Microbe-Immune-Stress Interactions Impact Behaviour during Postnatal Development.

Decades of research have established the role of microbiota-brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe-brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome-brain signaling pathways on neurodevelopment and behaviour.

Predictors of Changes in Daily Activity in Transition-Age Autistic Youth.

Transitioning into adulthood is fraught with challenges for autistic youth. A greater understanding of the facilitators of community involvement in school and employment during this period is warranted. The current study examines changes in service need and receipt, and the stability of accessing daily structured activities, for autistic young adults over their transition period compared to adolescents and adults that did not enter the transition period. Baseline caregiver survey data were taken from the Canadian Autism Spectrum Disorders Alliance National Autism Needs Assessment Survey in 2014, and caregivers (n = 304) completed the same set of questions in 2017 about sociodemographic factors, clinical need, service receipt and typical weekday activities. Three cohorts were compared: (1) pretransition age youth, (2) transition-age youth, and (3) young adults who were past transition age. Results suggest that transition-age youth were found to have a unique set of priority service needs compared to pre transition-age adolescent and to adult groups, and both transition-age and adult groups had lower levels of priority service receipt compared to pretransition-age adolescents. The transition-age group experienced the greatest loss of structured weekday activity between time points, and were more likely than pretransition-age adolescents to not have structured weekday activities at Time 2. A recovery of structured daily activity was not observed in young adults. Our results highlight the tumultuous nature of the transition period for autistic youth, which continues into adulthood, and the urgent need for supports during this time. LAY SUMMARY: This research highlights that autistic young people who are transitioning to adulthood are at greatest risk of losing structured weekday activities, and that once in adulthood, many continue to struggle to obtain meaningful community engagement. These results can help guide the design of adolescent and young adult transition programs.

Effects of exercise and enrichment on behaviour in CD-1 mice.

A host of scholarly work has characterized the positive effects of exercise and environmental enrichment on behaviour and cognition in animal studies. The purpose of this study was to investigate the uptake and longitudinal impact of exercise and enrichment on the behavioural phenotype of male and female CD-1 mice. CD-1 mice housed in standard (STD) or exercise and enrichment (EE) conditions post-weaning were tested in the 3-chamber sociability test, open field, and elevated plus maze and exercise activity was monitored throughout the enrichment protocol. Male and female EE mice both showed reduced anxiety and activity in the open field and elevated plus maze relative to sex-matched STD mice. EE altered social behaviours in a sex-specific fashion, with only female EE mice showing increased social preference relative to female STD mice and a preference for social novelty only present in male EE mice. This sexual dimorphism was not observed to be a product of exercise uptake, as CD-1 mice of both sexes demonstrated a consistent trend of wheel rotation frequencies. These findings suggest the importance of considering variables such as sex and strain on experimental design variables in future work on environmental enrichment.

Priority service needs and receipt across the lifespan for individuals with autism spectrum disorder.

Individuals with Autism Spectrum Disorder (ASD) have a range of health, community, and social support needs across the lifespan that create age-specific challenges in navigating service sectors. In this study, we set out to identify the priority needs of individuals with ASD across the lifespan, and the factors that predict receiving priority services. Participants included 3,317 individuals with ASD from a Canada-wide online caregiver survey, stratified into five age groups (preschool, elementary school age, adolescence, emerging adulthood, adulthood). Priority receipt was calculated as a ratio of current services that corresponded to individualized priority need. Age-stratified Poisson regression analyses were used to identify the sociodemographic, clinical and systemic predictors of priority receipt. Results indicate that the distribution of priority need varied by age, except for social skills programming, which was a high across all groups. The number of high and moderate priority needs diversified with age. Overall, 30% of individuals had none of their priority needs met and priority receipt decreased with age. Systemic factors were most consistently related to priority receipt across the lifespan. Understanding patterns and correlates of priority needs and use that currently exist in different age groups can inform policies to improve service access. Autism Res 2017, 10: 1436-1447. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Developmental expression of the neuroligins and neurexins in fragile X mice.

Neuroligins and neurexins are transsynaptic proteins involved in the maturation of glutamatergic and GABAergic synapses. Research has identified synaptic proteins and function as primary contributors to the development of fragile X syndrome. Fragile X mental retardation protein (FMRP), the protein that is lacking in fragile X syndrome, binds neuroligin-1 and -3 mRNA. Using in situ hybridization, we examined temporal and spatial expression patterns of neuroligin (NLGN) and neurexin (NRXN) mRNAs in the somatosensory (S1) cortex and hippocampus in wild-type (WT) and fragile X knockout (FMR1-KO) mice during the first 5 weeks of postnatal life. Genotype-based differences in expression included increased NLGN1 mRNA in CA1 and S1 cortex, decreased NLGN2 mRNA in CA1 and dentate gyrus (DG) regions of the hippocampus, and increased NRXN3 mRNA in CA1, DG, and S1 cortex between female WT and FMR1-KO mice. In male mice, decreased expression of NRXN3 mRNA was observed in CA1 and DG regions of FMR1-KO mice. Sex differences in hippocampal expression of NLGN2, NRXN1, NRXN2, and NRXN3 mRNAs and in S1 cortex expression of NRXN3 mRNAs were observed WT mice, whereas sex differences in NLGN3, NRXN1, NRXN2, and NRXN3 mRNA expression in the hippocampus and in NLGN1, NRXN2 and NRXN3 mRNA expression in S1 cortex were detected in FMR1-KO mice. These results provide a neuroanatomical map of NLGN and NRXN expression patterns over postnatal development in WT and FMR1-KO mice. The differences in developmental trajectory of these synaptic proteins could contribute to long-term differences in CNS wiring and synaptic function.

Temporal and spectral differences in the ultrasonic vocalizations of fragile X knock out mice during postnatal development.

The fmr1 knock out (KO) mouse has been a useful animal model to understand pathology and treatment of FXS, both anatomically and behaviorally. Ultrasonic vocalizations (USVs) are a behavioral tool to assess early life communication deficits in mice. Here, we report on the temporal and spectral features of USVs emitted after maternal separation in wild type (FVB/N) and fmr1 KO pups at postnatal days (P) P4, P7 and P10. The results show changes in the number and duration of calls in fmr1 KO pups and wild type pups were dependent on age and call type. Fmr1 KO pups showed an increased number of USVs at P7 but not at P4 or P10. This increase was specific to Frequency Jump calls. In addition, fmr1 KO mice showed a developmental shift in the temporal distribution of calls, with P10 mice calling in distinct bout patterns. Overall, these findings provide evidence that changes in USV outcomes were specific to certain call types and ages in fmr1 KO mice. Because early postnatal life is a window during which multiple neural systems activate and become established, behavioral measures such as using USVs as a measure of communication, may be useful as a predictor of brain changes and later developmental behavioral changes. Work is needed to better understand the functional outcomes of altered development of USVs and how these changes contribute to later emergence of autistic-like behaviors in animal models of autism.

In utero exposure to valproic acid and autism--a current review of clinical and animal studies.

Valproic acid (VPA) is both an anti-convulsant and a mood stabilizer. Clinical studies over the past 40 years have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism. Two recent FDA warnings related to use of VPA in pregnancy emphasize the need to reevaluate its use clinically during child-bearing years. The emerging clinical evidence showing a link between VPA exposure and both cognitive function and risk of autism brings to the forefront the importance of understanding how VPA exposure influences neurodevelopment. In the past 10 years, animal studies have investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure. Behavioral studies show that VPA exposure in both rats and mice leads to autistic-like behaviors in the offspring, including social behavior deficits, increased repetitive behaviors, and deficits in communication. Based on this work VPA maternal challenge in rodents has been proposed as an animal model to study autism. This model has both face and construct validity; however, like all animal models there are limitations to its translation to the clinical setting. Here we provide a review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies.

Synaptically-competent neurons derived from canine embryonic stem cells by lineage selection with EGF and Noggin.

Pluripotent stem cell lines have been generated in several domestic animal species; however, these lines traditionally show poor self-renewal and differentiation. Using canine embryonic stem cell (cESC) lines previously shown to have sufficient self-renewal capacity and potency, we generated and compared canine neural stem cell (cNSC) lines derived by lineage selection with epidermal growth factor (EGF) or Noggin along the neural default differentiation pathway, or by directed differentiation with retinoic acid (RA)-induced floating sphere assay. Lineage selection produced large populations of SOX2+ neural stem/progenitor cell populations and neuronal derivatives while directed differentiation produced few and improper neuronal derivatives. Primary canine neural lines were generated from fetal tissue and used as a positive control for differentiation and electrophysiology. Differentiation of EGF- and Noggin-directed cNSC lines in N2B27 with low-dose growth factors (BDNF/NT-3 or PDGFαα) produced phenotypes equivalent to primary canine neural cells including 3CB2+ radial progenitors, MOSP+ glia restricted precursors, VIM+/GFAP+ astrocytes, and TUBB3+/MAP2+/NFH+/SYN+ neurons. Conversely, induction with RA and neuronal differentiation produced inadequate putative neurons for further study, even though appropriate neuronal gene expression profiles were observed by RT-PCR (including Nestin, TUBB3, PSD95, STX1A, SYNPR, MAP2). Co-culture of cESC-derived neurons with primary canine fetal cells on canine astrocytes was used to test functional maturity of putative neurons. Canine ESC-derived neurons received functional GABA(A)- and AMPA-receptor mediated synaptic input, but only when co-cultured with primary neurons. This study presents established neural stem/progenitor cell populations and functional neural derivatives in the dog, providing the proof-of-concept required to translate stem cell transplantation strategies into a clinically relevant animal model.