motion information or by external sensory information from environmental cues. To determine whether grid cell activity reflects distance traveled or elapsed time independent of external information, we recorded grid cells as animals ran in place on a treadmill. Grid cell activity was only weakly influenced by location, but most grid cells and other neurons recorded from the same electrodes strongly signaled a combination of distance and time, with some signaling only distance or time. Grid cells were more sharply tuned to time and distance than non-grid cells. Many grid cells exhibited multiple firing fields during treadmill running, parallel to the periodic firing fields observed in open fields, suggesting a common mode of information processing. These observations indicate that, in the absence of external dynamic cues, grid cells integrate self-generated distance and time information to encode a representation of experience.

Linking Cellular Mechanisms to Behavior: Entorhinal Persistent Spiking and Membrane Potential Oscillations May Underlie Path Integration, Grid Cell Firing, and Episodic Memory

The entorhinal cortex plays an important role in spatial memory and episodic memory functions. These functions may result from cellular mechanisms for integration of the afferent input to entorhinal cortex. This article reviews physiological data on persistent spiking and membrane potential oscillations in entorhinal cortex then presents models showing how both these cellular mechanisms could contribute to properties observed during unit recording, including grid cell firing, and how they could underlie behavioural functions including path integration. The interaction of oscillations and persistent firing could contribute to encoding and retrieval of trajectories through space and time as a mechanism relevant to episodic memory.

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.

A Model Combining Oscillations and Attractor Dynamics for Generation of Grid Cell Firing

Different models have been able to account for different features of the data on grid cell firing properties, including the relationship of grid cells to cellular properties and network oscillations. This paper describes a model that combines elements of two major classes of models of grid cells: models using interactions of oscillations and models using attractor dynamics. This model includes a population of units with oscillatory input representing input from the medial septum. These units are termed heading angle cells because their connectivity depends upon heading angle in the environment as well as the spatial phase coded by the cell. These cells project to a population of grid cells. The sum of the heading angle input results in standing waves of circularly symmetric input to the grid cell population. Feedback from the grid cell population increases the activity of subsets of the heading angle cells, resulting in the network settling into activity patterns that resemble the patterns of firing fields in a population of grid cells. The properties of heading angle cells firing as conjunctive grid-by-head-direction cells can shift the grid cell firing according to movement velocity. The pattern of interaction of oscillations requires use of separate populations that fire on alternate cycles of the net theta rhythmic input to grid cells.

Segregation of cortical head direction cell assemblies on alternating theta cycles

High-level cortical systems for spatial navigation, including entorhinal grid cells, critically depend on input from the head direction system. We examined spiking rhythms and modes of synchrony between neurons participating in head direction networks for evidence of internal processing, independent of direct sensory drive, which may be important for grid cell function. We found that head direction networks of rats were segregated into at least two populations of neurons firing on alternate theta cycles (theta cycle skipping) with fixed synchronous or anti-synchronous relationships. Pairs of anti-synchronous theta cycle skipping neurons exhibited larger differences in head direction tuning, with a minimum difference of 40 degrees of head direction. Septal inactivation preserved the head direction signal, but eliminated theta cycle skipping of head direction cells and grid cell spatial periodicity. We propose that internal mechanisms underlying cycle skipping in head direction networks may be critical for downstream spatial computation by grid cells.

Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory

Understanding the mechanisms of episodic memory requires linking behavioral data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action.

Head direction is coded more strongly than movement direction in a population of entorhinal neurons.

The spatial firing pattern of entorhinal grid cells may be important for navigation. Many different computational models of grid cell firing use path integration based on movement direction and the associated movement speed to drive grid cells. However, the response of neurons to movement direction has rarely been tested, in contrast to multiple studies showing responses of neurons to head direction. Here, we analyzed the difference between head direction and movement direction during rat movement and analyzed cells recorded from entorhinal cortex for their tuning to movement direction. During foraging behavior, movement direction differs significantly from head direction. The analysis of neuron responses shows that only 5 out of 758 medial entorhinal cells show significant coding for both movement direction and head direction when evaluating periods of rat behavior with speeds above 10 cm/s and ±30° angular difference between movement and head direction. None of the cells coded movement direction alone. In contrast, 21 cells in this population coded only head direction during behavioral epochs with these constraints, indicating much stronger coding of head direction in this population. This suggests that the movement direction signal required by most grid cell models may arise from other brain structures than the medial entorhinal cortex. This article is part of a Special Issue entitled SI: Brain and Memory.

2009 Special Issue: A phase code for memory could arise from circuit mechanisms in entorhinal cortex

Neurophysiological data reveals intrinsic cellular properties that suggest how entorhinal cortical neurons could code memory by the phase of their firing. Potential cellular mechanisms for this phase coding in models of entorhinal function are reviewed. This mechanism for phase coding provides a substrate for modeling the responses of entorhinal grid cells, as well as the replay of neural spiking activity during waking and sleep. Efforts to implement these abstract models in more detailed biophysical compartmental simulations raise specific issues that could be addressed in larger scale population models incorporating mechanisms of inhibition.