Elsevier

Psychoneuroendocrinology

Volume 58, August 2015, Pages 51-66
Psychoneuroendocrinology

Activation of the G protein-coupled estrogen receptor, but not estrogen receptor α or β, rapidly enhances social learning

https://doi.org/10.1016/j.psyneuen.2015.04.002Get rights and content

Highlights

  • Social learning can be modulated by rapid effects of estrogen receptor activation.

  • 17β-estradiol rapidly facilitates expression of a socially learned food preference.

  • Specific GPER1 activation facilitates social learning, more prolonged than estradiol effects.

  • ERα or ERβ activation either rapidly impairs or has no effect on social learning.

Summary

Social learning is a highly adaptive process by which an animal acquires information from a conspecific. While estrogens are known to modulate learning and memory, much of this research focuses on individual learning. Estrogens have been shown to enhance social learning on a long-term time scale, likely via genomic mechanisms. Estrogens have also been shown to affect individual learning on a rapid time scale through cell-signaling cascades, rather than via genomic effects, suggesting they may also rapidly influence social learning. We therefore investigated the effects of 17β-estradiol and involvement of the estrogen receptors (ERs) using the ERα agonist propyl pyrazole triol, the ERβ agonist diarylpropionitrile, and the G protein-coupled ER 1 (GPER1) agonist G1 on the social transmission of food preferences (STFP) task, within a time scale that focused on the rapid effects of estrogens. General ER activation with 17β-estradiol resulted in a modest facilitation of social learning, with mice showing a preference up to 30 min of testing. Specific activation of the GPER1 also rapidly enhanced social learning, with mice showing a socially learned preference up to 2 h of testing. ERα activation instead shortened the expression of a socially learned food preference, while ERβ activation had little to no effects. Thus, rapid estrogenic modulation of social learning in the STFP may be the outcome of competing action at the three main receptors. Hence, estrogens’ rapid effects on social learning likely depend on the specific ERs present in brain regions recruited during social learning.

Introduction

Social learning is a highly advantageous strategy for animals living in social groups. It allows animals to gain information about their environment from conspecifics, rather than by more costly and risky individual, trial-and-error learning (Galef, 1996). We examined social learning using the social transmission of food preferences (STFP), in which mice tend to prefer a novel food they have smelled previously on another mouse's breath (Clipperton et al., 2008, Valsecchi and Galef, 1989). The STFP is true social learning as it relies on a social interaction between a “demonstrator” that has eaten a novel-flavored food, and an “observer” naïve to the test foods. An observer will not show a preference for a food it has smelled on the muzzle of a dead conspecific, on a cotton surrogate mouse, or in proximity to a conspecific that has not consumed that food (Choleris et al., 2011, Valsecchi and Galef, 1989).

Estrogens modulate performance on the STFP. Female observer mice with high circulating estrogens, whether in the high-estrogen proestrus phase of the estrous cycle or ovariectomized and given exogenous estradiol, show a prolonged preference for a demonstrated food (Choleris et al., 2011, Sánchez-Andrade et al., 2005). These improvements are likely due to genomic effects of estradiol. Estrogens can also affect learning and memory on a rapid time scale, affecting behavior minutes to hours after treatment, involving cell signaling events that occur prior to any genomic mechanisms (Boulware et al., 2013, Fernandez et al., 2008, Frye et al., 2007, Inagaki et al., 2010, Kelly and Levin, 2001, Luine et al., 2003, Phan et al., 2012, Phan et al., 2011, Rhodes and Frye, 2004, Rhodes and Frye, 2006). When administered before the acquisition/encoding phase of memory, the common circulating estrogen, 17β-estradiol (17β-E2), enhanced learning on non-social recognition and spatial tasks within 40 min of treatment (Phan et al., 2012). Whether estrogens rapidly affect social learning has not yet been determined.

Estradiol affects behavior by binding to estrogen receptors (ERs), the better known being ERα, ERβ, and the more recently described G protein-coupled ER 1 (GPER1). ERα and ERβ are genetically similar and are better known for their effects on gene transcription (Heldring et al., 2007), while GPER1 is a membrane-bound receptor, genetically and structurally distinct from ERα and ERβ (Carmeci et al., 1997, Thomas et al., 2005). Notably, all three ERs are expressed in the cytosol and/or on the plasma membrane and have been shown to initiate rapid estrogenic effects via intracellular signaling cascades (Brailoiu et al., 2007, Micevych and Dominguez, 2009, Wong and Moss, 1992).

Specific ER involvement in social learning has been investigated with ERα and ERβ agonists 48 h prior to learning, thus incorporating genomic mechanisms. The ERβ agonist prolonged the preference for the demonstrated food in female OVX mice, similar to the effects of estradiol benzoate, while treatment with the ERα agonist blocked expression of the STFP (Clipperton et al., unpublished results; Clipperton et al., 2008). Whether the differential roles of ERα and ERβ in social learning also exist for rapid effects is currently unknown. In non-social learning tasks, ERα or GPER1 activation improved social recognition, object recognition, and spatial object placement learning in a rapid time frame (Gabor et al., unpublished results, reported in Ervin et al., 2013, Phan et al., 2011). Because it involves learning about a conspecific stimulus, rather than from a conspecific demonstrator, social recognition is considered a form of individual or non-social learning (for further discussion see Choleris et al., 2009, Choleris et al., 2012). An ERβ agonist also enhanced object placement learning, but impaired social recognition (Phan et al., 2011). Therefore it seems that while estradiol may modulate performance on a variety of social and non-social learning tasks, the effects may depend upon the specific ERs involved, the time-scale and associated mechanisms of action on which treatments are implemented (rapid versus long-term), or both (recently reviewed in Ervin et al., 2013). Whether rapid actions of estradiol and its receptors differently affect social learning, compared to previous studies of non-social learning, remains to be determined.

Our aims were to first ascertain whether 17β-E2 rapidly modulates learning in the STFP and if so, determine the ERs responsible for its effects. We therefore treated experimentally naïve, female ovariectomized (OVX) observer mice with 17β-E2 or the selective ERα agonist propyl pyrazole triol (PPT), the ERβ agonist diarylpropionitrile (DPN), or the GPER1 agonist G1 15 min before the acquisition phase of the STFP. The first measurement of food intake, indicating whether social learning had occurred, was taken 45–50 min after estrogen treatment, thus focusing on rapid effects of treatment. As 17β-E2 rapidly facilitates various types of individual learning (Phan et al., 2012), we expected estradiol to also rapidly enhance performance in STFP. Any of the three ER agonists could potentially rapidly enhance social learning, given their effects on individual learning paradigms (Phan et al., 2011) and the STFP (Clipperton et al., 2008). In addition to drug-specific effects, we expected all treatments would affect learning in a dose-dependent manner, following an inverse U-shaped dose response curve commonly seen in studies with estrogens (Clipperton et al., 2008, Jacome et al., 2010, Phan et al., 2011recently reviewed in Luine and Frankfurt, 2012). Thus the middle dose tested would be most effective at modifying learning.

Section snippets

Animals and housing

Two-month-old female CD1 mice (Mus musculus) from Charles River, QC, Canada were housed in groups of 2–3 in polyethylene cages (26 cm × 16 cm × 12 cm) with corncob bedding and environmental enrichment in a climate-controlled colony room (21 ± 1 °C) at the University of Guelph Central Animal Facility. Mice were maintained on a 12 h reverse light cycle (lights on at 2000 h) with ad libitum tap water and food (Teklad Global 14% Protein Rodent Maintenance Diet, Harlan Teklad, Madison, WI). All mice underwent

Results

Overall, our results suggest that 17β-E2 rapidly facilitates performance on the STFP following an inverse U-shaped dose response curve. GPER1 activation similarly enhanced social learning, thus improving effects of estradiol may be mediated by GPER1, whereas ERα and ERβ activation may rapidly impair social learning.

Overall drug effects

The results of these investigations show that 17β-E2 and activation of the GPER1 with the agonist G1 facilitate social learning in a difficult version of the STFP, compared with controls showing no social learning (Figure 1, Figure 2). Mice treated with the GPER1 agonist also showed a prolonged socially learned food preference, up to 2 h, compared with those treated with 17β-E2, which showed a socially acquired food preference up to 30 min. This suggests that the enhancing effects of GPER1,

Role of the funding source

The research presented in this manuscript received financial support from a Natural Sciences and Engineering Research Council of Canada discovery grant to EC (400212). This funding source covered operating costs to facilitate research, and in no way influenced experimental design or interpretation of results.

Conflict of interest

Funding for this work was provided by a discovery grant provided by the Natural Sciences and Engineering Research Council of Canada to E.C. (400212). Financial support for K.E. was provided by an Ontario Graduate Scholarship and a Queen Elizabeth II Graduate Scholarship in Science and Technology from the Ontario Student Assistance Program. The authors declare no conflict of interest.

Acknowledgements

The authors thank Jeffrey Friesen, Jenna Boyd, Jonathan Zicherman, Gregory Montini, and Ayrton Melendez for their help with data collection. Many thanks also to our animal care technician Linda Groocock for the exemplary care she provided for the animals used in the experiments. The authors also wish to thank 4 anonymous reviewers for their thoughtful comments on an early version of the manuscript.

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