Sex‐ and Region‐Specific Glial Reactivity in Hyperthyroid Mice Lacks Correlation With the Noncognitive and Non‐Depressive‐Like Behavioral Alterations

ABSTRACT Background Glial reactivity is implicated in hyperthyroidism‐associated cognitive and psychiatric disorders, yet in vivo imaging evidence of glial reactivity in hyperthyroidism remains to be elucidated. This study aimed to detect hyperthyroidism‐induced glial reactivity using 1 8 F‐DPA714 positron emission tomography/computed tomography (PET/CT) imaging and investigate the associations with behavioral alterations in mice. Methods C57BL/6J mice were randomly divided into hyperthyroid (T4) and control groups. 1 8 F‐DPA714 PET/CT imaging quantified glial reactivity as standardized uptake value (SUV) in eight brain regions. Immunohistochemistry for ionized calcium‐binding adapter molecule 1 (IBA‐1) and glial fibrillary acidic protein (GFAP) validated glial reactivity in CA1 pyramidal layer of the hippocampus and layer IV of the somatosensory cortex. Behavioral tests included sucrose preference, forced swim, and water maze. Results Cortical and hippocampal IBA‐1 and GFAP densities were significantly elevated in T4 mice, with sex‐dependent GFAP expression (male higher in cortex, female higher in hippocampus). PET/CT showed that T4 markedly increased SUV in striatum, thalamus, hypothalamus, brainstem, and midbrain in female mice only, while in cortex, hippocampus, and amygdala, T4 increased SUV in both sexes. Hyperthyroid mice did not show cognitive decline or depressive‐like behaviors. Instead, male T4 mice displayed shortened immobility time, and both sexes showed increased platform crossings and greater target quadrant distance. No significant associations were found between glial reactivity measures and behavioral outcomes. Conclusions Hyperthyroidism induces sex‐ and region‐specific glial reactivity detected by 1 8 F‐DPA714 PET/CT and pathology, which lacks correlation with the observed noncognitive and non‐depressive‐like behavioral alterations in mice.