Thalamic regulation of switching between cortical representations enables cognitive flexibility


Interactions between the prefrontal cortex (PFC) and mediodorsal thalamus are critical for cognitive flexibility, yet the underlying computations are unknown. To investigate frontothalamic substrates of cognitive flexibility, we developed a behavioral task in which mice switched between different sets of learned cues that guided attention toward either visual or auditory targets. We found that PFC responses reflected both the individual cues and their meaning as task rules, indicating a hierarchical cue-to-rule transformation. Conversely, mediodorsal thalamus responses reflected the statistical regularity of cue presentation and were required for switching between such experimentally specified cueing contexts. A subset of these thalamic responses sustained context-relevant PFC representations, while another suppressed the context-irrelevant ones. Through modeling and experimental validation, we find that thalamic-mediated suppression may not only reduce PFC representational interference but could also preserve unused cortical traces for future use. Overall, our study provides a computational foundation for thalamic engagement in cognitive flexibility.

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Fig. 1: Prefrontal neurons display selectivity indicative of a hierarchical cue to rule transformation during attentional switching.
Fig. 2: MD responses reflect the cueing context.
Fig. 3: Flexible switching between contexts is associated with MD-dependent changes in PFC activity.
Fig. 4: Distinct MD neurons augment and suppress context-relevant PFC representations.
Fig. 5: Benefit of PFC–MD over PFC-only architecture on switching contexts.

Data availability

All data are available from the corresponding author upon reasonable request.


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We thank R.D. Wimmer for help with experiments and members of the Halassa Lab for technical assistance and discussions. We also thank W. Gerstner, M. Fee, E. Miller, and M. Wilson for helpful discussions, and we thank J.W. Pillow and D. Zlotowski for advice on the GLM. This work was supported by grants from the National Institutes of Health and from the Brain and Behavior, Klingenstein, Pew, and Simons Foundations, as well as the Human Frontiers Science Program to M.M.H. and the German Federal Ministry of Education and Research to A.G. through a Bernstein Award to R. Memmesheimer.

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R.V.R. conceived and performed experiments, analyzed and interpreted data, and wrote the paper. A.G. developed, simulated, and analyzed the thalamocortical computational model. M.M.H. conceived and supervised experiments, analyzed and interpreted the data, and wrote the paper. M.M.H. also acquired funding.

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Correspondence to Michael M. Halassa.

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Rikhye, R.V., Gilra, A. & Halassa, M.M. Thalamic regulation of switching between cortical representations enables cognitive flexibility. Nat Neurosci 21, 1753–1763 (2018).

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