Stress System Activation in Children and Adolescents With Autism Spectrum Disorder

The mission of the human stress system is the maintenance of homeostasis in the presence of real or perceived, acute or chronic stressors. The hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system (ANS) are the stress system-related neuroendocrine pathways. There is abundant evidence that children and adolescents with autism spectrum disorder (ASD) may exhibit atypical function within the HPA axis and the ANS both at the resting state and during the presence of social and/or non-social stressors. The aim of this review is to provide an up-to-date summary of the findings regarding stress system alterations in children and adolescents with ASD. We focus on the variations of stress hormones circadian rhythms, specifically cortisol and alpha-amylase (i.e., a surrogate index of epinephrine/norepinephrine secretion), and on the alterations of stress system responsivity to different stressors. Also, we present imaging and immunological findings that have been associated with stress system dysregulation in children and adolescents with ASD. Finally, we review the pivotal role of HPA axis-ANS coordination, the developmental trajectory of the stress system in ASD, and the possible role of early life stress in the dysregulation of the stress system demonstrated in children and adolescents with ASD. This synthesis will hopefully provide researchers with a foundation for an integrated approach to future research into stress system variations in children and adolescents with ASD.

A deep generative model for multi-view profiling of single-cell RNA-seq and ATAC-seq data

Here, we present a multi-modal deep generative model, the single-cell Multi-View Profiler (scMVP), which is designed for handling sequencing data that simultaneously measure gene expression and chromatin accessibility in the same cell, including SNARE-seq, sci-CAR, Paired-seq, SHARE-seq, and Multiome from 10X Genomics. scMVP generates common latent representations for dimensionality reduction, cell clustering, and developmental trajectory inference and generates separate imputations for differential analysis and cis-regulatory element identification. scMVP can help mitigate data sparsity issues with imputation and accurately identify cell groups for different joint profiling techniques with common latent embedding, and we demonstrate its advantages on several realistic datasets.

The Effects of Traffic Air Pollution in and around Schools on Executive Function and Academic Performance in Children: A Rapid Review

This review summarises the extant literature investigating the relation between traffic-related air pollution levels in and around schools and executive functioning in primary-school-aged children. An electronic search was conducted using Web of Science, Scopus, and Education Literature Datasets databases (February 2020). Review articles were also searched, and forwards and backwards searches of identified studies were performed. Included papers were assessed for quality. We included 9 separate studies (published in 13 papers). Findings suggest that indoor and outdoor particulate matter with a diameter of 2.5 μm or less (PM2.5) negatively influences executive function and academic achievement and that indoor and outdoor nitrogen dioxide (NO2) adversely affects working memory. Evidence for the effects of particulate matter with a diameter of 10 μm or less (PM10) is limited but suggests potential wide-ranging negative effects on attention, reasoning, and academic test scores. Air pollution in and around schools influences executive function and appears to impede the developmental trajectory of working memory. Further research is required to establish the extent of these effects, reproducibility, consequences for future attainment, and place within the wider context of cognitive development.

Postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary gland

The pituitary gland controls sexually dimorphic processes such as growth, pubertal onset, and lactation. However, the mechanisms underlying sex biases in pituitary gene regulation are not fully understood. To capture pituitary gene regulation dynamics during postnatal development, we ascertained gene and miRNA expression across five postnatal days that span the pubertal transition in mice. Using three prime untranslated region and small RNA sequencing, we observed over 900 instances of sex-biased gene expression, including 18 genes that were putative targets of 5 sex-biased miRNAs. In addition, by combining bulk RNA-seq with scRNA-seq pituitary data, we obtained evidence that cell-type proportion sex differences exist prior to puberty and contribute substantially to the observed sex-biased gene expression post-puberty. This work provides a resource for postnatal mouse pituitary gene regulation and highlights the importance of sex-biases in both cell-type composition and gene regulation when understanding the sexually dimorphic processes regulated by the pituitary gland.

Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level

Background: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. Methods: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. Results: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. Conclusions: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

Ret loss-of-function decreases enteric neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Ret loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

Prenatal immune stress induces a prolonged blunting of microglia activation that impacts striatal connectivity

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

A Developmental Study of Mirror-Gazing-Induced Anomalous Self-Experiences and Self-Reported Schizotypy from 7 to 28 Years of Age

<b><i>Introduction:</i></b> The mirror-gazing task (MGT) is an experimental paradigm inducing anomalous perceptions and anomalous experiences of self-face (ASEs) in the general population, ranging from changes in light and color, to face deformation, to experiencing one’s specular image as another identity. Subclinical ASEs have been related to the emergence of the risk for developing psychotic disorders, and inducing such states in the general population could shed light on the factors underlying interindividual differences in proneness to these phenomena. We aimed to examine the influence of schizotypal personality traits on proneness to experiencing induced ASEs from a developmental perspective, from childhood to adulthood. <b><i>Methods:</i></b> Two hundred and sixteen children, adolescents, and young adults participated in the MGT, and their schizotypal personality traits were assessed with the Schizotypal Personality Questionnaire. Statistical analyses assessed the relationship between schizotypy dimensions and induced ASEs, and we further tested their dynamic relationship as function of age (from childhood to adulthood). <b><i>Results:</i></b> Results confirmed the developmental trajectory of the different schizotypy dimensions, with scores peaking during adolescence, and proneness to induced ASEs seemed to follow a similar developmental trajectory. Moreover, positive (<i>p</i> = 0.001) and disorganized (<i>p</i> = 0.004) dimensions were found to contribute to the proneness to experiencing induced ASEs. Finally, the developmental model showed that positive schizotypy (<i>p</i> = 0.035) uniquely distinguished between experiencing other-identity phenomena between childhood and adulthood. <b><i>Conclusion:</i></b> This study has the potential to inform research on early detection of psychosis through a developmental approach and links the concept of schizotypy with processes of perceptual self-distortions.

Developmental resilience of synaptome architecture

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to repair themselves. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show synaptome remodelling confers resilience to neurodevelopmental disorders.