Deconstructing Sociability, An Autism-Relevant Phenotype, in Mouse Models

Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Translational Research Laboratory, Philadelphia, USA.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology (Impact Factor: 1.54). 10/2011; 294(10):1713-25. DOI: 10.1002/ar.21318
Source: PubMed


Reduced sociability is a core feature of autism spectrum disorders (ASD) and is highly disabling, poorly understood, and treatment refractory. To elucidate the biological basis of reduced sociability, multiple laboratories are developing ASD-relevant mouse models in which sociability is commonly assessed using the Social Choice Test. However, various measurements included in that test sometimes support different conclusions. Specifically, measurements of time the "test" mouse spends near a confined "stimulus" mouse (chamber scores) sometimes support different conclusions from measurements of time the test mouse sniffs the cylinder containing the stimulus mouse (cylinder scores). This raises the question of which type of measurements are best for assessing sociability. We assessed the test-retest reliability and ecological validity of chamber and cylinder scores. Compared with chamber scores, cylinder scores showed higher correlations between test and retest measurements, and cylinder scores showed higher correlations with time spent in social interaction in a more naturalistic phase of the test. This suggests that cylinder scores are more reliable and valid measures of sociability in mouse models. Cylinder scores are reported less commonly than chamber scores, perhaps because little work has been done to establish automated software systems for measuring the former. In this study, we found that a particular automated software system performed at least as well as human raters at measuring cylinder scores. Our data indicate that cylinder scores are more reliable and valid than chamber scores, and that the former can be measured very accurately using an automated video analysis system in ASD-relevant models.

Download full-text

Full-text preview

Available from:
  • Source
    • "The apparatus was cleaned with 5% acetic acid solution between each test. The time spent sniffing each cylinder (Fairless et al., 2011) was manually scored by an experimenter blind to the treatments to evaluate the level of preference for the unfamiliar juvenile compared with the object. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28-42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects’ propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally thirty minutes before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.
    Journal of Psychiatric Research 06/2014; DOI:10.1016/j.jpsychires.2014.05.017 · 3.96 Impact Factor
  • Source
    • "Time spent in each chamber, the number of entries into each chamber, and total distance travelled were recorded by automated software (EZ Video, AccuScan Systems, Columbus, OH). The time the subject mouse spent sniffing either stranger mouse and/or the grid enclosure was also recorded by an observer as recommended by Fairless et al. [64]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism is a complex neurodevelopmental disorder characterized by impaired reciprocal social interaction, communication deficits and repetitive behaviors. A very large number of genes have been linked to autism, many of which encode proteins involved in the development and function of synaptic circuitry. However, the manner in which these mutated genes might participate, either individually or together, to cause autism is not understood. One factor known to exert extremely broad influence on brain development and network formation, and which has been linked to autism, is the neurotransmitter serotonin. Unfortunately, very little is known about how alterations in serotonin neuronal function might contribute to autism. To test the hypothesis that serotonin dysfunction can contribute to the core symptoms of autism, we analyzed mice lacking brain serotonin (via a null mutation in the gene for tryptophan hydroxylase 2 (TPH2)) for behaviors that are relevant to this disorder. Mice lacking brain serotonin (TPH2-/-) showed substantial deficits in numerous validated tests of social interaction and communication. These mice also display highly repetitive and compulsive behaviors. Newborn TPH2-/- mutant mice show delays in the expression of key developmental milestones and their diminished preference for maternal scents over the scent of an unrelated female is a forerunner of more severe socialization deficits that emerge in weanlings and persist into adulthood. Taken together, these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism. Our findings should stimulate new studies that focus on determining how brain hyposerotonemia during critical neurodevelopmental periods can alter the maturation of synaptic circuits known to be mis-wired in autism and how prevention of such deficits might prevent this disorder.
    PLoS ONE 11/2012; 7(11):e48975. DOI:10.1371/journal.pone.0048975 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sociability--the tendency to seek social interaction--propels the development of social cognition and social skills, but is disrupted in autism spectrum disorders (ASD). BALB/cJ and C57BL/6J inbred mouse strains are useful models of low and high levels of juvenile sociability, respectively, but the neurobiological and developmental factors that account for the strains' contrasting sociability levels are largely unknown. We hypothesized that BALB/cJ mice would show increasing sociability with age but that C57BL/6J mice would show high sociability throughout development. We also hypothesized that littermates would resemble one another in sociability more than non-littermates. Finally, we hypothesized that low sociability would be associated with low corpus callosum size and increased brain size in BALB/cJ mice. Separate cohorts of C57BL/6J and BALB/cJ mice were tested for sociability at 19-, 23-, 31-, 42-, or 70-days-of-age, and brain weights and mid-sagittal corpus callosum area were measured. BALB/cJ sociability increased with age, and a strain by age interaction in sociability between 31 and 42 days of age suggested strong effects of puberty on sociability development. Sociability scores clustered according to litter membership in both strains, and perinatal litter size and sex ratio were identified as factors that contributed to this clustering in C57BL/6J, but not BALB/cJ, litters. There was no association between corpus callosum size and sociability, but smaller brains were associated with lower sociability in BALB/cJ mice. The associations reported here will provide directions for future mechanistic studies of sociability development.
    Behavioural brain research 12/2011; 228(2):299-310. DOI:10.1016/j.bbr.2011.12.001 · 3.03 Impact Factor
Show more