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

17R-estradiol (E2) regulates various forms of social behavior through the activation of two types of estrogen receptors, ERa and ERR. The lateral septum (LS) is thought to be one of the potential target sites of E2, but the role played by ERa and ERR in this brain area remains largely unknown. In the present study, we first analyzed the distribution of ERa and ERR with double fluorescent immunohistochemistry in a transgenic mouse line in which red fluorescent protein (RFP) signal has been a reliable marker of ERR expression. The overall number of ERR-RFP-expressing cells was significantly higher (about 2.5 times) compared to ERa-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 vectormediated small interference RNA (siRNA) techniques in male mice. We found ERR specific behavioral alterations during a social interaction test, suggesting involvement of ERR-expressing LS neurons in the regulation of social anxiety and social interest. Further, we investigated the neuronal projections of ERa- and ERR-expressing LS cells by injecting an anterograde viral tracer in ERa-Cre and ERR-iCre mice. Dense expression of green fluorescence protein (GFP) in synaptic terminals was observed in ERR-iCre mice in areas known to be related to the modulation of anxiety. These findings collectively suggest that ERR expressed in the LS plays a major role in the estrogenic control of social anxiety-like behavior.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).