SEX DIFFERENCES IN THE FOREBRAIN DOPAMINERGIC CIRCUIT

Abstract

Several psychiatric disorders exhibit different incidence rates in men and women and areassociated with dysfunctions in forebrain dopaminergic circuits. Although anatomical and functional sex differences in the brain have been studied, little is known about sex differences in the forebrain dopaminergic circuits associated with behavioral dysfunction. We hypothesized that known sex differences in forebrain dopamine circuit-associated behaviors would be the result of sex differences in forebrain dopamine circuit anatomy. As a first step to address this hypothesis, we combined a mouse transgenic driver line (tyrosine hydroxylase promoter-driven Cre recombinase) with virally encoded fluorescent reporters (FLEX-tdTomato and SynaptophysinGFP) to compare the density of midbrain dopaminergic axon projections and terminal boutons in dopamine projection target regions. Using this technique, we analyzed projections from the ventral tegmental area (VTA) to prefrontal cortex and basolateral amygdala (BLA) in male and female adult mice. Multiple analyses at 10x and 25x magnification revealed higher bouton density in BLA in males compared to females. To determine if this anatomical difference is mediated by gonadal steroid hormones, subjects were treated with a drug used to reduce gonadal steroid hormone production in clinical populations, leuprolide acetate (Lupron), before anatomical measures. Leuprolide administration resulted in a reduction in circulating testosterone, but did not show an effect on dopamine circuit anatomy. The finding of an anatomical sex difference in the forebrain dopamine circuit provides a structural foundation for further investigation of how sex differences in brain circuits may underlie behavioral dysfunction that play roles in psychiatric illnesses.