Dopamine D1 Receptor on Vasoactive Intestinal Polypeptide-Expressing Interneurons in the Orbitofrontal Cortex Regulates Spatial Working Memory Acquisition in Mice

GABAergic vasoactive intestinal polypeptide-positive (VIP+) interneurons represent a primary interneuron subclass in the cortex, known for their disinhibitory role in local microcircuits, their regulation of sensory gain, and their modulation of goal-oriented learning. The orbitofrontal cortex (OFC) is essential for decision-making and functions as a key node in the dopamine-mediated reward pathway. To investigate the importance of dopamine signaling in OFC VIP+ interneurons during working memory, we evaluated the role of the dopamine D1 receptor (D1R). We found that cell-type-specific knockdown of D1R did not alter the basal activity of VIP+ interneurons or the general behavior of mice. However, this knockdown compromised the D1R-mediated regulation of VIP+ neuronal output. Notably, the deficit of D1R in the VIP+ interneurons of the OFC specifically impaired the acquisition of working memory in the reward-alternation T-maze test.