Distinct dynamics of social motivation drive differential social behavior in laboratory rat and mouse strains

Animal models are crucial for understanding mammalian social behavior and associated pathologies. Mice and rats are frequently used, but their behavioral differences are not fully understood. While mice benefit from extensive genetic tools, advancements in rat genome editing are closing the technological gap. This necessitates considering physiological, anatomical, biochemical, and behavioral differences when selecting a model. Previous research indicated significant differences in social behavior between rats and mice, yet quantitative comparisons were limited. This study uses an automated system for detailed analysis of social investigation behavior in small rodents to compare the dynamics of social behavior between C57BL/6J mice and Sprague-Dawley (SD) rats, two strains commonly used in behavioral research and as models of neuropathological conditions. The researchers hypothesize that these two strains will exhibit distinct dynamics in their social behavior due to differences in their underlying social motivation systems.

The literature highlights the value of animal models in studying social behavior and related disorders, but emphasizes the complexity of mammalian social interactions, particularly in comparison to human social relationships. While both mice and rats have long served as model organisms, the availability of genetic tools has favored mice in recent decades. However, the emergence of genome-editing technologies for rats is narrowing the gap between the two, making it crucial to investigate and understand their differences. Although the existence of differences in social behavior between mice and rats is generally acknowledged, few studies have directly compared and quantitatively analyzed these differences. This research builds on previous work by the authors that developed an automated experimental system for detailed analysis of social investigation behavior in small rodents.

The study employed identical experimental setups adapted to the different sizes of mice and rats. Social preference (SP) and social-novelty preference (SNP) tests were conducted using previously described methods. Behavioral data were analyzed using custom software to track investigation time, investigation bouts (categorized by duration), transitions between stimuli, and the relative differential investigation (RDI). To assess the influence of anxiety, a 20-minute habituation period preceding the SP test was used as an open-field test. To examine whether the observed differences originated from the subjects or the stimuli, a movement-monitoring system using piezoelectric sensors was implemented to record the movements of the social stimuli. c-Fos immunohistochemistry was used to analyze neuronal activation in brain areas associated with social investigation (medial amygdala (MeA), nucleus accumbens (NAc), dorsal lateral septum (LSD), and ventral lateral septum (LSV)). A computational discrete-time Markov model was developed to simulate social behavior and test hypotheses regarding the role of social motivation. A social vs. food paradigm was introduced to assess social motivation by inducing competition between social and food stimuli under varying levels of food deprivation. Statistical analyses included t-tests, ANOVAs (including repeated measures and mixed-model ANOVAs), and Wilcoxon signed-rank tests, as appropriate.

The study revealed significant differences in social preference dynamics between C57BL/6J mice and SD rats. SD rats displayed immediate and strong social preference, while C57BL/6J mice exhibited a low level of social motivation at the beginning of the test, gradually increasing over time. Heatmaps of investigation behavior clearly illustrated these differences. SD rats showed significantly higher RDI values compared to C57BL/6J mice. Examination of ICR mice and Wistar Hannover rats showed that they exhibited SP dynamics more similar to SD rats than to C57BL/6J mice, suggesting strain-specific rather than species-specific differences. In the SNP test, C57BL/6J mice showed similar dynamics to the SP test, whereas SD rats showed no preference for the novel social stimulus unless the exposure to the familiar stimulus was extended. Analysis of stimulus movements revealed that while C57BL/6J mice avoided investigating the social stimulus following its major movements, SD rats were attracted to it. c-Fos staining showed that SD rats exhibited significantly higher c-Fos expression in MeA and NAc following a 2-minute SP test, unlike C57BL/6J mice. However, C57BL/6J mice showed significant c-Fos induction in MeA and NAc shell after a 5-minute SP test. The competition paradigm demonstrated that SD rats maintained strong social preference even under food deprivation, while C57BL/6J mice readily shifted their preference to food. A computational model successfully replicated the behavioral dynamics of both strains in both SP and SNP tests, supporting the hypothesis that differences in social motivation drive the distinct patterns of social investigation behavior.

The findings highlight strain-specific differences in social investigation behavior between C57BL/6J mice and SD rats, particularly regarding the dynamics of social motivation. The differences are not simply explained by species-specific factors, given that other strains (ICR and Wistar) demonstrated intermediate behaviors. The analysis of stimulus movements indicated that differences in subject responses, rather than stimulus behavior, drive the observed behavioral variations. The c-Fos data provide neurobiological evidence supporting the hypothesis of differing social motivation systems. The competition paradigm further confirms the higher social motivation in SD rats compared to C57BL/6J mice. The computational model successfully captures the observed behavioral patterns, emphasizing the role of social motivation dynamics in shaping social behavior. The study's implications are significant for researchers selecting appropriate animal models for studying social behavior and related disorders. Researchers must carefully consider strain-specific characteristics to ensure the relevance of their findings.

This study demonstrates significant strain-specific differences in social investigation behavior and motivation between C57BL/6J mice and SD rats. These differences, reflected in behavioral dynamics and c-Fos expression, highlight the importance of careful model selection in social neuroscience research. Future research could explore the genetic and epigenetic mechanisms underlying these strain differences, and investigate the interplay between social motivation and other behavioral factors.

The study focused primarily on male subjects, limiting the generalizability of findings to female rodents. The computational model, while successfully replicating observed behaviors, is a simplification of complex biological systems. Further research is needed to fully elucidate the intricate mechanisms governing social motivation and behavior in these strains.