Peroxisome Proliferator-Activated Receptor-δ Deficiency in Microglia Results in Exacerbated Axonal Injury and Tissue Loss in Experimental Autoimmune Encephalomyelitis.

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor that functions to maintain metabolic homeostasis, regulate cell growth, and limit the development of excessive inflammation during immune responses. Previously, we reported that PPAR-δ-deficient mice develop a more severe clinical course of experimental autoimmune encephalomyelitis (EAE); however, it was difficult to delineate the role that microglia played in this disease phenotype since PPAR-δ-deficient mice exhibited a number of immune defects that enhanced CNS inflammation upstream of microglia activation. Here, we specifically investigated the role of PPAR-δ in microglia during EAE by using mice where excision of a floxed allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene (: ).

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling.

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior.

Multisite Comparison of MRI Defacing Software Across Multiple Cohorts.

With improvements to both scan quality and facial recognition software, there is an increased risk of participants being identified by a 3D render of their structural neuroimaging scans, even when all other personal information has been removed. To prevent this, facial features should be removed before data are shared or openly released, but while there are several publicly available software algorithms to do this, there has been no comprehensive review of their accuracy within the general population. To address this, we tested multiple algorithms on 300 scans from three neuroscience research projects, funded in part by the Ontario Brain Institute, to cover a wide range of ages (3-85 years) and multiple patient cohorts.

Quantitative and Qualitative Sex Modulations in the Brain Anatomy of Autism.

Background: Sex-based neurobiological heterogeneity in autism is poorly understood. Research is disproportionately biased to males, leading to an unwarranted presumption that autism neurobiology is the same across sexes. Previous neuroimaging studies using amalgamated multicenter datasets to increase autistic female samples are characterized by large statistical noise.

Sex differences in fetal Doppler parameters during gestation.

Background: Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy.

Combination of histochemical analyses and micro-MRI reveals regional changes of the murine cervix in preparation for labor.

The cervix is responsible for maintaining pregnancy, and its timely remodeling is essential for the proper delivery of a baby. Cervical insufficiency, or "weakness", may lead to preterm birth, which causes infant morbidities and mortalities worldwide. We used a mouse model of pregnancy and term labor, to examine the cervical structure by histology (Masson Trichome and Picrosirius Red staining), immunohistochemistry (Hyaluronic Acid Binding Protein/HABP), and ex-vivo MRI (T-weighted and diffusion tensor imaging), focusing on two regions of the cervix (i.

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development.

Background: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.

Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.

CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures.

LAMA: automated image analysis for the developmental phenotyping of mouse embryos.

Advanced 3D imaging modalities, such as micro-computed tomography (micro-CT), have been incorporated into the high-throughput embryo pipeline of the International Mouse Phenotyping Consortium (IMPC). This project generates large volumes of raw data that cannot be immediately exploited without significant resources of personnel and expertise. Thus, rapid automated annotation is crucial to ensure that 3D imaging data can be integrated with other multi-dimensional phenotyping data.

Arginase-1 deficiency in neural cells does not contribute to neurodevelopment or functional outcomes after sciatic nerve injury.

Arginase-1 (Arg1) is an enzyme controlling the final step of the urea cycle, with highest expression in the liver and lower expression in the lungs, pancreas, kidney, and some blood cells. Arg1 deficiency is an inherited urea cycle disorder presenting with neurological dysfunction including spastic diplegia, intellectual and growth retardation, and encephalopathy. The contribution of Arg1 expression in the central and peripheral nervous system to the development of neurological phenotypes remains largely unknown.

Sex differences in uterine artery Doppler during gestation in pregnancies complicated by placental dysfunction.

Background: There is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies.

Methods: A prospective longitudinal study was conducted in 240 pregnant women.

Sex differences in modulation of fetoplacental vascular resistance in growth-restricted mouse fetuses following betamethasone administration: comparisons with human fetuses.

Background: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown.

Exploring the Neural Structures Underlying the Procedural Memory Network as Predictors of Language Ability in Children and Adolescents With Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

: There is significant overlap in the type of structural language impairments exhibited by children with autism spectrum disorder (ASD) and children with attention deficit hyperactivity disorder (ADHD). This similarity suggests that the cognitive impairment(s) contributing to the structural language deficits in ASD and ADHD may be shared. Previous studies have speculated that procedural memory deficits may be the shared cognitive impairment.

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels.

Background: Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential.

Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos.

Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity.

Characterization of mice bearing humanized androgen receptor genes (h/mAr) varying in polymorphism length.

The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al., 2006).

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.

Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12.

Cognitive and behavioral risk factors for low quality of life in survivors of childhood acute lymphoblastic leukemia.

Background: With high survival rates for pediatric acute lymphoblastic leukemia (ALL), long-term quality of life is a prominent consideration in treatment. We concurrently evaluated cognition, behavior, and quality of life in child and adolescent ALL survivors and determined associations between them.

Methods: The sample included 83 controls (mean age: 12.

Beyond diagnosis: Cross-diagnostic features in canonical resting-state networks in children with neurodevelopmental disorders.

Children with neurodevelopmental disorders (NDDs) share common behavioural manifestations despite distinct categorical diagnostic criteria. Here, we examined canonical resting-state network connectivity in three diagnostic groups (autism spectrum disorder, attention-deficit/hyperactivity disorder and paediatric obsessive-compulsive disorder) and typically developing controls (TD) in a large single-site sample (N = 407), applying diagnosis-based and dimensional approaches to understand underlying neurobiology across NDDs. Each participant's functional network graphs were computed using five graph metrics.

Dried blood spots for the identification of bio-accumulating organic compounds: current challenges and future perspectives.

The is a concept that underlines the critical relationship between health and environmental exposures, including environmental toxicants. Currently, most environmental exposures that contribute to the exposome have not been characterized. Dried-blood spots (DBS) offer a cost-effective, reliable approach to characterize the blood exposome, which consists of diverse endogenous and exogenous chemicals, including persistent and bioaccumulating organic compounds.

The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death.

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown.

Determination of fetal heart rate short-term variation from umbilical artery Doppler waveforms.

Objective: To evaluate the feasibility of using umbilical artery (UA) Doppler waveforms to measure fetal heart rate (FHR) short-term variation (STV) across gestation.

Methods: This was a prospective longitudinal study, conducted at two study sites, of 195 pregnancies considered low risk. Pulsed-wave Doppler of the UAs was performed at 4-weekly intervals, between 14 and 40 weeks of gestation, using a standardized imaging protocol.

Quantitative MRI outcomes in child and adolescent leukemia survivors: Evidence for global alterations in gray and white matter.

Introduction: Cure rates for pediatric acute lymphoblastic leukemia (ALL) have reached an all-time high (>90%); however, neurocognitive difficulties continue to affect quality of life in at least a subset of survivors. There are relatively few quantitative neuroimaging studies in child and adolescent ALL survivors treated with chemotherapy only. Use of different outcome measures or limited sample sizes restrict our ability to make inferences about patterns of brain development following chemotherapy treatment.

IRX3/5 regulate mitotic chromatid segregation and limb bud shape.

Pattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner.