Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia Venturino, Alessandro ; https://orcid.org/0000-0003-2356-9403 Alam, Amin Negrello, Thomas Jin, Kelly van Velthoven, Cindy T. J. Cubero, Ryan J ; https://orcid.org/0000-0003-0002-1867 Yeung, Jake ; https://orcid.org/0000-0003-1732-1559 Koppensteiner, Peter ; https://orcid.org/0000-0002-3509-1948 Tasic, Bosiljka Siegert, Sandra ; https://orcid.org/0000-0001-8635-0877 ddc:570 Anesthesia recovery is critical for resuming normal physiological and neuronal functions; however, the mechanisms involved remain elusive. Here, we identify a female-selective corticosterone-mediated microglia-neuron interaction during ketamine anesthesia recovery, absent in males. This microglia-neuron interaction induces plastic and functional neuronal changes, as evidenced by increased mEPSC frequency, which was occluded upon microglia depletion. We showed that this process is driven through up-regulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein, Fkbp51, in female microglia. Fkbp5/Fkbp51 is a key intermediary in a corticosteroid-induced stress response, and its involvement points toward a critical interface between endocrine signaling and microglia. To counteract the observed ketamine anesthesia-mediated increase in blood corticosterone during recovery, we removed the primary source of corticosterone by adrenalectomy. Close microglia-neuron interaction was reduced and increased again following corticosterone injection. Our findings identify a sex-specific microglia-mediated mechanism of neuronal plasticity during anesthesia recovery, driven by corticosterone, thereby enhancing our understanding of sex differences in brain function. AAAS 2026 info:eu-repo/semantics/article doc-type:Article Article http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/22951 https://research-explorer.ista.ac.at/download/22951/22980 Venturino A, Alam A, Negrello T, et al. Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia. <i>Science Advances</i>. 2026;12(31). doi:<a href="https://doi.org/10.1126/sciadv.adz6517">10.1126/sciadv.adz6517</a> eng info:eu-repo/semantics/altIdentifier/doi/10.1126/sciadv.adz6517 info:eu-repo/semantics/altIdentifier/e-issn/2375-2548 info:eu-repo/semantics/altIdentifier/pmid/42536755 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess