Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly characterized by deficient sociability and repetitive behaviors. Effective treatment for the core symptoms of ASD is still lacking. Behavioral interventions show limited effectiveness, while pharmacotherapy focuses on the amelioration of secondary symptomatology. Oxytocin (OXT) is a neuropeptide known for its prosocial impact, making it a candidate drug for ASD treatment. Its alleviating effect has been and still is widely researched, but outcomes reported by clinical studies are ambiguous. We examined the effect of daily intranasal OXT (0.8 IU/kg) administration for 4 weeks on the ASD-like phenotype in Shank3^−/− adult mice. Animals treated with OXT spent twice as much time interacting with the social partner as early as after 2 weeks of treatment. Furthermore, OXT-treated mice exhibited reduced explorative behavior by 50%, after 4 weeks of treatment, and a 30% reduction in repetitive behavior, 4 weeks after treatment termination. One-fold higher sociability and 30% reduced exploration due to OXT lasted up to 4 weeks following the treatment termination. However, social disinterest was elevated by roughly 10% as well, indicating a form of social ambivalence. Obtained results support the therapeutic potential of intranasally administered OXT in alleviating social shortfalls in a genetic model of ASD. Subsequent research is necessary to elucidate the benefits and risks of the long-term OXT administration, as well as its applicability in other ASD models and the potential treatment effect on social communication, which was not measured in the present study.

Although autism spectrum disorder (ASD) is mainly characterized by developmental delay in social and communication skills, it has been shown that neuromotor deficits are an early component of ASD. The neuromotor development of B6.129-Shank3^tm2Gfng/J (Shank3B^−/−) mice as an animal model of autism has not been analyzed yet. The aim of this study was to compare the early neuromotor development of Shank3B^−/− to wild-type mice. The mice underwent a multitude of neurodevelopmental tests and observations from postnatal day 1 (PND = 1) to weaning. Shank3B^−/− mice opened their eyes later than their wild-type litter mates (p < 0.01). Shank3B^−/− mice were also slower in the negative geotaxis test from PND = 13 to PND = 16 (p < 0.001) in both sexes. The results of this study indicate neurodevelopmental deficits in Shank3B^−/− mice. The test is partially dependent on truncal motor control, and these lines of evidence suggest a phenotype of developmental hypotonia, which corresponds with the phenotypes seen in patients with Phelan-McDermid Syndrome. There was no observable effect of sex in any of the tests. There were no observed differences in upper and lower incisor eruption, ear unfolding, air righting, surface righting and ear twitch reflexes. Further studies should prove whether the delay in neuromotor development is linked to social or communication deficits, and thus, whether it may serve as an early indicator of autistic-like phenotype in mice.

The increasing incidence of autism spectrum disorder (ASD) increases the urgency of establishing the mechanism of its development for effective prevention and treatment. ASD’s etiology includes genetic predisposition and environmental triggers, both of which can play a role in the changed microbiota. Recent research has proved the impact of maternal microbiota on the neurodevelopment of the child. To investigate the co-play of genetic and microbiota factors in ASD development, we performed fecal microbiota transplantation (FMT) from children with ASD to female Shank3b^+/− mice and studied the autism-like symptoms in the male Shank3b^−/− and wild-type (WT) offspring. WT animals with prenatal exposure to ASD microbiota had delayed neurodevelopment and impaired food intake behavior, but also elevated plasma leptin concentration and body weight. Shank3b^−/− mice after FMT ASD exhibited impaired learning and exacerbated anxiety-like behavior in adulthood. Interestingly, FMT ASD improved learning in adolescent Shank3b^−/− mice. Prenatal exposure to ASD microbiota decreased the activity of hypocretin neurons of the lateral hypothalamic area in both genotypes. The combination of genetic predisposition and FMT ASD led to an increased colon permeability, evaluated by zonula occludens (ZO1, ZO3) and claudin factors. These results suggest the effect of parental FMT exposure on shaping offspring behavior in Shank3b^−/− mice and the potential of microbiota in the modulation of ASD.

A rapid increase in autism spectrum disorder (ASD) prevalence, high heritability, and higher incidence in boys suggest a role of gene-environment interactions, likely involving sex hormones in its etiology. Prenatal exposure to high testosterone concentration has been linked to risk of ASD, however, experimental proof in genetically predisposed animals is lacking. Since neonatal development in mice mirrors late prenatal neurodevelopment in humans, we investigated the effects of neonatal testosterone administration on the behavior of female and male Shank3b^(-/-) mice. On postnatal day 1, neonate Shank3b^(-/-) and wild-type pups of both sexes received a single dose of testosterone (1 mg) or vehicle subcutaneously. Behavioral phenotyping of mice was conducted in adolescence and adulthood. ASD-like behavior was unaffected by the combination of neonatal exposure to testosterone, male sex, and Shank3b deficiency in both adolescence and adulthood. In adolescence, testosterone-treated mice showed 32% higher object-avoidance behavior in comparison to control mice. Shank3b^(-/-) mice spent threefold longer time self-grooming, buried half as many marbles, and vertically explored 23% less than wild-type mice. In adulthood, neonatal exposure to testosterone reduced vertical exploration by 34% and locomotor activity by 15%. Shank3b^(-/-) mice self-groomed threefold longer, buried 31% fewer marbles, and spent 37% less time by vertical exploration than wild-type mice. Neonatal exposure to testosterone seems to affect object avoidance and exploration, rather than ASD-like behavior. Early testosterone exposure or its synergistic effects with sex and genetic predisposition on the ASD-like phenotype later in life seem to be limited.

Background: Squirrel monkeys (SQMs) are a non‐human primate (NHP) model of Alzheimer’s disease (AD) pathology with extensive cerebral amyloid angiopathy (CAA). Our work characterizes neuroimaging biomarkers associated with aging and neurodegeneration. Previously, we demonstrated the sensitivity of 1) in vivo regional quantitative R2* alterations to track age‐related changes in neuropathology and 2) ex vivo diffusion‐weighted (DWI) MRI metrics to visualize changes in brain microstructure. We recently extended our analyses to in vivo multi‐shell diffusion metrics for detection and classification of amyloid‐related imaging abnormalities (ARIA), which have been linked to parenchymal vasogenic edema and sulcal effusions. To further facilitate quantitative analysis of MR markers (diffusion and R2*) we have built a novel pipeline for atlas‐based region‐of‐interest (ROI) segmentation using a SQM brain atlas modified from Schilling et al. (2017). Here we evaluate age‐related changes in R2* values and region‐specific volume using this automated workflow.Method: Young and geriatric female SQMs underwent 2D T₂‐weighted (T₂‐w) Turbo Spin Echo (TSE) RARE and FLAIR MRI scans, in addition to multi‐shell DWI acquisitions. DTI and DKI metrics were derived from DWI datasets, including mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA). We utilized in vivo multi‐gradient echo (MGE) scans to generate R2* maps for ROI‐based quantitative assessments of SQM neuropathology.Result: We identified multiple instances of asymmetric hyperintensities (ARIA‐E) in geriatric SQMs using 2D T₂‐w TSE RARE, FLAIR, and DWI MRI sequences in vivo. While RARE and FLAIR scans demonstrated abnormalities in SQM brains, diffusion metrics MD and MK revealed greater propagation of the lesions through WM tracks. Histological analyses of the underlying neuropathology (e.g. myelin, neuroglia, and amyloid burden) are underway. Significant increases in R2* values with age were observed in all defined cortical regions, with subsequent histological confirmation of severe CAA, microhemorrhages, and iron deposits. Preliminary volumetric measurements revealed significant decreases with age in the prefrontal cortex. Additional morphometric analyses are ongoing.Conclusion: We safely monitored age‐dependent changes in neuroimaging parameters derived from diffusion‐weighted, T₂‐w TSE RARE, and FLAIR acquisitions. Our study highlights the utility of the SQM model to uncover potential long‐term consequences of ARIA and validates diffusion MRI methodologies to target brain integrity.