Sociability versus empathy in adolescent mice: Different or distinctive?

Abstract

In recent years, a growing number of pre-clinical studies have made use of the social abilities of mice, asking how gene variants (e.g., null, transgenic or mutant alleles) give rise to abnormalities in neurodevelopment. Two distinct courses of research provide the foundation for these studies. One course has mostly focused on how we can assess "sociability" using metrics, often automated, to quantitate mouse approach and withdrawal responses to a variety of social stimuli. The other course has focused on psychobiological constructs that underlie the socio-emotional capacities of mice, including motivation, reward and empathy. Critically, we know little about how measures of mouse sociability align with their underlying socio-emotional capacities. In the present work, we compared the expression of sociability in adolescent mice from several strains versus a precisely defined behavioral model of empathy that makes use of a vicarious fear learning paradigm. Despite substantial strain-dependent variation within each behavioral domain, we found little evidence of a relationship between these social phenotypes (i.e., the rank order of strain differences was unique for each test). By contrast, emission of ultrasonic vocalizations was highly associated with sociability, suggesting that these two measures reflect the same underlying construct. Taken together, our results indicate that sociability and vicarious fear learning are not manifestations of a single, overarching social trait. These findings thus underscore the necessity for a robust and diverse set of measures when using laboratory mice to model the social dimensions of neuropsychiatric disorders.

Keywords: BTBR; fear conditioning; social neuroscience; vicarious fear learning, autism.

Figure 1.

Cartoon depiction of behavioral procedures. The social investigation phenotype of test mice was measured following reunion with a same-sex cage mate after 24 h of isolation on PD 23–26 and PD 44–47. Between these time points on PD 31–41 mice were conditioned and tested for direct, vicarious or jointly acquired fear as described in the Methods section.

Figure 2.

Strain differences in social investigation. Sociability testing was conducted during (A) early and (B) late adolescence. Mice were monitored for 300 s. Data are presented as the mean ± std. error. Genotypes are arranged on the abscissa using the rank-order of means for SI. N=25–40 mice per genotype (balanced across sex) for each time point. N=12 mice for MSM. * = FVB > all other strains, P<0.0001; ƒ = ND4/BTBR > B6/DBA2/MSM/BALB, P<0.0001; # = BTBR > B6, P=0.01; ¶ = ND4 > B6/DBA2/MSM/BTBR/BALB, P<0.0001; + = BALB < all other strains, P<0.0001.

Figure 3.

Lack of stimulus mouse genotype and maternal genotype influence on social investigation. Sociability testing was conducted during early adolescence with BALB and FVB test mice. Test mice were reunited (A) with a same-sex B6 cage mate or (B) with a same-sex, same-strain cage mate after being raised by a B6 mother. Mice were monitored for 300 s. Data are presented as the mean ± std. error. N=16 mice per genotype (balanced across sex) for each experiment. *** = main effect of genotype, P<0.0001.

Figure 4.

Strain differences in ultrasonic vocalization emission. USV production was monitored during sociability testing on (A) PD 23–26 and (B) PD 44–47. Mice were monitored for 300 s. Data are presented as the mean ± std. error. Genotypes are arranged on the abscissa using the rank-order of means for USV production. N=19–40 mice per genotype (balanced across sex) for each time point. N=12 for MSM. * = FVB > all other strains; = ND4 > B6/DBA2/MSM/BTBR/BALB, P<0.0001; ‡ = B6/ND4 > DBA2, P<0.0001; Δ = DBA2 > BTBR/BALB, P=0.0007; + = BALB < all other strains, P<0.0001.

Figure 5.

Relationship between social investigation and ultrasonic vocalization emission. Linear regression analysis for (A) PD 23–26 and (B) PD 44–47, with the SI phenotype of each mouse on the abscissa and USV production of each mouse on the ordinate.

Figure 6.

Baseline and cue-induced freezing following vicarious conditioning. Vicarious freezing (A) 15 min and (B) 24 h post-conditioning. Data are presented as the mean ± std. error. Genotypes are arranged on the abscissa using the rank-order of means for cued-induced freezing. N=16–24 mice per genotype (balanced across sex). + = B6 > all other strains, P<0.0001; ƒ = BALB/BTBR/ND4 > DBA2/FVB, P<0.0001; # = BALB>ND4, P=0.002; * = Cued > Baseline, P<0.05.

Figure 7.

Relationship between social investigation and vicarious freezing. Linear regression analysis for (A, C) PD 23–26 and (B, D) PD 44–47, with the SI phenotype of each mouse on the abscissa and the vicarious freezing response of each mouse on the ordinate.

Figure 8.

Contextual and cue-induced freezing following direct and joint conditioning. Freezing (A,B) 15 min and (C,D) 24 h post-conditioning for direct and jointly conditioned mice, respectively. Data are presented as the mean ± std. error. Genotypes are arranged on the abscissa using the rank-order of means for the cued component of freezing. N=13–20 and 15–24 mice per genotype (balanced across sex) for the direct and joint groups, respectively. + = B6 > all other strains, P<0.0001; ƒ = BTBR > ND4/DBA2/FVB/BALB, P<0.0001; # = ND4>DBA2/FVB/BALB, P<0.001; ¶ DBA2>FVB/BALB, P=0.0002; Δ= BALB < all other strains, P<0.0001 ‡ = BALB > DBA2/FVB, P<0.0001; ∞ = DBA2>ND4, P=0.0004 * = Cued > Context, P<0.05; ** = Context > Cued, P<0.05