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Exposure to early life stress (ELS) has been linked to at least double the risk of psychopathology as well as higher morbidity and earlier mortality across the lifespan. For this reason, the field of developmental psychopathology has spent decades identifying factors that explain which individuals are at risk for negative health outcomes. Preclinical experiments in this field commonly test the two-hit hypothesis, which explores how ELS potentiates vulnerability to pathogenic physiological and behavioral outcomes when an individual is exposed to a stressor later in development. Yet, translation of the two-hit hypothesis to humans is conceptually and practically challenging, thus impeding progress in the field. This review summarizes the two-hit hypothesis used in preclinical experiments as it pertains to two putative pathways linking ELS to psychopathology: the innate immune and neuroendocrine systems. This review also identifies important considerations when translating this model to humans and provides several recommendations. Specifically, attention to the biological salience of different forms of ELA and the concordance of that salience with later probes of the system are needed. Further, the consequences of ELS may be context-specific rather than ubiquitous, at least among young people. Within this conceptualization, second hits may be best operationalized using standardized acute challenges to the innate immune and neuroendocrine systems (e.g., psychosocial stress). Third, more explicit reporting of sex differences in the human literature is needed. Finally, preclinical experimental designs that more accurately reflect the natural occurrence of ELS in community samples will more effectively advance the understanding of developmental mechanisms that occur as a consequence of ELS.

Arterial ischemic stroke is common in neonates-1 per 2,300-5,000 births-and therapeutic targets remain insufficiently defined. Sphingosine-1-phosphate receptor 2 (S1PR2), a major regulator of the CNS and immune systems, is injurious in adult stroke. Here, we assessed whether S1PR2 contributes to stroke induced by 3 h transient middle cerebral artery occlusion (tMCAO) in S1PR2 heterozygous (HET), knockout (KO), and wild type (WT) postnatal day 9 pups. HET and WT of both sexes displayed functional deficits in Open Field test whereas injured KO at 24 h reperfusion performed similarly to naives. S1PR2 deficiency protected neurons, attenuated infiltration of inflammatory monocytes, and altered vessel-microglia interactions without reducing increased cytokine levels in injured regions at 72 h. Pharmacologic inhibition of S1PR2 after tMCAO by JTE-013 attenuated injury 72 h after tMCAO. Importantly, the lack of S1PR2 alleviated anxiety and brain atrophy during chronic injury. Altogether, we identify S1PR2 as a potential new target for mitigating neonatal stroke.

Summary: Autism spectrum disorder (ASD) affects social interaction and communication. Emerging evidence links ASD to gut microbiome alterations, suggesting that microbial composition may play a role in the disorder. This study employs explainable artificial intelligence (XAI) to examine the contributions of individual microbial species to ASD. By using local explanation embeddings and unsupervised clustering, the research identifies distinct ASD subgroups, underscoring the disorder’s heterogeneity. Specific microbial biomarkers associated with ASD are revealed, and the best classifiers achieved an AU-ROC of 0.965 ± 0.005 and an AU-PRC of 0.967 ± 0.008. The findings support the notion that gut microbiome composition varies significantly among individuals with ASD. This work’s broader significance lies in its potential to inform personalized interventions, enhancing precision in ASD management and classification. These insights highlight the importance of individualized microbiome profiles for developing tailored therapeutic strategies for ASD.

Summary: The ability to suppress inappropriate actions and respond rapidly to appropriate ones matures late in life, after puberty. We investigated the development of this capability in monkeys trained to look away from a lone, bright stimulus (antisaccade task). We evaluated behavioral performance and recorded neural activity in the prefrontal cortex both before and after the transition from puberty to adulthood. Compared to when young, adult monkeys processed the stimulus more rapidly, resisted more effectively the involuntary urge to look at it, and adhered to the task rule more consistently. The spatially selective visuomotor neurons in the prefrontal cortex provided neural correlates of these behavioral changes indicative of a faster transition from stimulus-driven (exogenous) to goal-driven (endogenous) control within the time course of each trial. The results reveal parallel signatures of cognitive maturation in behavior and prefrontal activity that are consistent with improvements in attentional allocation after adolescence.

Summary: Although the roles of embryonic yolk sac-derived, resident microglia in neurodevelopment were extensively studied, the possible involvement of bone marrow-derived cells remains elusive. In this work, we used a fate-mapping strategy to selectively label bone marrow-derived cells and their progeny in the brain (FLT3+IBA1+). FLT3+IBA1+ cells were confirmed to be transiently present in the healthy brain during early postnatal development. FLT3+IBA1+ cells have a distinct morphology index at postnatal day(P)0, P7, and P14 compared with neighboring microglia. FLT3+IBA1+ cells also express the microglial markers P2RY12 and TMEM119 and interact with VGLUT1 synapses at P14. Scanning electron microscopy indeed showed that FLT3+ cells contact and engulf pre-synaptic elements. Our findings suggest FLT3+IBA1+ cells might assist microglia in their physiological functions in the developing brain including synaptic pruning which is performed using their purinergic sensors. Our findings stimulate further investigation on the involvement of peripheral macrophages during homeostatic and pathological development.

Summary: Axolotls are uniquely able to completely regenerate the spinal cord after amputation. The underlying governing mechanisms of this regenerative response have not yet been fully elucidated. We previously found that spinal cord regeneration is mainly driven by cell-cycle acceleration of ependymal cells, recruited by a hypothetical signal propagating from the injury. However, the nature of the signal and its propagation remain unknown. In this theoretical study, we investigated whether the regeneration-inducing signal can follow a reaction-diffusion process. We developed a computational model, validated it with experimental data, and showed that the signal dynamics can be understood in terms of reaction-diffusion mechanism. By developing a theory of the regenerating outgrowth in the limit of fast reaction-diffusion, we demonstrate that control of regenerative response solely relies on cell-to-signal sensitivity and the signal reaction-diffusion characteristic length. This study lays foundations for further identification of the signal controlling regeneration of the spinal cord.

Summary: Neurons in the neocortex are generated during embryonic development. While the adult ventricular-subventricular zone (V-SVZ) contains cells with neural stem/progenitors’ characteristics, it remains unclear whether it has the capacity of producing neocortical neurons. Here, we show that generating neurons with transcriptomic resemblance to upper layer neocortical neurons continues in the V-SVZ of mouse models of a human condition known as periventricular heterotopia by abrogating Flna and Flnb. We found such surplus neurogenesis was associated with V-SVZ’s upregulation of oxidative phosphorylation, mitochondrial biogenesis, and vascular abundance. Additionally, spatial transcriptomics analyses showed V-SVZ’s neurogenic activation was coupled with transcriptional enrichment of genes in diverse pathways for energy metabolism, angiogenesis, cell signaling, synaptic transmission, and turnovers of nucleic acids and proteins in upper cortical layers. These findings support the potential of generating neocortical neurons in adulthood through boosting brain-wide vascular circulation, aerobic adenosine triphosphate synthesis, metabolic turnover, and neuronal activity.

The epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth; however, its requirement for brain development remains unclear. Here we used a conditional mouse allele for Egfr to examine its contributions to perinatal forebrain development at the tissue level. Subtractive bulk ventral and dorsal forebrain deletions of Egfr uncovered significant and permanent decreases in oligodendrogenesis and myelination in the cortex and corpus callosum. Additionally, an increase in astrogenesis or reactive astrocytes in effected regions was evident in response to cortical scarring. Sparse deletion using mosaic analysis with double markers (MADM) surprisingly revealed a regional requirement for EGFR in rostrodorsal, but not ventrocaudal glial lineages including both astrocytes and oligodendrocytes. The EGFR-independent ventral glial progenitors may compensate for the missing EGFR-dependent dorsal glia in the bulk Egfr-deleted forebrain, potentially exposing a regenerative population of gliogenic progenitors in the mouse forebrain.

Infancy is a sensitive period of development, during which experiences of parental care are particularly important for shaping the developing brain. In a longitudinal study of N = 95 mothers and infants, we examined links between caregiving behavior (maternal sensitivity observed during a mother–infant free‐play) and infants’ neural response to emotion (happy, angry, and fearful faces) at 5 and 7 months of age. Neural activity was assessed using functional Near‐Infrared Spectroscopy (fNIRS) in the dorsolateral prefrontal cortex (dlPFC), a region involved in cognitive control and emotion regulation. Maternal sensitivity was positively correlated with infants’ neural responses to happy faces in the bilateral dlPFC and was associated with relative increases in such responses from 5 to 7 months. Multilevel analyses revealed caregiving‐related individual differences in infants’ neural responses to happy compared to fearful faces in the bilateral dlPFC, as well as other brain regions. We suggest that variability in dlPFC responses to emotion in the developing brain may be one correlate of early experiences of caregiving, with implications for social‐emotional functioning and self‐regulation. [ABSTRACT FROM AUTHOR]

A growing literature links socioeconomic disadvantage and adversity to brain function, including disruptions in reward processing. Less research has examined exposure to community violence (ECV) as a specific adversity related to differences in reward-related brain activation, despite the prevalence of community violence exposure for those living in disadvantaged contexts. The current study tested whether ECV was associated with reward-related ventral striatum (VS) activation after accounting for familial factors associated with differences in reward-related activation (e.g. parenting and family income). Moreover, we tested whether ECV is a mechanism linking socioeconomic disadvantage to reward-related activation in the VS. We utilized data from 444 adolescent twins sampled from birth records and residing in neighborhoods with above-average levels of poverty. ECV was associated with greater reward-related VS activation, and the association remained after accounting for family-level markers of disadvantage. We identified an indirect pathway in which socioeconomic disadvantage predicted greater reward-related activation via greater ECV, over and above family-level adversity. These findings highlight the unique impact of community violence exposure on reward processing and provide a mechanism through which socioeconomic disadvantage may shape brain function. [ABSTRACT FROM AUTHOR]

Summary: Cilia are slender, hair-like structures extending from cell surfaces and playing essential roles in diverse physiological processes. Within the nervous system, primary cilia contribute to signaling and sensory perception, while motile cilia facilitate cerebrospinal fluid flow. Here, we investigated the impact of ciliary loss on neural circuit development using a zebrafish line displaying ciliogenesis defects. We found that cilia defects after neurulation affect neurogenesis and brain morphology, especially in the cerebellum, and lead to altered gene expression profiles. Using whole brain calcium imaging, we measured reduced light-evoked and spontaneous neuronal activity in all brain regions. By shedding light on the intricate role of cilia in neural circuit formation and function in the zebrafish, our work highlights their evolutionary conserved role in the brain and sets the stage for future analysis of ciliopathy models.

Summary: Plasticity during the critical period is important for the functional maturation of cortical neurons. While characteristics of plasticity are diverse among cortical layers, it is unknown whether critical period timing is controlled by a common or unique molecular mechanism among them. We here clarified layer-specific regulation of the critical period timing of ocular dominance plasticity in the primary visual cortex. Mice lacking the endocannabinoid synthesis enzyme diacylglycerol lipase-α exhibited precocious critical period timing, earlier maturation of inhibitory synaptic function in layers 2/3 and 4, and impaired development of the binocular matching of orientation selectivity exclusively in layer 2/3. Activation of cannabinoid receptor restored ocular dominance plasticity at the normal critical period in layer 2/3. Suppression of GABAA receptor rescued precocious ocular dominance plasticity in layer 4. Therefore, endocannabinoids regulate critical period timing and maturation of visual function partly through the development of inhibitory synaptic functions in a layer-dependent manner.

Summary: Although human cortical interneurons (cINs) are a minority population in the cerebral cortex, disruption of interneuron development is a frequent contributor to neurodevelopmental disorders. Here, we utilized a model for deriving cINs from human embryonic stem cells to profile chromatin state changes and generate an atlas of cis-regulatory elements (CREs) controlling human cIN development. We used these data to define candidate transcription factors (TFs) that may bind these CREs to regulate interneuron progenitor specification. Among these were RFX3 and RFX4, risk genes for autism spectrum disorder (ASD) with uncharacterized roles in human neuronal development. Using RFX3 and RFX4 knockdown models, we demonstrated new requirements for both genes in interneuron progenitor specification, with RFX3 deficiency causing precocious neuronal differentiation while RFX4 deficiency instead resulted in cessation of progenitor cell proliferation. Together, this work both defined central features of cis-regulatory control and identified new TF requirements for human interneuron development.

Summary: Aging is a complex biological process with sexually dimorphic aspects. Although cognitive aging of Caenorhabditis elegans hermaphrodites has been studied, less is known about cognitive decline in males. We found that cognitive aging has both sex-shared and sex-dimorphic characteristics, and we identified neuron-specific age-associated sex-differential targets. In addition to sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age, while the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age, indicating possible X chromosome dysregulation that contributes to sexual dimorphism in cognitive aging. Finally, the sex-differentially expressed gene hrg-7, an aspartic-type endopeptidase, regulates male cognitive aging but does not affect hermaphrodites’ behaviors. These results suggest that males and hermaphrodites exhibit different age-related neuronal changes. This study will strengthen our understanding of sex-specific vulnerability and resilience and identify pathways to target with treatments that could benefit both sexes.

Summary: Mitochondrial division controls the size, distribution, and turnover of this essential organelle. A dynamin-related GTPase, Drp1, drives membrane division as a force-generating mechano-chemical enzyme. Drp1 is regulated by multiple mechanisms, including phosphorylation at two primary sites: serine 579 and serine 600. While previous studies in cell culture systems have shown that Drp1 S579 phosphorylation promotes mitochondrial division, its physiological functions remained unclear. Here, we generated phospho-mimetic Drp1 S579D and phospho-defective Drp1 S579R mice using the CRISPR-Cas system. Both mouse models exhibited normal growth, development, and breeding. We found that Drp1 is highly phosphorylated at S579 in brain neurons. Notably, the Drp1 S579D mice showed decreased anxiety-like behaviors, whereas the Drp1 S579R mice displayed increased anxiety-like behaviors. These findings suggest a critical role for Drp1 S579 phosphorylation in brain function. The Drp1 S579D and S579R mice thus offer valuable in vivo models for specific analysis of Drp1 S579 phosphorylation.

Summary: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population average level during typical neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.

Emerging neuroimaging studies investigating changes in the brain aim to collect sufficient data points to examine trajectories of change across key developmental periods. Yet, current studies are often constrained by the number of time points available now. We demonstrate that these constraints should be taken seriously and that studies with two time points should focus on particular questions (e.g., group-level or intervention effects), while complex questions of individual differences and investigations into causes and consequences of those differences should be deferred until additional time points can be incorporated into models of change. We generated underlying longitudinal data and fit models with 2, 3, 4, and 5 time points across 1000 samples. While fixed effects could be recovered on average even with few time points, recovery of individual differences was particularly poor for the two time point model, correlating at r = 0.41 with the true individual parameters - meaning these scores share only 16.8% of variance As expected, models with more time points recovered the growth parameter more accurately; yet parameter recovery for the three time point model was still low, correlating around r = 0.57. We argue that preliminary analyses on early subsets of time points in longitudinal analyses should focus on these average or group-level effects and that individual difference questions should be addressed in samples that maximize the number of time points available. We conclude with recommendations for researchers using early time point models, including ideas for preregistration, careful interpretation of 2 time point results, and treating longitudinal analyses as dynamic, where early findings are updated as additional information becomes available.

Social touch is closely related to the establishment and maintenance of social bonds in humans, and the sensory brain circuit for gentle brushing is already active soon after birth. Brain development is known to be sexually dimorphic, but the potential effect of sex on brain activation to gentle touch remains unknown. Here, we examined brain activation to gentle skin stroking, a tactile stimulation that resembles affective or social touch, in term‐born neonates. Eighteen infants aged 11–36 days, recruited from the FinnBrain Birth Cohort Study, were included in the study. During natural sleep, soft brush strokes were applied to the skin of the right leg during functional magnetic resonance imaging (fMRI) at 3 cm/s velocity. We examined potential differences in brain activation between males (n = 10) and females (n = 8) and found that females had larger blood oxygenation level dependent (BOLD) responses (brushing vs. rest) in bilateral orbitofrontal cortex (OFC), right ventral striatum and bilateral inferior striatum, pons, and cerebellum compared to males. Moreover, the psychophysiological interactions (PPI) analysis, setting the left and right OFC as seed regions, revealed significant differences between males and females. Females exhibited stronger PPI connectivity between the left OFC and posterior cingulate or cuneus. Our work suggests that social touch neural responses are different in male and female neonates, which may have major ramifications for later brain, cognitive, and social development. Finally, many of the sexually dimorphic brain responses were subcortical, not captured by surface‐based neuroimaging, indicating that fMRI will be a relevant technique for future studies. [ABSTRACT FROM AUTHOR]

Summary: Mutations of TRAPPC12 are associated with progressive childhood encephalopathy including abnormal white matter. However, the underlying pathogenesis is still unclear. Here, we found that Trappc12 deficiency in CG4 and oligodendrocyte progenitor cells (OPCs) affects their differentiation and maturation. In addition, TRAPPC12 interacts with Mea6/cTAGE5, and Mea6/cTAGE5 ablation in OPCs affects their proliferation and differentiation, leading to marked hypomyelination, compromised synaptic functionality, and aberrant behaviors in mice. We reveal that TRAPPC12 is associated with COPII components at ER exit site, and Mea6/cTAGE5 cKO disrupts the trafficking pathway by affecting the distribution and/or expression of TRAPPC12, SEC13, SEC31A, and SAR1. Moreover, we observed marked disturbances in the secretion of pleiotrophin (PTN) in Mea6-deficient OPCs. Notably, exogenous PTN supplementation ameliorated the differentiation deficits of these OPCs. Collectively, our findings indicate that the association between TRAPPC12 and MEA6 is important for cargo trafficking and white matter development.

Summary: Functional connectome gradients represent fundamental organizing principles of the brain. Here, we report the development of the connectome gradients in preterm and term babies aged 31–42 postmenstrual weeks using task-free functional MRI and its association with postnatal cognitive growth. We show that the principal sensorimotor-to-visual gradient is present during the late preterm period and continuously evolves toward a term-like pattern. The global measurements of this gradient, characterized by explanation ratio, gradient range, and gradient variation, increased with age (p

Summary: Synapses are fundamental components of the animal nervous system. Synaptic cytoskeleton is essential for maintaining proper neuronal development and wiring. Perturbations in neuronal microtubules (MTs) are correlated with numerous neuropsychiatric disorders. Despite discovering multiple synaptic MT regulators, the importance of MT stability, and particularly the polarity of MT in synaptic function, is still under investigation. Here, we identify Patronin, an MT minus-end-binding protein, for its essential role in presynaptic regulation of MT organization and neuromuscular junction (NMJ) development. Analyses indicate that Patronin regulates synaptic development independent of Klp10A. Subsequent research elucidates that it is short stop (Shot), a member of the Spectraplakin family of large cytoskeletal linker molecules, works synergistically with Patronin to govern NMJ development. We further raise the possibility that normal synaptic MT polarity contributes to proper NMJ morphology. Overall, this study demonstrates an unprecedented role of Patronin, and a potential involvement of MT polarity in synaptic development.

Summary: Human vision relies heavily on prior knowledge. Here, we show for the first time that prior-knowledge-induced reshaping of visual inputs emerges gradually in late childhood. To isolate the effects of prior knowledge on perception, we presented 4- to 12-year-olds and adults with two-tone images – hard-to-recognize degraded photos. In adults, seeing the original photo triggers perceptual reorganization, causing mandatory recognition of the two-tone version. This involves top-down signaling from higher-order brain areas to early visual cortex. We show that children younger than 7–9 years do not experience this knowledge-guided shift, despite viewing the original photo immediately before each two-tone. To assess computations underlying this development, we compared human performance to three neural networks with varying architectures. The best-performing model behaved much like 4- to 5-year-olds, displaying feature-based rather than holistic processing strategies. The reconciliation of prior knowledge with sensory input undergoes a striking age-related shift, which may underpin the development of many perceptual abilities.

Exposure to early life stress (ELS) has been linked to at least double the risk of psychopathology as well as higher morbidity and earlier mortality across the lifespan. For this reason, the field of developmental psychopathology has spent decades identifying factors that explain which individuals are at risk for negative health outcomes. Preclinical experiments in this field commonly test the “two-hit hypothesis”, which explores how ELS potentiates vulnerability to pathogenic physiological and behavioral outcomes when an individual is exposed to a stressor later in development. Yet, translation of the two-hit hypothesis to humans is conceptually and practically challenging, thus impeding progress in the field. This review summarizes the two-hit hypothesis used in preclinical experiments as it pertains to two putative pathways linking ELS to psychopathology: the innate immune and neuroendocrine systems. This review also identifies important considerations when translating this model to humans and provides several recommendations. Specifically, attention to the “biological salience” of different forms of ELA and the concordance of that salience with later probes of the system are needed. Further, the consequences of ELS may be context-specific rather than ubiquitous, at least among young people. Within this conceptualization, “second hits” may be best operationalized using standardized acute challenges to the innate immune and neuroendocrine systems (e.g., psychosocial stress). Third, more explicit reporting of sex differences in the human literature is needed. Finally, preclinical experimental designs that more accurately reflect the natural occurrence of ELS in community samples will more effectively advance the understanding of developmental mechanisms that occur as a consequence of ELS.

Summary: Sensitivity to face-to-face stimuli configurations, which likely indicates interaction, seems to appear early in infants’ development, and recently a preference for face-to-face (vs. other spatial configurations) has been shown to occur in macaque monkeys. It is unknown, however, whether such a preference is acquired through experience or as an evolutionary-given biological predisposition. Here, we exploited a precocial social animal, the domestic chick, as a model system to address this question. Visually naive chicks were tested for their spontaneous preferences for face-to-face vs. back-to-back hen dyads of point-light displays depicting biological motion. We found that female chicks have a spontaneous preference for the facing interactive configuration. Males showed no preference, as expected due to the well-known low social motivation of males in this highly polygynous species. These findings support the idea of an innate and sex-dependent predisposition toward social and interacting stimuli in a vertebrate brain such as that of chicks.

Summary: Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6’s role in brain development and in NPC fate determination while providing data on species generality and differentiation.

Summary: The becoming of the human being is a multisensory process that starts in the womb. By integrating spontaneous neuronal activity with inputs from the external world, the developing brain learns to make sense of itself through multiple sensory experiences. Over the past ten years, advances in neuroimaging and electrophysiological techniques have allowed the exploration of the neural correlates of multisensory processing in the newborn and infant brain, thus adding an important piece of information to behavioral evidence of early sensitivity to multisensory events. Here, we review recent behavioral and neuroimaging findings to document the origins and early development of multisensory processing, particularly showing that the human brain appears naturally tuned to multisensory events at birth, which requires multisensory experience to fully mature. We conclude the review by highlighting the potential uses and benefits of multisensory interventions in promoting healthy development by discussing emerging studies in preterm infants.

Summary: Prdm12 is a transcriptional regulator essential for the emergence of the somatic nociceptive lineage during sensory neurogenesis. The exact mechanisms by which Prdm12 promotes nociceptor development remain, however, poorly understood. Here, we report that the trigeminal and dorsal root ganglia hypoplasia induced by the loss of Prdm12 involves Bax-dependent apoptosis and that it is accompanied by the ectopic expression of the visceral sensory neuron determinants Phox2a and Phox2b, which is, however, not sufficient to impose a complete fate switch in surviving somatosensory neurons. Mechanistically, our data reveal that Prdm12 is required from somatosensory neural precursors to early post-mitotic differentiating nociceptive neurons to repress Phox2a/b and that its repressive function is context dependent. Together, these findings reveal that besides its essential role in nociceptor survival during development, Prdm12 also promotes nociceptor fate via an additional mechanism, by preventing precursors from engaging into an alternate Phox2 driven visceral neuronal type differentiation program.

Summary: Myelin sheath in the central nervous system (CNS) is essential for efficient action potential conduction. Microglia, the macrophages in the CNS, are suggested to regulate myelin development. However, the specific involvement of microglia in initial myelination is yet to be elucidated. Here, first, by culturing neural stem cells, we demonstrated that myelin sheath formation only occurred in the presence of a microglia-conditioned medium. Furthermore, the absence of C1q, a microglia-derived factor, resulted in myelination failure in the neural stem cell culture. Additionally, adding native human C1q protein was sufficient to induce myelination in vitro. Finally, in the C1q conditional knockout mouse model (C1qaFL/FL: Cx3cr1CreER), C1q deficiency prior to the onset of myelination led to reduced myelin thickness and elevated g-ratio during initial myelination. This study uncovers the pivotal role of microglia-derived C1q in developmental myelination and could potentially pave the way for new therapeutic strategies for treating demyelinating diseases.

Summary: Mutations in the human fasciculation and elongation protein zeta 1 (FEZ1) gene are found in schizophrenia and Jacobsen syndrome patients. Here, using human cerebral organoids (hCOs), we show that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. FEZ1 deletion disrupts expression of neuronal and synaptic development genes. Using single-cell RNA sequencing, we detected abnormal expansion of homeodomain-only protein homeobox (HOPX)- outer radial glia (oRG), concurrent with a reduction of HOPX+ oRG, in FEZ1-null hCOs. HOPX− oRGs show higher cell mobility as compared to HOPX+ oRGs. Ectopic localization of neuroprogenitors to the outer layer is seen in FEZ1-null hCOs. Anomalous encroachment of TBR2+ intermediate progenitors into CTIP2+ deep layer neurons further indicated abnormalities in cortical layer formation these hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.

Summary: Action-outcome associations depend on prefrontal cortex (PFC) projections to the dorsal striatum. To assess how these projections form, we measured PFC axon patterning, synapse formation, and functional maturation in the postnatally developing mouse striatum. Using Hotspot analysis, we show that PFC axons form an adult-like pattern of clustered terminations in the first postnatal week that remains largely stable thereafter. PFC-striatal synaptic strength is adult-like by P21, while excitatory synapse density increases until adulthood. We then tested how the targeted deletion of a candidate adhesion/guidance protein, Cadherin-8 (Cdh8), from corticostriatal neurons regulates pathway development. Mutant mice showed diminished PFC axon targeting and reduced spontaneous glutamatergic synaptic activity in the dorsal striatum. They also exhibited impaired behavioral performance in action-outcome learning. The data show that PFC-striatal axons form striatal territories through an early, directed growth model and they highlight essential contributions of Cdh8 to the anatomical and functional features critical for the formation of action-outcome associations.

Summary: Prenatal alcohol exposure (PAE) impairs recovery from cerebrovascular ischemic stroke in adult rodents. Since the gut becomes dysbiotic following stroke, we assessed links between PAE and enteric portal inflammation. Adult control and PAE rat offspring received a unilateral endothelin-1-induced occlusion of the middle cerebral artery. Post-stroke behavioral disabilities and brain cytokines were assessed. Mesenteric adipose and liver transcriptomes were assessed from stroke-exposed and stroke-naive offspring. We identified, in the liver of stroke-naive animals, a moderate correlation between PAE and a gene network for inflammatory necroptosis. PAE inhibited the acute-phase brain inflammatory cytokine response to stroke. Post-stroke neurological function was correlated with an adipose gene network associated with B-lymphocyte differentiation and nuclear factor κB (NF-κB) signaling and with a liver pro-inflammatory gene network. Collectively, PAE inhibits brain inflammation but results in an inflammatory signature in enteric portal tissues after stroke, suggesting that PAE persistently and adversely impacts the gut-brain axis following adult-onset disease.

Summary: Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between unexposed and paracetamol-exposed neonates, however, causality and impact of long-term prenatal paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on an in vitro model of early human neurodevelopment. We exposed human embryonic stem cells undergoing neuronal differentiation with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in neurotransmission and cell fate determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.

Summary: Disorders of folic acid metabolism during pregnancy lead to fetal neural tube defects (NTDs). However, the mechanisms still require further investigation. Here, we aim to analyze the brain metabolic profiles of 30 NTDs and 30 healthy fetuses. Our results indicated that low-folate diet during early life played a causal role in cerebral metabolism, especially in lipometabolic disturbance, highlighting the importance of folate in modulating brain development and metabolism. Next, we established a mouse model of NTDs. Interestingly, the differential metabolites are mainly involved in glycerophospholipid metabolism and biosynthesis of unsaturated fatty acids both in human and mice fetal brain. Since intestinal microbes could critically regulate neurofunction via the intestinal-brain axis, we further found the abundances of Firmicutes and Bacteroidetes in the gut of pregnant mice were correlated with the abundances of lipid metabolism related metabolites in the fetal brain. This finding probably reflects the intergenerational microbial-metabolism biomarkers of NTDs.

Summary: Cell differentiation is associated with global changes in translational activity. Here, we characterize how mRNA poly(A) tail processing supports this dynamic. We observe that decreased translation during neuronal differentiation of P19 cells correlates with the downregulation of 5′-terminal oligopyrimidine (TOP) transcripts which encode the translational machinery. Despite their downregulation, TOP transcripts remain highly stable and show increased translation as cells differentiate. Changes in TOP mRNA metabolism are reflected by their accumulation with poly(A) tails ∼60-nucleotide (nt) long. The dynamic changes in poly(A) processing can be partially recapitulated by depleting LARP1 or activating the mTOR pathway in undifferentiated cells. Although mTOR-induced accumulation of TOP mRNAs with tails ∼60-nt long does not trigger differentiation, it is associated with reduced proliferation of neuronal progenitors. We propose that while TOP mRNAs are transcriptionally silenced, their post-transcriptional regulation mediated by a specific poly(A) processing ensures an adequate supply of ribosomes to complete differentiation.

Summary: The enteric nervous system (ENS) regulates many gastrointestinal functions including peristalsis, immune regulation and uptake of nutrients. Defects in the ENS can lead to severe enteric neuropathies such as Hirschsprung disease (HSCR). Zebrafish have proven to be fruitful in the identification of genes involved in ENS development and HSCR pathogenesis. However, composition and specification of enteric neurons and glial subtypes at larval stages, remains mainly unexplored. Here, we performed single cell RNA sequencing of zebrafish ENS at 5 days post-fertilization. We identified vagal neural crest progenitors, Schwann cell precursors, and four clusters of differentiated neurons. In addition, a previously unrecognized elavl3+/phox2bb-population of neurons and cx43+/phox2bb-enteric glia was found. Pseudotime analysis supported binary neurogenic branching of ENS differentiation, driven by a notch-responsive state. Taken together, we provide new insights on ENS development and specification, proving that the zebrafish is a valuable model for the study of congenital enteric neuropathies.

Summary: Alternative pre-mRNA splicing plays critical roles in brain development. SRSF10 is a splicing factor highly expressed in central nervous system and plays important roles in maintaining normal brain functions. However, its role in neural development is unclear. In this study, by conditional depleting SRSF10 in neural progenitor cells (NPCs) in vivo and in vitro, we found that dysfunction of SRSF10 leads to developmental defects of the brain, which manifest as abnormal ventricle enlargement and cortical thinning anatomically, as well as decreased NPCs proliferation and weakened cortical neurogenesis histologically. Furthermore, we proved that the function of SRSF10 on NPCs proliferation involved the regulation of PI3K-AKT-mTOR-CCND2 pathway and the alternative splicing of Nasp, a gene encoding isoforms of cell cycle regulators. These findings highlight the necessity of SRSF10 in the formation of a structurally and functionally normal brain.

Summary: Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

Handwriting is linked to a variety of systems in the human brain and has been likewise demonstrated to be affected by a variety of neurological and developmental disorders. In this paper we provide a narrative review of recent findings regarding the quantitative evaluation of handwriting product in people with autism spectrum disorder. We summarize the experimental approaches and variables measured by most representative studies, such as handwriting speed and quality. We highlight the key issues such as small sample sizes resulting in underpowered designs. Lastly, we draw conclusions and delineate potential research directions, such as the use of machine learning to evaluate multivariate components of handwriting.

Identification of informative signatures from electrophysiological signals is important for understanding brain developmental patterns, where techniques such as magnetoencephalography (MEG) are particularly useful. However, less attention has been given to fully utilizing the multidimensional nature of MEG data for extracting components that describe these patterns. Tensor factorizations of MEG yield components that encapsulate the data's multidimensional nature, providing parsimonious models identifying latent brain patterns for meaningful summarization of neural processes. To address the need for meaningful MEG signatures for studies of pediatric cohorts, we propose a tensor-based approach for extracting developmental signatures of multi-subject MEG data. We employ the canonical polyadic (CP) decomposition for estimating latent spatiotemporal components of the data, and use these components for group level statistical inference. Using CP decomposition along with hierarchical clustering, we were able to extract typical early and late latency event-related field (ERF) components that were discriminative of high and low performance groups ( p < 0.05 ) and significantly correlated with major cognitive domains such as attention, episodic memory, executive function, and language comprehension. We demonstrate that tensor-based group level statistical inference of MEG can produce signatures descriptive of the multidimensional MEG data. Furthermore, these features can be used to study group differences in brain patterns and cognitive function of healthy children. We provide an effective tool that may be useful for assessing child developmental status and brain function directly from electrophysiological measurements and facilitate the prospective assessment of cognitive processes. [ABSTRACT FROM AUTHOR]

Summary: We investigated how astrocytes in layer 5 mouse visual cortex mature over postnatal days (P) 3–50. Across this age range, resting membrane potential increased, input resistance decreased, and membrane responses became more passive with age. Two-photon (2p) and confocal imaging of dye-loaded cells revealed that gap-junction coupling increased starting ∼P7. Morphological reconstructions revealed increased branch density but shorter branches after P20, suggesting that astrocyte branches may get pruned as tiling is established. Finally, we visualized spontaneous Ca2+ transients with 2p microscopy and found that Ca2+ events decorrelated, became more frequent and briefer with age. As astrocytes mature, spontaneous Ca2+ activity thus changes from relatively cell-wide, synchronous waves to local transients. Several astrocyte properties were stably mature from ∼P15, coinciding with eye opening, although morphology continued to develop. Our findings provide a descriptive foundation of astrocyte maturation, useful for the study of astrocytic impact on visual cortex critical period plasticity.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Summary: Hypothalamic pro-opiomelanocortin (POMC) neuron development is considered to play an essential role in the development of obesity. However, the underlying mechanisms remain unclear. Casein kinase 1α (CK1α) was expressed in the embryonic mouse hypothalamus at high levels and colocalized with POMC neurons. CK1α deletion in POMC neurons caused weight gain, metabolic defects, and increased food intake. The number of POMC-expressing cells was considerably decreased in Csnk1a1fl/fl;POMCcre (PKO) mice from embryonic day 15.5 to postnatal day 60, while apoptosis of POMC neurons was not affected. Furthermore, unchanged POMC progenitor cells and a decreased POMC phenotype established CK1α function in hypothalamic POMC neuron development. CK1α deletion led to elevated Notch intracellular domain (NICD) protein expression, and NICD inhibition rescued the PKO mouse phenotype. In summary, CK1α is involved in hypothalamic POMC expression via NICD-POMC signaling, deepening our understanding of POMC neuron development and control of systemic metabolic functions.

Summary: Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder associated with progressive neurodegenerative phenotypes. Its therapeutic options are very limited. Here, we show that lithium treatment improves ataxia and feeding phenotypes, attenuates cerebellar inflammation and degeneration, and extends survival in Npc1 mouse models. In addition, lithium suppresses STING activation, SREBP2 processing to its mature form and the expression of the target genes in the Npc1 mice and in Npc1-deficient fibroblasts. Lithium impedes STING/SREBP2 transport from the ER to the Golgi, a step required for STING activation and SREBP2 processing, probably by lowering cytosolic calcium concentrations. This effect of lithium on STING/SREBP2 transport provides a mechanistic explanation for lithium’s effects on Npc1 mice. Thus, this study reveals a potential therapeutic option for NP-C patients as well as a strategy to reduce active STING/SREBP2 pathway.

Summary: Arterial ischemic stroke is common in neonates—1 per 2,300–5,000 births—and therapeutic targets remain insufficiently defined. Sphingosine-1-phosphate receptor 2 (S1PR2), a major regulator of the CNS and immune systems, is injurious in adult stroke. Here, we assessed whether S1PR2 contributes to stroke induced by 3 h transient middle cerebral artery occlusion (tMCAO) in S1PR2 heterozygous (HET), knockout (KO), and wild type (WT) postnatal day 9 pups. HET and WT of both sexes displayed functional deficits in Open Field test whereas injured KO at 24 h reperfusion performed similarly to naives. S1PR2 deficiency protected neurons, attenuated infiltration of inflammatory monocytes, and altered vessel-microglia interactions without reducing increased cytokine levels in injured regions at 72 h. Pharmacologic inhibition of S1PR2 after tMCAO by JTE-013 attenuated injury 72 h after tMCAO. Importantly, the lack of S1PR2 alleviated anxiety and brain atrophy during chronic injury. Altogether, we identify S1PR2 as a potential new target for mitigating neonatal stroke.

Summary: DOPEY2 has been shown to be associated with Down syndrome and PCDH7 might be involved in Rett syndrome and MECP2 duplication syndrome. The mechanism how both proteins play roles in these syndromes are largely unknown. Here, we show that Dopey2 and Pcdh7 balance the proliferation and differentiation of neural stem cells and progenitors during embryonic neurogenesis to generate proper size and architecture of zebrafish brains. Dopey2 and Pcdh7 mutually restricted expression of each other in zebrafish embryos. Dopey2 was responsible for the proliferation of neural stem cells/progenitors, whereas Pcdh7 was responsible for the differentiation of neural stem cells/progenitors. Both proteins were shown to orchestrate the proper development and arrangement of neural cells in zebrafish embryonic brains. The results provide an insight into mechanisms to understand how the embryonic brain is constituted and how developmental defects occur in the brains of patients with Down syndrome, Rett syndrome, or MECP2 duplication syndrome.