This work was supported by the

This work was supported by the National Natural Science Foundation of China (Grants 81471101 and 81870852), the Natural Science Foundation of Jiangsu Province (Grant BK20181146), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grants 18KJA320007 and 17KJB320018), the Qing Lan Project of Jiangsu Province, the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grants KYCX17_1717 and KYCX18_2180) and the Jiangsu Students’ Innovation and Entrepreneurship Training Program (Grant 201810313038Y).
Introduction Glucocorticoids can have paradoxical effects on mood ranging from depression to euphoria. Depression and anxiety are the most common side effects of glucocorticoid excess, which can be due either to tumors stimulating glucocorticoid secretion in Cushing’s syndrome or to exogenous glucocorticoids given systemically for anti-inflammatory or immunosuppressive therapy (Jacobson, 2014). However, reports of euphoria or mania after glucocorticoid administration, as well as depression during glucocorticoid discontinuation and depressive symptoms in Addison’s disease (Jacobson, 2014), indicate that glucocorticoids can have mood-elevating as well as dysphoric effects. These effects can limit the therapeutic uses of glucocorticoids and have been implicated in clinical mood disorders. Endogenous glucocorticoids bind two receptors in brain. The mineralocorticoid receptor (MR) is a higher affinity, lower capacity receptor whose CNS expression is concentrated in limbic regions. The glucocorticoid receptor (GR) is a lower affinity receptor that is widely expressed throughout the isoxazole receptor (Jacobson, 2005). GR is more likely than MR to mediate glucocorticoid effects on mood, not only because the lower affinity of GR affords a greater capacity to respond to the high glucocorticoid levels usually associated with psychiatric side effects, but also because most synthetic glucocorticoids used clinically have low or negligible affinity for MR (Schimmer and Funder, 2018). Glucocorticoid levels are often abnormal in depression, and limited but intriguing evidence for antidepressant actions of either GR antagonists or glucocorticoid supplementation in depression suggests that excessive or inadequate glucocorticoid levels, respectively, might contribute to depression symptoms (reviewed in (Jacobson, 2014)). Given the widespread expression of GR in brain, the diverse and contradictory effects of glucocorticoids would logically seem to be mediated by different brain regions. However, the specific brain regions mediating the psychoactive effects of glucocorticoids are incompletely defined. GR are strongly expressed by the serotonergic dorsal raphé nucleus (DRN) and the noradrenergic locus coeruleus (LC), which are primary targets of current antidepressants (Harfstrand et al., 1986, Heydendael and Jacobson, 2009). My laboratory has previously shown antidepressant-specific regulation of DRN and LC GR gene expression in association with glucocorticoid-dependent effects on the expression of rate-limiting enzymes for serotonin and norepinephrine synthesis, suggesting that GR can have brain region-specific effects on mood by regulating these monoamines (Heydendael and Jacobson, 2009). We have further shown that virally-transduced GR deletion from the DRN reduces depression-like behaviors, implying that DRN GR promote depression-like behavior (Vincent and Jacobson, 2014). However, the role of LC GR in these behaviors is unknown. Central noradrenergic signaling, to which the LC is a major contributor (Aston-Jones, 2004, Bangasser et al., 2016, was recently implicated in the mood-elevating actions of glucocorticoids. Transgene-mediated deletion of the glucocorticoid receptor (GR), achieved by crossing floxed GR mice with mice carrying a Cre transgene controlled by the dopamine beta-hydroxylase promoter, increased baseline depression-like behavior in female but not male mice (Chmielarz et al., 2013). However, because this transgenic approach deleted GR from all noradrenergic cells, including seven noradrenergic brain regions and the adrenal medulla, the location of GR mediating this effect is unknown. LC norepinephrine (NE) neurons express GR and have been implicated in depression subtypes associated with abnormal glucocorticoid sensitivity (Brady, 1994, Harfstrand et al., 1986, Wong et al., 2000). The LC is also a sexually dimorphic brain region (Bangasser et al., 2016). The current experiments therefore tested the hypothesis that GR deletion from locus coeruleus norepinephrine neurons would increase depression-like behavior specifically in female mice.