Grid cells recorded in medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4–11 Hz). 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 generation of entorhinal grid cell periodicity and head direction selectivity.

ABSTRACT:As a rat navigates through a familiar environment, its position in space is encoded by firing rates of place cells and grid cells. Oscillatory interference models propose that this positional firing rate code is derived from a phase code, which stores the rat's position as a pattern of phase angles between velocity-modulated theta oscillations. Here we describe a three-stage network model, which formalizes the computational steps that are necessary for converting phase-coded position signals (represented by theta oscillations) into rate-coded position signals (represented by grid cells and place cells). The first stage of the model proposes that the phase-coded position signal is stored and updated by a bank of ring attractors, like those that have previously been hypothesized to perform angular path integration in the head-direction cell system. We show analytically how ring attractors can serve as central pattern generators for producing velocity-modulated theta oscillations, and we propose that such ring attractors may reside in subcortical areas where hippocampal theta rhythm is known to originate. In the second stage of the model, grid fields are formed by oscillatory interference between theta cells residing in different (but not the same) ring attractors. The model's third stage assumes that hippocampal neurons generate Gaussian place fields by computing weighted sums of inputs from a basis set of many grid fields. Here we show that under this assumption, the spatial frequency spectrum of the Gaussian place field defines the vertex spacings of grid cells that must provide input to the place cell. This analysis generates a testable prediction that grid cells with large vertex spacings should send projections to the entire hippocampus, whereas grid cells with smaller vertex spacings may project more selectively to the dorsal hippocampus, where place fields are smallest. V

Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers.

Intrinsic persistent spiking mechanisms in medial entorhinal cortex (mEC) neurons may play a role in active maintenance of working memory. However, electrophysiological studies of rat mEC units have primarily focused on spatial modulation. We sought evidence of differential spike rates in the mEC in rats trained on a T-maze, cued spatial delayed response task. Animals begin at the base of the T-maze where a 1-sec white noise and visual light cue are presented on the left or right side of the maze. Rats are rewarded for responding toward the cued direction. In correct trials, we observed decreased spike rates during the delay period, the time interval between cue presentation and reward delivery. Firing-rate histograms show significant decreases during the delay period compared to 5-sec windows from both pre-cue and post-reward periods. We analyzed how running speed and trajectory specificity correlated to spike rate. Twice as many cells were responsive to cue alone compared to running speed. Trajectory specificity did not relate significantly to firing rate. Decreased spike rate may reflect active maintenance in other structures inhibiting mEC. Alternately, the reduction may reflect decreases in background activity during enhanced attention and cholinergic modulation. Lastly, animals often ran through the T-maze choice-point with varying speed. We calculated the spatial posterior probability density from spike rates during these choice-point passes. Slow passes through the choice point were characterized by greater probability of decoding to the reward locations on correct trials compared to quick passes on the maze consistent with similar "look-ahead" properties previously reported in the hippocampus and ventral striatum.[Supplemental material is available for this article.]Multiple memory systems play a role in decision-making mechanisms in animals performing behavioral tasks. Of these systems, working memory provides a temporary store for information during performance of cognitive tasks (Baddeley and Wilson 2002;Hasselmo and Stern 2006). Previous studies in animals suggest that localized networks in the prefrontal cortex perform active maintenance of neural activity representing familiar stimuli in delayed-match-to-sample tasks (Fuster 1973), cued-choice behavior (Fujisawa et al. 2008), and object recognition (Asaad et al. 1998). However, parahippocampal structures have also been implicated as a buffer for working memory in rodents and primates (Hasselmo and Stern 2006). Unit recording has demonstrated entorhinal neurons that fire during the delay period of delayedmatch-to-sample tasks in rats (Young et al. 1997) and monkeys (Suzuki et al. 1997).Intracellular recording from in vitro slice preparations of rat medial entorhinal cortex (mEC) demonstrates neurons that persistently spike after a single depolarization during pharmacological activation of acetylcholine receptors (Klink and Alonso 1997;Egorov et al. 2002;Yoshida et al. 2008). Several computational models have demonstrated how these intrinsic mechani...

The p.(Val113Ile) mutation results in an alteration of the atypical LCD phenotype associated with the p.(Leu558Pro) mutation. This represents only the second report of the alteration of the phenotype of a dystrophy by a second, non-homozygous pathogenic mutation, and thus provides insight into the phenotype-genotype correlation of the dystrophies.