Inbred strains of mice are useful model systems for studying the interactions of genetic and environmental contributions during neurodevelopmental stages. We recently reported an inbred strain, BTBR T + tf/J (BTBR), which, as compared to the commonly used C57BL/6J (B6) strain, displays lower social interactions as juveniles, lower social approach in adult ages, and higher levels of repetitive self-grooming throughout developmental stages. The present study investigated whether the early postnatal maternal environment contributes substantially to the unusually low expression of social behaviors and high self-grooming in BTBR as compared to B6. Within 24 hours of birth, entire litters of pups were cross-fostered to either a dam of the same strain or a dam of the opposite strain. Control litters were left with their own mothers. Offspring were tested for juvenile play at postnatal day 21±1, for sociability at 8 weeks of age in an automated 3-chambered social approach test, and for self-grooming at 9-11 weeks of age. Results indicate that deficits in play behaviors in juvenile BTBR pups were not rescued by a B6 maternal environment. Similarly, a BTBR maternal environment did not induce play deficits in B6 pups. Cross-fostering had no effect on sociability scores in adults. The high self-grooming in BTBR and low self-grooming in B6 were not affected by maternal environment. These findings favor a genetic interpretation of the unusual social behaviors and self-grooming traits of BTBR, and support the use of the BTBR inbred strain as a mouse model to study genetic mechanism of autism.

Mice are a nocturnal species, whose social behaviors occur primarily during the dark phase of the circadian cycle. However, laboratory rodents are frequently tested during their light phase, for practical reasons. We investigated the question of whether light phase testing presents a methodological pitfall for investigating mouse social approach behaviors. Three lines of mice were systematically compared. One cohort of each line was raised in a conventional lighting schedule and tested during the light phase, under white light illumination; another cohort was raised in a reverse lighting schedule and tested during their dark phase, under dim red light. Male C57BL/6J (B6) displayed high levels of sociability in our three-chambered automated social approach task when tested in either phase. BTBR T+ tf/J (BTBR) displayed low levels of sociability in either phase. Five cohorts of vasopressin receptor subtype 1b (Avpr1b) null mutants, heterozygotes, and wildtype littermate controls were tested in the same social approach paradigm: three in the dark phase and two in the light phase. All three genotypes displayed normal sociability in four out of the five replications. In the juvenile play test, testing phase had no effect on play soliciting behaviors in Avpr1b mice, but had modest effects on nose sniff and huddling. Taken together, these findings indicate that testing phase is not a crucial factor for studying some forms of social approach in juvenile and adult mice.

The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

Using a P7 rat model of hypoxic-ischemic (HI) brain injury we have shown that exposure to hypoxia and hyperoxia (HHI) results in generation of reactive oxygen species, inflammation and cell death-all risk factors for subsequent deficits in neuronal development and function. Hyperoxia increases oxidative stress that can trigger inflammatory cascades, neutrophil activation, and brain microvascular injury. Our experiments utilize a modified version of the Rice-Vanucci model of perinatal hypoxia-ischemia in Wistar rat pups that undergo exposure to 100% oxygen. By using T2weighted magnetic resonance imaging we documented enhanced cortical lesions in HHI animals. Electrochemical monitoring showed bursts of superoxide during 100% oxygen resuscitation. Western blot analyses showed increased cell death measured by cleaved caspase 3 and cytosolic oligonucleosomes, and augmented IL-1 signalling above and beyond levels reported for HI alone. Multiplex antibody cytokine assay demonstrates a spectrum of pro-inflammatory cytokines elevated at 24 h post injury. Consistent with the observed increases in oxidative stress components in the HI rat pups resuscitated with 100% oxygen, there was an increase in COX-2 levels likely to account in part for the increase in oxidative stress. In 80% of preterm infants, the common view is that the benefits of oxygen therapy outweigh the risks. We have shown deficits in attention, motor, visual-motor, and executive processing skills in preterm infants otherwise considered ''healthy,'' but these are not apparent before entry into formal learning settings [Smith et al., 2008. Int. J. Dev. Neurosci. 26 (1): 125-131]. Few clinical studies have attempted to target improving outcomes in this large preterm population. These deficits may be accounted for by inflammation caused by the use of 100% oxygen resuscitation. Our long-term goal is to guide clinical trials of oxygen resuscitation by exploring its consequences in the P7 rat model of HI and developing novel interventions that will enhance benefits while decreasing inflammatory consequences.Autism is a neurodevelopmental disorder of complex etiology. Both genetic and environmental factors have been implicated. BTBR T+tf/J (BTBR) is an inbred strain of mice that displays social deficits and repetitive behaviors analogous to the first and third defining symptoms of autism, representing a promising mouse model for autism. In searching for the causes of the autism-like phenotypes in BTBR, we tested possible hypotheses: (1) early postnatal maternal environment, and (2) the complete absence of a corpus callosum (CC), in the BTBR brain.To test the maternal hypothesis, entire litters of pups were cross-fostered to either a dam of the same strain or one of the opposite strain, within 24 h after birth. Offspring were tested for juvenile play at postnatal day 21 (PND21), for sociability and selfgrooming between 8 and 11 weeks. Results indicate that crossfostering had no effect on play behaviors in juveniles of, and did not affect sociability and self-groomin...