Single-neuron activity in prefrontal cortex (PFC) is tuned to mixtures of multiple task-related aspects. Such mixed selectivity is highly heterogeneous, seemingly disordered and therefore difficult to interpret. We analysed the neural activity recorded in monkeys during an object sequence memory task to identify a role of mixed selectivity in subserving the cognitive functions ascribed to PFC. We show that mixed selectivity neurons encode distributed information about all task-relevant aspects. Each aspect can be decoded from the population of neurons even when single-cell selectivity to that aspect is eliminated. Moreover, mixed selectivity offers a significant computational advantage over specialized responses in terms of the repertoire of input-output functions implementable by readout neurons. This advantage originates from the highly diverse non-linear selectivity to mixtures of task-relevant variables, a signature of high-dimensional neural representations. Crucially, this dimensionality is predictive of animal behaviour as it collapses in error trials. Our findings suggest to move the focus of attention from neurons that exhibit easily interpretable response tuning to the widely observed, but rarely analysed, mixed selectivity neurons.

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Storing memories of ongoing, everyday experiences requires a high degree of plasticity, but retaining these memories demands protection against changes induced by further activity and experience. Models in which memories are stored through switch-like transitions in synaptic efficacy are good at storing but bad at retaining memories if these transitions are likely, and they are poor at storage but good at retention if they are unlikely. We construct and study a model in which each synapse has a cascade of states with different levels of plasticity, connected by metaplastic transitions. This cascade model combines high levels of memory storage with long retention times and significantly outperforms alternative models. As a result, we suggest that memory storage requires synapses with multiple states exhibiting dynamics over a wide range of timescales, and we suggest experimental tests of this hypothesis.

Summary Spatial working memory, the caching of behaviorally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. While the prefrontal cortex and hippocampus are known to jointly contribute to successful spatial working memory, the anatomical pathway and temporal window for interaction of these structures critical to spatial working memory has not yet been established. Here, we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.

Highlights d The geometry of abstraction supports generalization d Hippocampal and PFC representations are simultaneously abstract and high dimensional d Multiple task-relevant variables are represented in an abstract format d Representations in simulated neural networks are similar to recorded ones