Prefronto-thalamic control of cognitive flexibility – from mice to humans

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Besides processing and relaying sensory inputs to the cerebral cortex, there is ample evidence for the crucial involvement of the thalamus in various cognitive functions. One of these functions is cognitive flexibility, classically attributed to the prefrontal cortex (PFC), but which, according to recent empirical evidence, crucially depends on reciprocal connections anchored in the mediodorsal nucleus (MD) of the thalamus. For example, when mice decide between different sets of learned cues that direct attention to either visual or auditory targets, responses from the medial PFC reflect both the individual cues as well as their importance as task rule. The MD, on the other hand, appears to facilitate switching between cueing contexts by supporting or suppressing task-associated representations in the PFC with excitatory or inhibitory projections. This suggests that MD cells continuously track the statistical rules of cue associations. Whether such interactions between MD and prefrontal regions exist in the human brain, and whether they have comparable importance as those in mice, remains speculative. In the proposed functional magnetic resonance imaging (fMRI) study, we are addressing this challenging question. In collaboration with the group of Prof. Michael Halassa (Mc Govern Institute, Massachusetts Institute of Technology, Cambridge, MA, USA) we jointly investigated preliminary evidence for changes in effective connectivity between the MD and prefrontal representations using re-analyses of previously published fMRI data from healthy human subjects. In agreement with results from mice, we showed that when subjects changed their decision strategy, efferent projections originating in the MD had an excitatory influence on task-associated OFC representations involved in strategy switches, whereas OFC regions, responsible for strategy maintenance, received inhibitory projections from the MD. In the here proposed project, we shall investigate further networks connecting the MD to other prefrontal and limbic brain regions using a variant of the original cross-modal sensory attention task for mice. The newly developed fMRI design also allows to extend the existing MD network model by statistically disentangling behavioral and brain networks that serve strategy switching from those that allow perceptual switching. In addition, we question the extent to which reward and punishment modulate MD network interactions, and whether these processes underlie dopaminergic mechanisms.