Natural phasic inhibition of dopamine neurons signals cognitive rigidity.

Abstract

When animals unexpectedly fail, their dopamine neurons undergo phasic inhibition that canonically drives extinction learning, a cognitive-flexibility mechanism for discarding outdated strategies. However, the existing evidence equates natural and artificial phasic inhibition, despite their spatiotemporal differences. Addressing this gap, we targeted a GABAA-receptor antagonist precisely to dopamine neurons, yielding three unexpected findings. First, this intervention blocked natural phasic inhibition selectively, leaving tonic activity unaffected. Second, blocking natural phasic inhibition accelerated extinction learning, opposite to canonical mechanisms. Third, our approach selectively benefitted perseverative mice, restoring rapid extinction without affecting new reward learning. Our findings reveal that extinction learning is rapid by default and slowed by natural phasic inhibition, challenging foundational learning theories, while delineating a synaptic mechanism and therapeutic target for cognitive rigidity.