A claustro-cortical loop times state transitions for flexible behavior.

Metastable dynamics, in which neural activity moves between transiently stable patterns, have been proposed to underlie the real-time coordination on which the brain's cognitive and behavioral functions depend 1-3 . In the cortex, the simplest form of this regime is the alternation between active 'UP' states, in which neurons fire, and silent 'DOWN' states, in which firing is strongly reduced, a bistable architecture that shapes how afferent information is processed 4-8 . Such metastable dynamics are ubiquitous across cortex 9,10 , yet how their state transitions are timed and controlled, and how this timing shapes behavior, remain open questions. Here we show, in freely behaving mice performing a cue-guided switching task, that the metastable dynamics of frontal cortex are jointly shaped by its reciprocal loop with the claustrum, a small and widely connected subcortical structure, and that the loop's timing of these state transitions is required for efficient flexible behavior. Claustrum activity led the cortical UP-to-DOWN state transition, delivering to anterior cingulate cortex a low-dimensional drive aligned with the axis along which the cortical state switches. This drive was carried not by a rise in claustral firing but by transient coordination: population synchrony peaked at the transition even as mean rate fell. Silencing ACC-projecting claustrum terminals reduced directed claustro-cortical coupling, biased cortex away from the DOWN state by prolonging UP states and shortening DOWN states, and selectively impaired cue-driven switching while sparing exploratory foraging. These results place flexible behavior under the control of a defined cortico-subcortical loop that times cortical state transitions, offering a circuit-level entry point into the cognitive rigidity of many psychiatric and neurological conditions 11-13 .