Nature. 2026 May 6. doi: 10.1038/s41586-026-10443-5. Online ahead of print.
ABSTRACT
Cognitive flexibility refers to the adaptive neural processes that adjust learned behaviours as circumstances shift, supporting optimal decision-making and behavioural control. This includes the capacity to modify specific behaviours as the contingency between cues and rewards degrades. Across species1-4, the medial prefrontal cortex (mPFC) has a well-established role in controlling contingency degradation5; however, the precise neural circuit mechanisms underlying this cognitive process remain unclear. To address this gap, we developed a quantitative model of cognitive flexibility that incorporates a meta-learning parameter into an established reward prediction error learning model6,7. Our meta-reward prediction error model significantly improves accurate representation of mouse cue-evoked licking behaviour in response to degraded or enhanced cue-reward associations. Using longitudinal two-photon calcium imaging and single-cell holographic optogenetics, we found that a subset of neurons in the mPFC specifically encode the contingency degradation in a significant and causal manner. Recognizing that behavioural flexibility probably requires interactions between the mPFC and canonical reward learning circuitry, we then examined how mPFC neural signalling during contingency degradation interacts with the ventral tegmental area (VTA)-a critical hub for reward processing8. Our imaging and optogenetics data show that mPFC sends this signal to VTA, with most mPFC→VTA neurons reflecting this transmission, and that selective optogenetic stimulation of these ensembles accelerates contingency degradation. These findings reveal how prefrontal circuits facilitate flexibility, selectively halting learned behaviours through connections with subcortical reward networks.
PMID:42092148 | DOI:10.1038/s41586-026-10443-5
