Abstract Behavioral flexibility refers to the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a novel context-dependent bilateral tactile detection task where mice responded to left and right whisker deflections in a rule-dependent manner and exhibited varying degrees of flexible switching behavior. Recording from optogenetically-tagged neurons in the LC during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation improved task performance and accelerated task switching. Overall, our study provides strong evidence to demonstrate that LC activity mediates behavioral flexibility.

The locus coeruleus mediates behavioral flexibility