Climate change, wildfires, and environmental justice concerns have drawn increased attention to the impact of air pollution on children\'s health and development. Children are especially vulnerable to air pollution exposure, as their brains and bodies are still developing. The objective of this systematic review was to synthesize available empirical evidence on the associations between air pollution exposure and brain outcomes in developmental samples (ages 0-18 years old). Studies were identified by searching the PubMed and Web of Science Core Collection databases and underwent a two-phase screening process before inclusion. 40 studies were included in the review, which included measures of air pollution and brain outcomes at various points in development. Results linked air pollution to varied brain outcomes, including structural volumetric and cortical thickness differences, alterations in white matter microstructure, functional network changes, metabolic and molecular effects, as well as tumor incidence. Few studies included longitudinal changes in brain outcomes. This review also suggests methodologies for incorporating air pollution measures in developmental cognitive neuroscience studies and provides specific policy recommendations to reduce air pollution exposure and promote healthy brain development by improving access to clean air.

Development of attentional skills and inhibitory control rely on maturational changes in the brain across childhood and youth. However, both brain anatomy and different components of attention and inhibition show notable individual variation. Research on ADHD and inhibitory training and control have shown that variations in the thickness and surface area of particularly inferior cortical structures are associated with attentional control. However, the intricacies of how the development of inhibitory control is associated with the anatomical variations beyond the general age- and gender-dependent differences have not been resolved. Here, we sought to address these questions by quantifying the cortical thickness and surface area in frontal cortical regions and inhibitory control using the stop signal task performance in 6-14-year-old children. Our results showed that the thickness of the left medial orbitofrontal cortex and the surface area of the left caudal anterior cingulate were associated with the inhibitory performance, beyond the variance that could be explained by the subjects\' age and gender. The results highlight the importance of factoring in anatomical variations when following attentional development and the importance of evaluating multiple anatomical measures when aiming to link the properties of cortical structures with variations in cognitive performance.

Many sex differences in brain and behavior are established developmentally by the opposing processes of feminization and masculinization, which manifest following differential steroid hormone exposure in early life. The cellular mechanisms underlying masculinization are well-documented, a result of the fact that it is steroid-mediated and can be easily induced in newborn female rodents via exogenous steroid treatment. However, the study of feminization of particular brain regions has largely been relegated to being \"not masculinization\" given the absence of an identified initiating trigger. As a result, the mechanisms of this key developmental process remain elusive. Here we describe a novel role for microglia, the brain\'s innate immune cell, in the feminization of the medial amygdala and a complex social behavior, juvenile play. In the developing amygdala, microglia promote proliferation of astrocytes equally in both sexes, with no apparent effect on rates of cell division, but support cell survival selectively in females through the trophic actions of Tumor Necrosis Factor α (TNFα). We demonstrate that disrupting TNFα signaling, either by depleting microglia or inhibiting the associated signaling pathways, prevents the feminization of astrocyte density and increases juvenile play levels to that seen in males. This data, combined with our previous finding that male-like patterns of astrocyte density are sculpted by developmental microglial phagocytosis, reveals that sexual differentiation of the medial amygdala involves opposing tensions between active masculinization and active feminization, both of which require microglia but are achieved via distinct processes.

Carnitine palmitoyltransferase 2 (CPT2) is an inner mitochondrial membrane protein of the carnitine shuttle and is involved in the beta-oxidation of long chain fatty acids. Beta-oxidation provides an alternative pathway of energy production during early development and starvation. CPT2 deficiency is a genetic disorder that we recently showed can be associated with schizophrenia. We hypothesize that CPT2 deficiency during early brain development causes transcriptional, structural, and functional abnormalities that may contribute to a CNS environment that is susceptible to the emergence of schizophrenia. To investigate the effect of CPT2 deficiency on early vertebrate development and brain function, CPT2 was knocked down in a zebrafish model system. CPT2 knockdown resulted in abnormal lipid utilization and deposition, reduction in body size, and abnormal brain development. Axonal projections, neurotransmitter synthesis, electrical hyperactivity, and swimming behavior were disrupted in CPT2 knockdown zebrafish. RT-qPCR analyses showed significant increases in the expression of schizophrenia-associated genes in CPT2 knockdown compared to control zebrafish. Taken together, these data demonstrate that zebrafish are a useful model for studying the importance of beta-oxidation for early vertebrate development and brain function. This study also presents novel findings linking CPT2 deficiency to the regulation of schizophrenia and neurodegenerative disease-associated genes.

BACKGROUND: Recent evidence suggests an association of air pollution exposure with brain development, but evidence on white matter microstructure in children is scarce. We investigated how air pollution exposure during pregnancy and childhood impacts longitudinal development of white matter microstructure throughout adolescence.
METHODS: Our study population consisted of 4108 participants of Generation R, a large population-based birth cohort from Rotterdam, the Netherlands. Residential air pollution exposure to 14 air pollutants during pregnancy and childhood was estimated with land-use regression models. Diffusion tensor images were obtained around age 10 and 14, resulting in a total of 5422 useable scans (n = 3082 for wave 1 and n = 2340 for wave 2; n = 1314 for participants with data on both waves). We calculated whole-brain fractional anisotropy (FA) and mean diffusivity (MD) and performed single- and multi-pollutant analyses using mixed effects models adjusted for life-style and socioeconomic status variables.
RESULTS: Higher exposure to PM2.5 during pregnancy, and PM10, PM2.5, PM2.5-10, and NOX during childhood was associated with a consistently lower whole-brain FA throughout adolescence (e.g. - 0.07 × 10-2 FA [95%CI -0.12; -0.02] per 1 standard deviation higher PM2.5 exposure during pregnancy). Higher exposure to silicon (Si) in PM2.5 and oxidative potential of PM2.5 during pregnancy, and PM2.5 during childhood was associated with an initial higher MD followed by a faster decrease in MD throughout adolescence (e.g. - 0.02 × 10-5 mm2/s MD [95%CI -0.03; -0.00] per year of age per 1 standard deviation higher Si exposure during pregnancy). Results were comparable when performing the analysis in children with complete data on the outcome for both neuroimaging assessments.
CONCLUSIONS: Exposure to several pollutants was associated with a consistently lower whole-brain FA throughout adolescence. The association of few pollutants with whole-brain MD at baseline attenuated throughout adolescence. These findings suggest both persistent and age-limited associations of air pollution exposure with white matter microstructure.

BACKGROUND: Violence exposure during childhood and adolescence is associated with increased prevalence and severity of psychopathology. Neurobiological correlates suggest that abnormal maturation of emotion-related brain circuitry, such as amygdala-prefrontal cortex (PFC), may underlie the development of psychiatric symptoms after exposure; however, it remains unclear how amygdala-PFC circuit maturation is related to psychiatric risk in the context of violence.
METHODS: This study analyzed individual differences in amygdala-PFC circuit maturity using data collected from the Philadelphia Neurodevelopmental Cohort (PNC; N=1,133 youth). Neurodevelopment models of amygdala-PFC resting-state functional connectivity were built using deep learning, trained to predict chronological age in typically developing youth (neither violence exposed nor having a psychiatric diagnosis). Using the brain age gap estimate (BrainAGE), an index of relative circuit maturation, patterns of atypical neurodevelopment were interrogated.
RESULTS: Violence exposure was associated with delayed maturation of basolateral amygdala (BLA) - PFC circuits, driven by increased BLA - medial orbitofrontal cortex functional connectivity. Increased psychiatric symptoms, on the other hand, was associated with advanced maturation of BLA - PFC functional connectivity, driven by decreased BLA - dorsolateral PFC functional connectivity.
CONCLUSIONS: Delayed frontoamygdala maturation after exposure to violence suggests atypical, yet adaptive, development of threat appraisal processes, potentially reflecting greater threat generalization characteristic of younger children. Advanced circuit maturation with increasing symptoms suggests divergent neurodevelopmental mechanisms underlying illness after emotion-circuits have adapted to adversity, exacerbated by pre-existing vulnerabilities to early maturation. Disentangling the effects of adversity and psychopathology on neurodevelopment is crucial for helping youth recover from violence and preventing illness from continuing into adulthood.

BACKGROUND: Emotion regulation skills are linked to corticolimbic brain activity (e.g., dorsolateral prefrontal cortex (dlPFC) and limbic regions) and enable an individual to control their emotional experiences thus allowing healthy social functioning. Disruptions in emotion regulation skills are reported in neuropsychiatric disorders, including conduct disorder or oppositional defiant disorder (CD/ODD). Clinically recognized means to ameliorate emotion regulation deficits observed in CD/ODD include cognitive or dialectical behavioral skills therapy as implemented in the START-NOW program. However, the role of emotion regulation and its neural substrates in symptom severity and prognosis following treatment of adolescent CD/ODD has yet to be investigated.
METHODS: Cross-sectional data including fMRI responses during emotion regulation (N=114; average age=15years), repeated-measures assessments of symptom severity (pre-, post-treatment, long-term follow-up), and fMRI data collected prior to and following the START-NOW randomized controlled trial (n=44) for female adolescents with CD/ODD were analyzed using group comparisons and multiple regression.
RESULTS: First, behavioral and neural correlates of emotion regulation are disrupted in female adolescents with CD/ODD. Second, ODD symptom severity is negatively associated with dlPFC/precentral gyrus activity during regulation. Third, treatment-related symptom changes are predicted by pre-treatment ODD symptom severity and regulatory dlPFC/precentral activity. Additionally, pre-treatment dlPFC/precentral activity and ODD symptom severity predict long-term reductions in symptom severity following treatment for those participants that received the START NOW treatment.
CONCLUSIONS: Our findings demonstrate the important role that emotion regulation skills play in the characteristics of CD/ODD and show that regulatory dlPFC/precentral activity is positively associated with treatment response in female adolescents with CD/ODD.

Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711, it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal-ligand. The Z7 domain adopts a stable tertiary structure upon metal-binding. The NMR structure of Zn2+-bound Z7 shows the classical ββα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenylalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on the Kd values for Zn2+ and Co2+ and retain the high thermal stability of the WT domain above 80°C. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitrophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors.

Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Study success depends on the engagement and inclusion of diverse populations of pregnant participants and their children across the United States, including those at high and low risk for prenatal substance use. The Communications, Engagement, and Dissemination (CED) Committee is responsible for the development and implementation of a strategy to promote awareness about the study, encourage participation, and engage HBCD families, community partners, and collaborators. Initial work involved developing versatile recruitment and awareness materials with a consistent and inclusive message that reduces stigma and negative bias towards marginalized populations, including people with substance use and other mental health conditions. These efforts were shaped by an integrated product development workflow and early engagement with HBCD partners to address challenges. Ongoing work includes the expansion of HBCD outreach through newsletters and social media platforms with an emphasis on protecting participant privacy. Future activities will focus on disseminating scientific information through generation of infographics and webinars that will inform participants, families, and the public of discoveries generated from HBCD Study data.