Dakota F. Brockway, Samuel L. Boehm, Nilah D. Jordan, Max E. Joffe

Alcohol use disorder is characterized by maladaptive decision making and persistent alcohol seeking, yet the circuit mechanisms within the prefrontal cortex that drive alcohol motivation remain poorly understood. Vasoactive intestinal peptide (VIP) interneurons are powerful regulators of cortical network activity through disinhibitory circuit motifs and VIP neuromodulatory signaling. However, the role of VIP interneurons in alcohol-related behaviors has not been established. We investigated how VIP signaling in the prelimbic prefrontal cortex regulates alcohol motivation and prefrontal circuit activity. Whole-cell patch clamp electrophysiology revealed that VIP directly depolarizes VIP interneurons, suggesting that VIP signaling can amplify VIP interneuron activity within cortical circuits. Consistent with this mechanism, intoxicating doses of systemic alcohol administration increased calcium activity in VIP neurons measured using fiber photometry in vivo. To determine whether VIP neuron activity contributes to alcohol seeking, we manipulated VIP neurons during operant alcohol self-administration. Chemogenetic activation of VIP neurons significantly increased motivation for alcohol under progressive ratio schedules, indicating that VIP neuron activity promotes alcohol-seeking behavior. In addition to regulating interneuron activity, VIP signaling differentially modulated layer 5 pyramidal neurons depending on projection subtype. Electrophysiological recordings revealed that VIP excitation enhanced excitability in extratelencephalic neurons while suppressing action potential firing in intratelencephalic neurons, suggesting that VIP signaling may bias prefrontal output toward specific downstream circuits. Together, these findings identify VIP interneurons as a previously unrecognized regulator of alcohol motivation and suggest that alcohol recruits VIP signaling to reshape prefrontal cortical output.