The Lights Are On But Nobody's Home: Dissecting Prefrontal Cortex Contributions to Working Memory via Optogenetic Inhibition.

Abstract

Working memory enables the brain to store and manipulate information across time, yet the neural mechanisms that support this function remain debated. This study examines the causal role of the prefrontal cortex in working memory by employing optogenetic inhibition in mice engaged in a Parametric Working Memory task. In this task, head-fixed mice compare the temporal frequencies of two sequential visual stimuli separated by a delay period, turning left or right in a virtual T-maze based on the comparison. Using temporally targeted optogenetic suppression of inhibitory interneurons, we tested three hypotheses: (1) whether the PFC is necessary for task performance; (2) whether it specifically supports memory retention during the delay period; and (3) whether its contributions are magnified under high task difficulty. Surprisingly, PFC inactivation did not significantly impair behavioral accuracy, shift choice patterns, or disrupt stimulus-guided decision-making—even under cognitively demanding conditions. Logistic regression and psychometric analyses revealed preserved decision strategies and stimulus sensitivity during PFC suppression. Although subtle modulations in decision dynamics were observed, they did not reach statistical significance. These results suggest that the PFC may play a modulatory—but not essential—role in working memory, with core memory representations likely maintained by distributed circuits.