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bioRxiv · 10.64898/2026.04.01.715945

INTERFERON-REGULATORY FACTOR 7: A NEUROIMMUNE ROLE FOR VAPOR-INDUCED ESCALATIONS IN ETHANOL SELF-ADMINISTRATION

Lovelock, D. F.·Carew, J. M.·McNair, E. M.·Materia, B. M.·Darawsheh, S.·Downs, A. M.·Sizer, S. E.·McDonald, S. A.·McEligott, Z. A.·Coleman, L. G.·Besheer, J.
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Abstract

Neuroimmune signaling is increased in postmortem brain tissue from individuals with alcohol use disorder (AUD), and growing evidence suggests that it contributes to persistent alcohol-related neuroadaptations. Interferon regulatory factor 7 (IRF7), a transcription factor downstream of endosomal Toll-like receptor signaling, is induced in alcohol-relevant brain regions and may contribute to escalated drinking. Here, we tested whether chronic intermittent ethanol (CIE) vapor exposure engages IRF7 signaling during subsequent alcohol self-administration and whether this is associated with altered molecular E/I balance in the aIC and altered functional E/I balance in aICnucleus accumbens projection neurons. Female Wistar rats (n=30) were trained to self-administer alcohol (15% v/v; FR2 vs inactive lever) during 30-minute sessions. After establishing baseline drinking, rats underwent 1-3 cycles of CIE, which increased alcohol self-administration at the 72 h post vapor test. This increase positively correlated with IRF7 levels in the anterior insular cortex (aIC) and nucleus accumbens, while molecular, and immunofluorescence showed that CIE shifted aIC excitatory/inhibitory (E/I) balance toward reduced excitation. Electrophysiological recordings further showed reduced functional E/I balance in aIC neurons projecting to the nucleus accumbens. Knockdown of IRF7 in the aIC attenuated CIE induced escalation of alcohol self-administration, supporting a role for insular IRF7 signaling in alcohol related neuroadaptations that promote escalated drinking.

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Lovelock, D. F., Carew, J. M., McNair, E. M., Materia, B. M., Darawsheh, S., Downs, A. M., Sizer, S. E., McDonald, S. A., McEligott, Z. A., Coleman, L. G., Besheer, J.. 2026-04-05. INTERFERON-REGULATORY FACTOR 7: A NEUROIMMUNE ROLE FOR VAPOR-INDUCED ESCALATIONS IN ETHANOL SELF-ADMINISTRATION. https://doi.org/10.64898/2026.04.01.715945

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