Contents lists available at ScienceDirect Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh Dietary phytoestrogens modulate aggression and activity in social behavior circuits of male mice Kiran Veer Sandhu a , Yunus Emre Demiray a , Yuchio Yanagawa b , Oliver Stork a,c, ⁎ a Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany b Department of Genetic and Behavioural Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Maebashi 371-8511, Japan c Center for Behavioural Brain Sciences, Magdeburg, 39120 Magdeburg, Germany ARTICLE INFO Keywords: Phytoestrogens Social interaction Aggression c-Fos Immunohistochemistry Medial amygdala Male mouse ABSTRACT Phytoestrogens comprise biologically active constituents of human and animal diet that can impact on systemic and local estrogen functions in the brain. Here we report on the importance of dietary phytoestrogens for maintaining activity in a brain circuit controlling aggressive and social behavior of male mice. After six weeks of low-phytoestrogen chronic diet (diadzein plus genistein < 20 μg/g) a reduction of intermale aggression and altered territorial marking behavior could be observed, compared to littermates on a standard soy-bean based diet (300 μg/g). Further, mice on low-phyto diet displayed a decrease in sociability and a reduced preference for social odors, indicating a general disturbance of social behavior. Underlying circuits were investigated by analysing the induction of the activity marker c-Fos upon social encounter. Low-phyto diet led to a markedly reduced c-Fos induction in the medial as well as the cortical amygdala, the lateral septum, medial preoptic area and bed nucleus of the stria terminalis. No difference between groups was observed in the olfactory bulb. Together our data suggest that dietary phytoestrogens critically modulate social behavior circuits in the male mouse brain. 1. Introduction Phytoestrogens are plant-derived estrogen analogues enriched in soy and comprise an important biologically active constituent of human and laboratory animal diets. They have been widely used for the pre- vention of cancer, osteoporosis, menopausal symptoms and cardiovas- cular disease (Kronenberg and Fugh-Berman, 2002; Bolton, 2016). Moreover, they may bear therapeutic potential for neuropsychiatric disorders such as autism and schizophrenia, which are characterised by social impairments (Kulkarni et al., 2011; Crider and Pillai, 2017; Gogos et al., 2015; Crider et al., 2014). Phytoestrogens have been shown to modulate the DNA binding af- finity for the estrogen receptors (Kostelac et al., 2003). In addition to acting directly on brain estrogen receptors they also can affect their function indirectly via changing the levels of circulating estrogen (Weber et al., 2001). In rodents, dietary soy phytoestrogens are almost completely metabolized to equol, which accumulates in various brain regions (Lephart et al., 2001). Through its interaction with 5-α dihy- drotestosterone (DHT) equol can sequester it from androgen receptors (Lund et al., 2004). On the other hand, equol acts as an agonist to both ER α and ER β, although it binds more strongly to the latter (Morito et al., 2001). We have previously shown that chronic depletion of dietary phytoestrogens in the adult C57BL/6 mice induces anxiety-like behavior and changes in amygdala gene expression, without altering levels of circulating testosterone or estradiol (Sandhu et al., 2015). In the current study, we investigated the putative role of dietary phytoestrogens in modulating social behavior and underlying circuit activity in these animals. The function of estrogens and their disruptors in controlling social behavior is well studied in females, but much less in males (Ervin et al., 2015; Choleris et al., 2006; Clipperton-Allen et al., 2012; Murakami et al., 2011). However, estrogen has consistently been demonstrated to regulate male-specific social behavior including social preference, aggression and dominance (Ervin et al., 2015). Fur- ther, it is established that social interaction of male mice is modulated through the differential distribution of the estrogen receptors in the brain (Murakami et al., 2011). Thus a network of estrogen sensitive brain regions including the medial (MeA) and cortical amygdala (CoA), the bed nucleus of the stria terminalis (BNsT), medial preoptic area (MPOA) and lateral septum (LS) is critical for identification of conspecific pheromones and https://doi.org/10.1016/j.yhbeh.2019.104637 Received 18 October 2018; Received in revised form 6 November 2019; Accepted 10 November 2019 ⁎ Corresponding author at: Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany. E-mail address: oliver.stork@ovgu.de (O. Stork). Hormones and Behavior 119 (2020) 104637 0018-506X/ © 2019 Elsevier Inc. All rights reserved. T