Social Isolation and Enrichment Induce Unique miRNA Signatures in the Prefrontal Cortex and Behavioral Changes in Mice

Abstract

An extensive body of evidence supports the notion that exposure to an enriched/impoverished environment alters brain functions via epigenetic changes. However, how specific modifications of social environment modulate brain functions remains poorly understood. To address this issue, we investigate the molecular and behavioral consequences of briefly manipulating social settings in young and middle-aged wild-type mice. We observe that, modifications of the social context, only affect the performance in socially related tasks. Social enrichment increases sociability whereas isolation leads to the opposite effect. Our work also pointed out specific miRNA signatures associated to each social environment. These miRNA alterations are reversible and found selectively in the medial prefrontal cortex. Finally, we show that miRNA modifications linked to social enrichment or isolation might target rather different intracellular pathways. Together, these observations suggest that the prefrontal cortex may be a key brain area integrating social information via the modification of precise miRNA networks.

Keywords: Genetics; Neurogenetics; Neuroscience.

Graphical abstract

Figure 1

Mice Exposed to Different Social Environments Exhibit Subtle Behavioral Changes in Socially Related Tasks (A). Three-chamber test. No differences are found during the exploration phase (Upper panel) among all groups. In the social phase (Lower panel), 3-month-old-enriched mice showed a significant increase in their preference for exploring the social partner, whereas 9-month-old mice having been isolated exhibited the opposite effect (∗p < 0.05). (B). Interactions in neutral arena. Young mice exposed to the social enrichment protocol show an increase in the interaction time with a juvenile mouse in the neutral arena. All other social environments or age groups do not modify interaction time (∗p < 0.05). (C). Intruder test. No differences in exploration time are observed when a juvenile conspecific is introduced in the home cage of young and middle-aged mice exposed to different social environments. All values represent mean ± sem

Figure 2

Short Modifications of Social Environment Drive Specific and Reversible miRNA Changes (A) Results of discriminant analysis in 3- and 9-months mice exposed to different social environments. When the levels of 43 miRNAs in 5 different brain regions are considered, animals having been exposed to the same environment cluster in close proximity at both ages. (B) Principal component analysis (PCA) of the miRNA levels (43 different miRNAs) in the prefrontal cortex and the amygdala. Using the first two components, this analysis shows a striking difference in the impact of social environment among brain regions. Animals clearly split into the four quadrants according to their age and social environment in the prefrontal cortex (control and 9-month-enriched mice are in the bottom left quadrant; isolated mice occupy the two upper quadrants and the young enriched cluster in the bottom right quadrant), whereas they are intermingled in the amygdala. (C) miRNAs significantly altered by social enrichment and isolation. Upper panels: miRNAs significantly deregulated in 3-month-enriched mice (One-way ANOVA, ∗p < 0.05) include miR-140-5p and miR-181a-5p. Lower panels: miRNAs significantly deregulated in 9-month isolated mice (One-way ANOVA, ∗p < 0.05, ∗∗p < 0.01) include let-7a-5p, let-7d-5p, let-7e-5p, and miR-410-3p. (D) Reversal of miRNA changes in mice re-exposed to a control social environment. Upper panels: miRNAs significantly deregulated in 3-month-enriched mice return to control levels after 1 week back to the control settings (One-way ANOVA, ∗p < 0.05). Lower panels: only levels of miR-410-3p are normalized in 9-month isolated mice having been submitted to the reversal protocol. let-7a-5p, let-7d-5p, and let-7e-5p levels remain significantly elevated (One-way ANOVA, ∗p < 0.05, ∗∗p < 0.01). All values represent mean ± sem

Figure 3

In Silico Analysis of Target Networks Downstream of miRNAs Altered by Social Enrichment and Isolation (A). miRNA network visualization of social enrichment (left) or isolation (right). This analysis revealed a common target for social enrichment miRNAs, Tor1aip2, and two, Atp2b2 and Nf2, for the miRNAs altered by social isolation. (B). Pathway analysis of the target mRNAs in enriched and isolated animals using KEGG library. The table depicts the top 8 pathways showing a significant enrichment of mRNAs from each network. This analysis showed a sharp difference between social enrichment (mostly, associated to neuronal function) and isolation (mostly, linked to cell proliferation/cancer and specific cellular signaling pathways).