The glucocorticoid response element near the sphingosine-1-phopshate receptor 3 gene mitigates inflammatory processes and maladaptive behavior in females and stressed males

It is well established that glucocorticoid receptors (GRs) bind DNA, regulate gene expression, reduce inflammatory processes, and modulate behavior. However, the precise loci bound by GRs that are necessary for these effects are not fully understood. Here, we deleted the GR binding site near the sphingosine-1-phospate receptor 3 gene using a CRISPR/Cas9 approach (S1PR3GR-/GR- rats). Defeated S1PR3GR-/GR- males displayed increased inflammatory markers and social anxiety-like behavior. Similar effects were observed in non-stressed females, indicating a greater dependence for GR-induced S1PR3 in females. Coherent neural activity between the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was increased in S1PR3GR-/GR- males following 7 defeats. Chemogenetically inhibiting mPFC-projecting LC neurons during defeat increased subsequent social interaction in wild-type and S1PR3GR-/GR- males. Together, these findings demonstrate that GR-induced S1PR3 promotes resilience by mitigating stress-induced inflammatory processes and LC-mPFC coherence. One Sentence SummaryGlucocorticoid receptor-induced expression of sphingosine-1- phosphate receptor 3 reduces social anxiety-like behavior by mitigating stress-induced inflammatory processes and coherent neural activity between the locus coeruleus and medial prefrontal cortex.