Natural phasic inhibition of dopamine neurons signals cognitive rigidity

Abstract

Extinction learning is an essential form of cognitive flexibility, which enables obsolete reward associations to be discarded. Its downregulation can lead to perseveration, a symptom seen in several neuropsychiatric disorders. This balance is regulated by dopamine from VTADA (ventral tegmental area dopamine) neurons, which in turn are largely controlled by GABA (gamma amino-butyric acid) synapses. However, the causal relationship of these circuit elements to extinction and perseveration remain incompletely understood. Here, we employ an innovative drug targeting technology, DART (drug acutely restricted by tethering), to selectively block GABAA receptors on VTADA neurons as mice engage in Pavlovian learning. DART eliminated GABAA mediated pauses; brief decrements in VTADA activity canonically thought to drive extinction learning. However, contrary to the hypothesis that blocking VTADA pauses should eliminate extinction learning, we observed the opposite: accelerated extinction learning. Specifically, DART eliminated the naturally occurring perseveration seen in half of control mice. We saw no impact on Pavlovian conditioning, nor on other aspects of VTADA neural firing. These findings challenge canonical theories, recasting GABAA-mediated VTADA pauses from presumed facilitators of extinction to drivers of perseveration. More broadly, this study showcases the merits of targeted synaptic pharmacology, while hinting at circuit interventions for pathological perseveration.