{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:01:40Z","timestamp":1782280900112,"version":"3.54.5"},"posted":{"date-parts":[[2024,10,12]]},"group-title":"Neuroscience","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T00:00:00Z","timestamp":1728691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Individuals with alcohol use disorder (AUD) struggle with inhibitory control, decision making, and emotional processing. These cognitive symptoms reduce treatment adherence, worsen clinical outcomes, and promote relapse. Neuroimmune activation is a key factor in the pathophysiology of AUD, and targeting this modulatory system is less likely to produce unwanted side effects compared to directly targeting neurotransmitter dysfunction. Notably, the cytokine interleukin-1\u03b2 (IL-1\u03b2) has been broadly associated with the cognitive symptoms of AUD, though the underlying mechanisms are not well understood. Here we investigated how chronic intermittent 24-hour access two bottle choice ethanol drinking affects medial prefrontal cortex (mPFC)-related cognitive function and IL-1 synaptic signaling in male and female C57BL\/6J mice. In both sexes, ethanol drinking decreased reference memory and increased mPFC IL-1 receptor 1 (IL-1R1) mRNA levels. In neurons, IL-1\u03b2 can activate either pro-inflammatory or neuroprotective intracellular pathways depending on the isoform of the accessory protein (IL-1RAcP) recruited to the IL-1R1 complex. Moreover, ethanol drinking sex-dependently shifted mPFC IL-1RAcP isoform gene expression and IL-1\u03b2 regulation of mPFC GABA synapses, both of which may contribute to female mPFC resiliency and male mPFC susceptibility. This type of signaling bias has become a recent focus of rational drug development. Therefore, in addition to increasing our understanding of how IL-1\u03b2 sex-dependently contributes to mPFC dysfunction in AUD, our current findings also support the development of a new class of pharmacotherapeutics based on biased IL-1 signaling.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"simple\">\n                    <jats:list-item>\n                      <jats:p>- Female mice consumed more ethanol, but were less cognitively impaired than males<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>- Ethanol altered IL-1\u03b2 effects at mPFC GABA synapses, with females less sensitive than males<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        - Ethanol altered mPFC\n                        <jats:italic>Il1rap<\/jats:italic>\n                        mRNA to promote female neuroprotection and male neuroinflammation\n                      <\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.10.08.617276","type":"posted-content","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T23:25:20Z","timestamp":1728775520000},"source":"Crossref","is-referenced-by-count":1,"title":["Ethanol drinking sex-dependently alters cortical IL-1\u03b2 synaptic signaling and cognitive behavior in 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