Glucocorticoid receptor deletion from locus coeruleus norepinephrine neurons promotes depression-like social withdrawal in female but not male mice

Abnormal glucocorticoid levels can cause psychiatric symptoms ranging from depression to euphoria that have been implicated in mood disorders. My overarching hypothesis is that these opposing effects are mediated by glucocorticoid receptors (GR) in different brain regions. My laboratory has shown that GR in the serotonergic dorsal raphe nucleus (DRN) promote depression-like social and behavioral withdrawal in mice. We have also shown that GR in the DRN and noradrenergic locus coeruleus (LC) exhibit divergent regulation by antidepressants that have differential efficacy for depression subtypes with opposing abnormalities in glucocorticoids. The current study tested the hypothesis that LC GR would have effects opposite to those in the DRN by preventing rather than promoting social withdrawal. GR was deleted from LC NE neurons in female and male foxed GR mice by bilateral injections of lentivirus transducing Cre recombinase under control of a multimerized Phox 2a/2b response sequence (PRS) from the dopamine beta-hydroxylase promoter (PRS-Cre). Female but not male PRS-Cre mice exhibited lower social interaction compared to controls injected with lentivirus transducing green fluorescent protein (PRS-GFP). Differences in social interaction between PRS-GFP and PRS-Cre females were not associated with differences in exploratory behavior, plasma corticosterone, male-female differences in LC GR expression, or changes in LC mineralocorticoid receptor or tyrosine hydroxylase gene expression. These results indicate that LC NE GR have sex-dependent effects to prevent social withdrawal, supporting the concept that glucocorticoids exert opposing effects on depression symptoms via different brain targets, and potentially revealing novel drug targets to treat depression, particularly in women.