Differential distribution of estrogen receptor (ER)-α and ER-β in the midbrain raphe nuclei and periaqueductal gray in male mouse: Predominant role of ER-β in midbrain serotonergic systems

We examined the distribution of estrogen receptor (ER)-α and ER-β immunoreactive (ir) cells in the dorsal (DRN) and median/paramedian (MPRN) raphe nuclei in male mice. ER-α ir neurons were scattered across the three subdivisions (ventral, dorsal, and lateral) of the DRN and the MPRN. Robust ER-β ir cells were observed throughout the raphe nuclei, and were particularly abundant in the ventral and dorsal subdivisions of the DRN. Using dual-label immunocytochemistry for ER-α or ER-β with tryptophan hydroxylase (TPH), the rate-limiting enzyme for 5-hydroxytryptamine (5-HT) synthesis, over 90% of ER-β ir cells exhibited TPH-ir in all DRN subdivisions, whereas only 23% of ER-α ir cells contained TPH. Comparisons of ER-α knockout (αERKO) as well as ER-β knockout (βERKO) mice with their respective wild-type (WT) littermates revealed that gene disruption of either ER-α or ER-β did not affect the other ER subtype expression in the raphe nuclei. In situ hybridization histochemistry revealed that there was a small but statistically significant decrease in TPH mRNA expression in the ventral DRN subdivision in βERKO mice compared with βWT mice, whereas TPH mRNA levels were not affected in αERKO mice. These findings support a hypothesis that ER-β activation may contribute to the estrogenic regulation of neuroendocrine and behavioral functions, in part, by acting directly on 5-HT neurons in the raphe nuclei in male mice.