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Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A "Complete Deletion" (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus. [ABSTRACT FROM AUTHOR]

Background: Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal (i.e., hormonal) and chromosomal sex, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex specific deficits in social motivation. In this study, we aimed to determine if hormonal or chromosomal sex primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency., Methods: Four-core genotype (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation., Results: The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovaries, and by extension the presence of ovarian hormones, increased overall activity, social seeking, and social orienting regardless of genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX sex karyotype when combined with MYT1L genotype contributing to increased social orienting and seeking., Conclusions: Gonadal and chromosomal sex have independent mechanisms of driving increased social motivation in females. Additionally, sex chromosomes may interact with neurodevelopmental mutations to influence sex variation in atypical social behavior., Competing Interests: Competing Interests Statement: The authors declare no conflict of interest.