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While the dextran sulfate sodium (DSS) mouse model was previously applied to study gut\u2010brain interactions, those studies focused on acute protocols missing the chronic, relapsing\u2013remitting nature of human UC, when patients continue to experience central nervous system symptoms. Thus, we employed a chronic DSS treatment regimen comprising three cycles of active intestinal inflammation followed by remission phases to investigate region\u2010specific microglial dynamics and their functional consequences on neuronal synapses. Transient blood\u2013brain barrier alteration was detected during active chronic inflammation that was resolved during remission. Cortical microglia exhibited sustained iNOS\u2010enriched activation state during remission, which coincided with synaptic imbalance: VGLUT1+ glutamatergic synaptosomes increased significantly in remission, while VGAT+ GABAergic vesicles declined, alongside suppressed neuronal c\u2010fos expression. Hippocampal microglia adopted an ARG1\u2010dominant phenotype with enriched TREM2, P2Y12R, and F4\/80 expression during remission, indicating a phagocytic, reparative state. Hippocampal synaptosome analysis revealed selective excitatory enhancement with preserved inhibitory markers. Morphological analysis confirmed region\u2010specific remodeling: cortical microglia displayed delayed process elaboration during remission, while hippocampal responses varied from transient (CA1) to persistent (CA3) somatic hypertrophy. These findings establish that remission from peripheral inflammation does not fully restore brain immune homeostasis. Persistent, region\u2010specific microglial reactivity with cortical pro\u2010inflammatory states associated with synaptic dysfunction and hippocampal adaptive responses preserving circuit integrity provides a mechanistic understanding for neuropsychiatric comorbidities in UC and suggests that brain\u2010targeted therapies may be required to address the full disease burden.<\/jats:p>","DOI":"10.1002\/glia.70208","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:40:21Z","timestamp":1788342021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Persisting Region\u2010Specific Microglia Activation and Synaptic Imbalance During Remission in a\n                    <scp>DSS<\/scp>\n                    \u2010Induced Colitis Model"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3957-3848","authenticated-orcid":false,"given":"Lorena","family":"Morton","sequence":"first","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2930-2635","authenticated-orcid":false,"given":"Luis E.","family":"Villafuerte","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2993-7679","authenticated-orcid":false,"given":"Alejandra P.","family":"Garza","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Lindemann","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Infection Immunology Group, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Wider\u2010Ebersp\u00e4cher","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunja","family":"Bruder","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hospital Hygiene, Infection Immunology Group, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"},{"name":"Helmholtz Centre for Infection Research, Immune Regulation Group  Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9900-8605","authenticated-orcid":false,"given":"Ildiko R.","family":"Dunay","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Neurodegeneration, Medical Faculty Otto\u2010von\u2010Guericke University Magdeburg  Magdeburg Germany"},{"name":"Center for Behavioral Brain Sciences (CBBS)  Magdeburg Germany"},{"name":"German Center for Mental Health (DZPG)  Magdeburg Germany"},{"name":"Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C\u2010I\u2010R\u2010C)  Halle\u2010Jena\u2010Magdeburg 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