A single glucocorticoid response element regulates sociability in a sex-specific manner

Glucocorticoid receptors (GRs) regulate transcription to reduce inflammatory processes, modulate neuron function, and influence behavior. However, the precise loci bound by GRs that are critically important for these effects have not been fully determined. Here, we deleted the GR binding site near the sphingosine-1-phosphate receptor 3 (S1PR3) gene using a CRISPR/Cas9 approach in rats (S1PR3^GRE-/GRE- rats). Socially defeated S1PR3^GRE-/GRE- males displayed increased inflammatory markers and reduced sociability compared to defeated wild-type (WT) controls. Similar effects were observed in non-stressed females, indicating a greater dependence on the regulation of S1PR3 by GRs in females. Coherent neural activity between the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was increased in defeated S1PR3^GRE-/GRE- males whereas increases were observed in non-stressed S1PR3^GRE-/GRE females. Chemogenetically inhibiting mPFC-projecting LC neurons during defeat increased subsequent social interaction in WT and S1PR3^GRE-/GRE- males. Together, these findings demonstrate that GR-induced S1PR3 mitigates inflammatory processes and promotes resilience by reducing coherent neural activity between the LC and mPFC and may be an important mechanism through which the effects of stress in females can be mitigated.