Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks.

An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK and hPER3 proteins, respectively. In addition, hCLOCK expression is affected by glucocorticoids, consistent with the sex-dependency of the genetic associations and the modulation of glucocorticoid-mediated stress response, providing a mechanism by which the circadian clock controls outputs that may affect psychiatric disorders. We conclude that genetic polymorphisms in circadian genes (especially hClock and hPer3, where functional assays could be tested) influence risk of developing depression in a sex- and stress-dependent manner. These studies support a genetic connection between circadian disruption and mood disorders, and confirm a key connection between circadian gene variation and major depression.

Oestrogen receptor beta contributes to the transient sex difference in tyrosine hydroxylase expression in the mouse locus coeruleus.

Oestrogen receptors (ERs) are important for sexual differentiation of the brain. Previous studies in rats have reported that the locus coeruleus (LC), a catecholaminergic nucleus in the brain stem, is sexually dimorphic such that females have more neurones than males. We hypothesised that ERs may be important for sexual differentiation of this nucleus in mice. Because previous studies reported conflicting results regarding ER protein expression in the mouse LC, we evaluated ER alpha and ER beta gene expression by in situ hybridisation and the real-time reverse transcription-polymerase chain reaction. We demonstrated that both ER alpha and ER beta mRNAs are present in tyrosine hydroxylase-immunoreactive (TH-ir) cells in the male LC. In the female LC, ER alpha mRNA is present at levels similar to males, whereas ER beta mRNA expression is significantly lower than in males. Similar to rats, male mice have fewer TH-ir cells in the LC than females at 60 days after birth, but the difference is absent at 120 days after birth when females exhibit a similar reduction in TH-ir cells. The transient sex difference is ER beta-dependent because is it absent in ER beta knockout mice, and is due to regulation of TH expression and not from death of TH-ir cells. Testicular hormones produced at adolescence are necessary for the regulation of TH expression in the male LC because orchidectomy of pre-pubertal males prevented the decrease in TH-ir cells, whereas treatment of gonadectomized males with testosterone or its metabolite, 5 alpha-androstan-3beta,17beta-diol, restored the intact male phenotype. Overall, these studies indicate that ER beta is important in regulating TH expression in the mouse LC.