Medial entorhinal cortex (MEC) supports a wide range of navigational and memory related behaviors.Well-known experimental results have revealed specialized cell types in MEC --- e.g. grid, border, and head-direction cells --- whose highly stereotypical response profiles are suggestive of the role they might play in supporting MEC functionality. However, the majority of MEC neurons do not exhibit stereotypical firing patterns.How should the response profiles of these more "heterogeneous" cells be described, and how do they contribute to behavior?In this work, we took a computational approach to addressing these questions.We first performed a statistical analysis that shows that heterogeneous MEC cells are just as reliable in their response patterns as the more stereotypical cell types, suggesting that they have a coherent functional role.Next, we evaluated a spectrum of candidate models in terms of their ability to describe the response profiles of both stereotypical and heterogeneous MEC cells.We found that recently developed task-optimized neural network models are substantially better than traditional grid cell-centric models at matching most MEC neuronal response profiles --- including those of grid cells themselves --- despite not being explicitly trained for this purpose.Specific choices of network architecture (such as gated nonlinearities and an explicit intermediate place cell representation) have an important effect on the ability of the model to generalize to novel scenarios, with the best of these models closely approaching the noise ceiling of the data itself.We then performed in silico experiments on this model to address questions involving the relative functional relevance of various cell types, finding that heterogeneous cells are likely to be just as involved in downstream functional outcomes (such as path integration) as grid and border cells.Finally, inspired by recent data showing that, going beyond their spatial response selectivity, MEC cells are also responsive to non-spatial rewards, we introduce a new MEC model that performs reward-modulated path integration.We find that this unified model matches neural recordings across all variable-reward conditions.Taken together, our results point toward a conceptually principled goal-driven modeling approach for moving future experimental and computational efforts beyond overly-simplistic single-cell stereotypes.

Neural Coding analyses often reflect an assumption that neural populations respond uniquely and consistently to particular stimuli. For example, analyses of spatial remapping in hippocampal populations often assume that each environment has one unique representation and that remapping occurs over long time scales as an animal traverses between distinct environments. However, as neuroscience experiments begin to explore more naturalistic tasks and stimuli, and reflect more ambiguity in neural representations, methods for analyzing population neural codes must adapt to reflect these features. In this paper, we develop a new state-space modeling framework to address two important issues related to remapping. First, neurons may exhibit significant trial-to-trial or moment-to-moment variability in the firing patterns used to represent a particular environment or stimulus. Second, in ambiguous environments and tasks that involve cognitive uncertainty, neural populations may rapidly fluctuate between multiple representations. The state-space model addresses these two issues by integrating an observation model, which allows for multiple representations of the same stimulus or environment, with a state model, which characterizes the moment-by-moment probability of a shift in the neural representation. These models allow us to compute instantaneous estimates of the stimulus or environment currently represented by the population. We demonstrate the application of this approach to the analysis of population activity in the CA1 region of hippocampus of a mouse moving through ambiguous virtual environments. Our analyses demonstrate that many hippocampal cells express significant trial-to-trial variability in their representations and that the population representation can fluctuate rapidly between environments within a single trial when spatial cues are most ambiguous.

Models of the hexagonally arrayed spatial activity pattern of grid cell firing in the literature generally fall into two main categories: continuous attractor models or oscillatory interference models. Burak and Fiete (2009, PLoS Comput Biol) recently examined noise in two continuous attractor models, but did not consider oscillatory interference models in detail. Here we analyze an oscillatory interference model to examine the effects of noise on its stability and spatial firing properties. We show analytically that the square of the drift in encoded position due to noise is proportional to time and inversely proportional to the number of oscillators. We also show there is a relatively fixed breakdown point, independent of many parameters of the model, past which noise overwhelms the spatial signal. Based on this result, we show that a pair of oscillators are expected to maintain a stable grid for approximately t = 5mu(3)/(4pisigma)(2) seconds where mu is the mean period of an oscillator in seconds and sigma(2) its variance in seconds(2). We apply this criterion to recordings of individual persistent spiking neurons in postsubiculum (dorsal presubiculum) and layers III and V of entorhinal cortex, to subthreshold membrane potential oscillation recordings in layer II stellate cells of medial entorhinal cortex and to values from the literature regarding medial septum theta bursting cells. All oscillators examined have expected stability times far below those seen in experimental recordings of grid cells, suggesting the examined biological oscillators are unfit as a substrate for current implementations of oscillatory interference models. However, oscillatory interference models can tolerate small amounts of noise, suggesting the utility of circuit level effects which might reduce oscillator variability. Further implications for grid cell models are discussed.