Estrogen Receptor β in the Lateral Septum Mediates Estrogen Regulation of Social Anxiety-like Behavior in Male Mice

17β-estradiol (E2) regulates various forms of social behavior through the activation of two types of estrogen receptors, ERα and ERβ. The lateral septum (LS) is thought to be one of the potential target sites of E2, but the role played by ERα and ERβ in this brain area remains largely unknown. In the present study, we first analyzed the distribution of ERα and ERβ with double fluorescent immunohistochemistry in a transgenic mouse line in which red fluorescent protein (RFP) signal has been a reliable marker of ERβ expression. The overall number of ERβ-RFP-expressing cells was significantly higher (about 2.5 times) compared to ERα-expressing cells. The distribution of the two types of ERs was different, with co-expression only seen in about 1.2% of total ER-positive cells. Given these distinctive distribution patterns, we examined the behavioral effects of site-specific knockdown of each ER using viral vector-mediated small interference RNA (siRNA) techniques in male mice. We found ERβ-specific behavioral alterations during a social interaction test, suggesting involvement of ERβ-expressing LS neurons in the regulation of social anxiety and social interest. Further, we investigated the neuronal projections of ERα- and ERβ-expressing LS cells by injecting an anterograde viral tracer in ERα-Cre and ERβ-iCre mice. Dense expression of green fluorescence protein (GFP) in synaptic terminals was observed in ERβ-iCre mice in areas known to be related to the modulation of anxiety. These findings collectively suggest that ERβ expressed in the LS plays a major role in the estrogenic control of social anxiety-like behavior.