Sex differences in rapid non‐classical action of 17β‐estradiol on intracellular signaling and estrogen receptor alpha expression in basal forebrain cholinergic neurons in mouse

Sex differences in rapid non‐classical action of 17β‐estradiol on intracellular signaling and estrogen receptor alpha expression in basal forebrain cholinergic neurons in mouse:

Abstract

Rapid non‐classical effects of 17β‐estradiol (E2) on intracellular signaling have been identified in the basal forebrain but the extent to which these actions may be different in males and females is unknown. Previous work has shown that E2 rapidly phosphorylates cAMP responsive element binding protein (CREB) via ΕRα in female cholinergic neurons. Using this indicator, the present study examined whether non‐classical E2 actions occur in a sexually dimorphic manner within basal forebrain cholinergic (BFC) neurons in mice. In addition, we investigated the expression and intracellular distribution of ΕRα in cholinergic neurons in female and male mice. Animals were gonadectomized and 2 weeks later treated with E2. The number of CREB‐expressing cholinergic neurons was not altered in any of the brain regions following E2 treatment in both males and females. However, E2 treatment rapidly (<15min) increased (p<0.05) the number of cholinergic neurons expressing phosphorylated CREB (pCREB) in the substantia innominata and medial septum but not in the striatum in female mice. In contrast, E2 did not change pCREB expression in cholinergic neurons in male mice at any time point (15 min, 1 hr, 4 hr) irrespective to the neuroanatomical location. We also observed that in females, more cholinergic neurons expressed nuclear ΕRα in all regions while males showed more cholinergic neurons with cytoplasmic or both nuclear and cytoplasmic expression of ΕRα. Taken together, these results demonstrate a marked sex difference in the E2‐induced non‐classical effect and intracellular distribution of ΕRα in BFC neurons in vivo.