Sex differences in the regulation of tyrosine hydroxylase gene transcription by estrogen in the locus coeruleus of TH9-LacZ transgenic mice.

Although estrogen is recognized increasingly as having an important role in modulating extrahypothalamic brain function, the mechanisms through which this occur are not well established. The norepinephrine (NE) neurons of the locus coeruleus provide an important neuromodulatory influence upon multiple neural networks throughout the brain and estrogen has been implicated in their regulation. Using a tyrosine hydroxylase (TH) promoter-LacZ transgenic mouse model, which enables rates of TH gene transcription to be examined in vivo, we have examined here whether estrogen regulates expression of the TH gene in the locus coeruleus of males and females. Optical area measurements of Xgal reaction product in the locus coeruleus revealed that gonadectomy exerted opposite effects on TH gene transcription in males and females; transgene expression was increased in males (P<0.01) but reduced in females (P<0.05). Estrogen reversed these effects in both sexes by suppressing gene expression in males (P<0.05) but elevating it in the female (P<0.05). These studies reveal a marked and unexpected sex difference in the regulation of TH gene activity in the mouse. While estrogen in the male, synthesized from circulating testosterone, suppresses TH gene transcription, estrogen in the female enhances TH promoter activity. The present results indicate that estrogen may exert very different sex-dependent effects upon the biosynthesis of NE within the locus coeruleus.