While breastfeeding benefits early child neurocognition, its influences into adolescence, a period of intense brain remodeling and heightened mental health risk, remain unclear.

Breastfeeding and neurocognitive longitudinal associations were explored over a two-year period in the Adolescent Brain Cognitive Development (ABCD) Study® (nbaseline = 5098, ages 9-10, 49% female; nfollow-up = 3810, ages 11-12, 48% female). Breastfeeding duration was reported as never breastfed (15.8%), 1-6 months (34.6%), 7-12 months (26.4%), and >12 months (23.1%). MRI-derived estimates of cortical thickness, surface area, and cortical myelin were calculated across 148 brain regions alongside fluid cognition measures. Linear mixed-effects models tested the influence of breastfeeding duration and its interaction with age on neurocognitive outcomes. Significant cortical thickness and surface area associations were explored for cortical myelin differences. Parallel mediation analyses examined whether cortical features mediated the breastfeeding-fluid cognition relationship.

Breastfeeding duration was positively associated with cortical thickness (31 regions), surface area (45 regions), and fluid cognition (all p values < 0.05), and with greater cortical myelin in four regions and increases by follow-up in 12 regions (all p values < 0.05). Surface area mediated the breastfeeding-fluid cognition link (β = 0.008, CIboot95% = 0.005, 0.012).

These findings emphasize the importance of extending breastfeeding practices for optimal adolescent neurocognition.

Does breastfeeding influence neurocognition during early adolescence, and does it impact neurocognitive development at this stage? In this longitudinal study, breastfeeding demonstrated dose-dependent, lasting positive influences on neurocognition that remained stable over a 2-year period spanning late childhood to early adolescence. Specifically, individuals who were breastfed longer showed increased cortical thickness, surface area, cortical myelin, and fluid cognition, predictors of positive outcomes in later life, including physical and mental health. Our findings highlight the importance of breastfeeding and support its extended practice for optimal neurodevelopment and potential late-life benefits.

Caenorhabditis elegans and Drosophila melanogaster are powerful experimental models for uncovering fundamental tenets of nervous system organization and function. Findings over the last two decades show that molecular and cellular features are broadly conserved between invertebrates and vertebrates, indicating that insights derived from invertebrate models can broadly inform our understanding of glial operating principles across diverse species. In recent years, these model systems have led to exciting discoveries in glial biology and mechanisms of glia-neuron interactions. Here, we summarize studies that have applied current state-of-the-art "-omics" techniques to C. elegans and D. melanogaster glia. Coupled with the remarkable acceleration in the pace of mechanistic studies of glia biology in recent years, these indicate that invertebrate glia also exhibit striking molecular complexity, specificity, and heterogeneity. We provide an overview of these studies and discuss their implications as well as emerging questions where C. elegans and D. melanogaster are well-poised to fill critical knowledge gaps in our understanding of glial biology.

Pathogenic variants in WDFY3, a gene encoding for an autophagy adaptor termed ALFY, are linked to neurodevelopmental delay and altered brain size in human probands. While the role of WDFY3 loss-of-function is extensively studied in neurons, little is known about the effects of WDFY3 upregulation in different cell types of the central nervous system (CNS). We show that overexpression of the Drosophila melanogaster WDFY3 ortholog, Bchs, in either glia or neurons impaired autophagy and locomotion. Bchs glial overexpression also increased VNC size and glial nuclei number significantly, whereas neuronal Bchs overexpression affected wing and thorax morphology. We identified 79 genes that were differentially expressed and overlapped in flies that overexpress Bchs in glial and neuronal cells, respectively. Additionally, upon neuronal Bchs overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondrial function. Our data indicate that glial as well as neuronal Bchs upregulation can have detrimental outcomes on neural function.

Combinatorial treatments integrating cells and biomolecules within scaffolds have been investigated to address the multifactorial nature of spinal cord injury (SCI). Current regenerative treatments have been ineffective as they do not consider the spatial positions of various cell types to effectively form functional neural pathways. Emulating the complex heterogeneity of cells in the native spinal cord requires translating the existing biological understanding of spatial patterning in neural development, as well as the influence of biomolecule and mechanical patterning on regional specification and axonal regeneration, to engineer a scaffold for spinal cord regeneration. This review explores the potential of 3D bioprinting to precisely control material, cell and drug patterns in scaffolds, achieving spatial phenotype specification and providing axonal guidance to form appropriate connections. We also discuss the application of extrusion-based and digital light processing bioprinting in integrating mechanical, chemical and biological cues within a scaffold to advance spatially patterned 3D bioprinted scaffold, as well as current challenges and future perspectives in these bioengineering strategies.

Schizophrenia is one of the most severe and chronic psychiatric disorders. Over the years, numerous treatment options have been introduced for schizophrenia. Although they are relatively successful in managing the positive symptoms of schizophrenia, most of the current treatments have a negligible effect on the negative and cognitive symptoms. Thus, none of them could prevent the relapse of psychotic episodes. Among the numerous hypotheses explaining the development and progression of schizophrenia, the cytokine hypothesis explains the role of inflammatory markers as a significant culprit in the development of schizophrenia. Elevated cytokines are reported in animal models and schizophrenic patients. The cytokine hypothesis is based on how increased inflammatory markers can cause changes in the dopaminergic, glutamate, and tryptophan metabolism pathways, like that observed in schizophrenic patients. Reasons, such as autoimmune disease, maternal immune activation, infection, etc., can pave the way for the development of schizophrenia and are associated with the negative, positive and cognitive symptoms of schizophrenia. Thus, there is a need to focus on the significance of anti-inflammatory drugs against these symptoms. The development of new treatment strategies in the management of schizophrenia can provide better therapeutic outcomes in terms of the severity of symptoms and treatment of drug-resistant schizophrenia. This review attempts to explain the association between elevated inflammatory markers and various neurotransmitters, and the possible use of medications like nonsteroidal anti-inflammatory drugs, monoclonal antibodies, statins, and estrogens as adjuvant therapy. Over the years, these hypotheses have been the basis for drug discovery for the treatment of schizophrenia.

Aging increases the risk for Alzheimer's disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD's molecular mechanisms.

Some animals can regenerate large missing regions of their nervous system, requiring mechanisms to restore the pattern, numbers, and wiring of diverse neuron classes. Because injuries are unpredictable, regeneration must be accomplished from an unlimited number of starting points. Coordinated regeneration of neuron-glia architecture is thus a major challenge and remains poorly understood. In planarians, neurons and glia are regenerated from distinct progenitors. We found that planarians first regenerate neurons expressing a Delta-encoding gene, delta-2, at key positions in the central and peripheral nervous systems. Planarian glia are specified later from dispersed Notch-1-expressing mesoderm-like phagocytic progenitors. Inhibition of delta-2 or notch-1 severely reduced glia in planarians, but did not affect the specification of other phagocytic cell types. Loss of several delta-2-expressing neuron classes prevented differentiation of the glia associated with them, whereas transplantation of delta-2-expressing photoreceptor neurons was sufficient for glia formation at an ectopic location. Our results suggest a model in which patterned delta-2-expressing neurons instruct phagocytic progenitors to locally differentiate into glia, presenting a mechanism for coordinated regeneration of numbers and pattern of cell types.

Neural circuits distributed across different brain regions mediate how neural information is processed and integrated, resulting in complex cognitive capabilities and behaviour. To understand dynamics and interactions of neural circuits, it is crucial to capture the complete spectrum of neural activity, ranging from the fast action potentials of individual neurons to the population dynamics driven by slow brain-wide oscillations. In this Review, we discuss how advances in electrical and optical recording technologies, coupled with the emergence of machine learning methodologies, present a unique opportunity to unravel the complex dynamics of the brain. Although great progress has been made in both electrical and optical neural recording technologies, these alone fail to provide a comprehensive picture of the neuronal activity with high spatiotemporal resolution. To address this challenge, multimodal experiments integrating the complementary advantages of different techniques hold great promise. However, they are still hindered by the absence of multimodal data analysis methods capable of providing unified and interpretable explanations of the complex neural dynamics distinctly encoded in these modalities. Combining multimodal studies with advanced data analysis methods will offer novel perspectives to address unresolved questions in basic neuroscience and to develop treatments for various neurological disorders.

Molecular genetic approaches in small model organisms like Drosophila have helped to elucidate fundamental principles of neuronal cell biology. Much less is understood about glial cells, although interest in using invertebrate preparations to define their in vivo functions has increased significantly in recent years. This review focuses on our current understanding of the three major neuron-associated glial cell types found in the Drosophila central nervous system (CNS)-astrocytes, cortex glia, and ensheathing glia. Together, these cells act like mammalian astrocytes and microglia; they associate closely with neurons including surrounding neuronal cell bodies and proximal neurites, regulate synapses, and engulf neuronal debris. Exciting recent work has shown critical roles for these CNS glial cells in neural circuit formation, function, plasticity, and pathology. As we gain a more firm molecular and cellular understanding of how Drosophila CNS glial cells interact with neurons, it is clear that they share significant molecular and functional attributes with mammalian glia and will serve as an excellent platform for mechanistic studies of glial function.

Down syndrome (DS) is a genetic intellectual disorder caused by trisomy of chromosome 21 (Hsa21) and presents with a variety of phenotypes. The correlation between the chromosomal abnormality and the resulting symptoms is unclear, partly due to the spectrum of impairments observed. However, it has been determined that trisomy 21 contributes to neurodegeneration and impaired neurodevelopment resulting from decreased neurotransmission, neurogenesis, and synaptic plasticity. DS is linked to synaptic abnormalities and hindered hippocampal neuron development as well. Altered synaptic plasticity in the hippocampus decreases long-term potentiation, leading to short- and long-term learning and memory deficits. Individuals with DS show reduced gray matter, which affects cerebral cortex structure and impairs coordination and thought. Neurotransmitter excess, such as increased gamma-aminobutyric acid (GABA) release, causes over-inhibition and contributes to cognitive deficits. This inhibition also affects hippocampal synaptic plasticity. Additionally, DS often involves neurodegeneration of cholinergic neurons in the basal forebrain, further impairing learning and memory. Reduced glutamate transmission and decreased amyloid precursor protein metabolism contribute to synaptic plasticity deficits and behavioral changes in DS. Decreased neurotransmission, diminished motor neurons, and impaired cerebellar and cerebral development are the main causes of motor deficits in DS. This review discusses the stark structural changes in DS and their functional consequences.

After resection of eloquent gliomas, impacting motor pathways, patients frequently harbour pronounced motor deficits (MD), predominantly attributed to damage to the corticospinal tract (CST).

This study compares the results of conventional DTI-FT and q-ball (QBI)-high resolution FT with patient's postoperative morbidity, relating postoperative MD with the nearest distance from the lesion to the CST (nD-LCST).

In this ongoing prospective trial, we utilized probabilistic High-Resolution Fiber Tracking (HRFT) through q-ball imaging (QBI-FT) and conventional Diffusion Tensor Imaging Fiber Tracking (DTI-FT), based on equal and standard diffusion-weighted MRI. Our analysis focused on the normalized Distance from the lesion to the CST-FT (nD-LCST), compared with MD evaluated via standardized clinical examination.

Post-surgery, 4 patients developed new MD or deteriorated respectively. Among these, one patient was diagnosed with glioblastoma, one with diffuse astrocytoma, one with anaplastic astrocytoma, and one with oligodendroglioma. QBI-FT analysis revealed that patients with MD had a significantly lower median nD-LCST (-0.4 IQR = 2.1), in contrast to those without MD (8.4 IQR = 3.9; p = 0.029). Median values of QBI-FT were located within the tumor outlines, when MD deteriorated. Patients with postoperatively impaired MD had larger tumor volumes compared to those without MD.

Our preliminary findings suggest that QBI-FT may offer advantages over DTI-FT in predicting postoperative motor deficits, potentially enhancing neurosurgical planning. However, due to the small sample size of our study, these results are exploratory, and further research with larger patient populations is necessary to confirm the benefits of QBI-FT. QBI-FT shows promise as a complementary tractography technique suitable for clinical purposes alongside standard DTI-FT.

Nasal respiratory disorders are linked to craniofacial anomalies and systemic dysfunctions. However, the implications of nasal respiratory disorders on brain development and their subsequent impact on brain functionalization remain largely unknown. Here, we describe that nasal obstruction from postnatal developmental stages in mice precipitates deficits in cerebellum-associated behaviors and compromised refinement and maturation of neural circuits in the cerebellum. We show that mice with nasal obstruction during developmental phases exhibit marked impairments in motor function and exhibit increased immobility time in forced swimming test. Additionally, we identified critical periods during which nasal respiration is essential for optimizing motor function and preserving mental health. Our study also reveals that nasal obstruction in mice disrupts the typical developmental process of synapse elimination in the cerebellum and hinders the normal transition of activity patterns in cerebellar Purkinje cell populations during development. Through comparing activity patterns in mouse models subjected to nasal obstruction at various stages, we suggest that the maturation of specific activity pattern among Purkinje cell populations is fundamental to the functional integrity of the cerebellum. Our findings highlight the indispensable role of adequate nasal respiration during development for the establishment and functional integrity of neural circuits, thereby significantly affecting brain function.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons. An increasing body of evidence suggests that in the presence of inflammation and nerve damage, a significant number of satellite glial cells become activated, thus triggering a series of functional changes. This suggests that satellite glial cells are closely related to the occurrence of chronic pain. In this review, we first summarize the morphological structure, molecular markers, and physiological functions of satellite glial cells. Then, we clarify the multiple key roles of satellite glial cells in chronic pain, including gap junction hemichannel Cx43, membrane channel Pannexin1, K channel subunit 4.1, ATP, purinergic P2 receptors, and a series of additional factors and their receptors, including tumor necrosis factor, glutamate, endothelin, and bradykinin. Finally, we propose that future research should focus on the specific sorting of satellite glial cells, and identify genomic differences between physiological and pathological conditions. This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

Despite intense efforts at the bench, the development of successful brain-targeting therapeutics to relieve malicious neural diseases remains primitive. The brain, being a beautifully intricate organ, consists of heterogeneous arrays of neuronal and glial cells. Primarily acting as the support system for neuronal functioning and maturation, glial cells have been observed to be engaged more apparently in the progression and worsening of various neural pathologies. The diseased state is often related to metabolic alterations in glial cells, thereby modulating their physiological homeostasis in conjunction with neuronal dysfunction. A plethora of data indicates the effect of oxidative stress, protein aggregation, and DNA damage in neuroglia impairments. Still, a deeper insight is needed to gain a conflict-free understanding in this arena. As a consequence, glial cells hold the potential to be identified as promising targets for novel therapeutic approaches aimed at brain protection. In this review, we describe the recent strides taken in the direction of understanding the impact of oxidative stress, protein aggregation, and DNA damage on neuroglia impairment and neuroglia-directed nanotherapeutic approaches to mitigate the burden of various neural disorders.

Various chemical modifications of all RNA transcripts, or epitranscriptomics, have emerged as crucial regulators of RNA metabolism, attracting significant interest from both basic and clinical researchers due to their diverse functions in biological processes and immense clinical potential as highlighted by the recent profound success of RNA modifications in improving COVID-19 mRNA vaccines. Rapid accumulation of evidence underscores the critical involvement of various RNA modifications in governing normal neural development and brain functions as well as pathogenesis of brain disorders. Here we provide an overview of RNA modifications and recent advancements in epitranscriptomic studies utilizing animal models to elucidate important roles of RNA modifications in regulating mammalian neurogenesis, gliogenesis, synaptic formation, and brain function. Moreover, we emphasize the pivotal involvement of RNA modifications and their regulators in the pathogenesis of various human brain disorders, encompassing neurodevelopmental disorders, brain tumors, psychiatric and neurodegenerative disorders. Furthermore, we discuss potential translational opportunities afforded by RNA modifications in combatting brain disorders, including their use as biomarkers, in the development of drugs or gene therapies targeting epitranscriptomic pathways, and in applications for mRNA-based vaccines and therapies. We also address current limitations and challenges hindering the widespread clinical application of epitranscriptomic research, along with the improvements necessary for future progress.

Early life stress (ELS) can impact brain development and is a risk factor for neurodevelopmental disorders such as schizophrenia. Post-weaning social isolation (SI) is used to model ELS in animals, using isolation stress to disrupt a normal developmental trajectory. We aimed to investigate how SI affects the expression of genes in mouse hippocampus and to investigate how these changes related to the genetic basis of neurodevelopmental phenotypes. BL/6J mice were exposed to post-weaning SI (PD21-25) or treated as group-housed controls (n = 7-8 per group). RNA sequencing was performed on tissue samples from the hippocampus of adult male and female mice. Four hundred and 1,215 differentially-expressed genes (DEGs) at a false discovery rate of < 0.05 were detected between SI and control samples for males and females respectively. DEGS for both males and females were significantly overrepresented in gene ontologies related to synaptic structure and function, especially the post-synapse. DEGs were enriched for common variant (SNP) heritability in humans that contributes to risk of neuropsychiatric disorders (schizophrenia, bipolar disorder) and to cognitive function. DEGs were also enriched for genes harbouring rare de novo variants that contribute to autism spectrum disorder and other developmental disorders. Finally, cell type analysis revealed populations of hippocampal astrocytes that were enriched for DEGs, indicating effects in these cell types as well as neurons. Overall, these data suggest a convergence between genes dysregulated by the SI stressor in the mouse and genes associated with neurodevelopmental disorders and cognitive phenotypes in humans.

Animal behavior, from simple to complex, is dependent on the faithful wiring of neurons into functional neural circuits. Neural circuits undergo dramatic experience-dependent remodeling during brief developmental windows called critical periods. Environmental experience during critical periods of plasticity produces sustained changes to circuit function and behavior. Precocious critical period closure is linked to autism spectrum disorders, whereas extended synaptic remodeling is thought to underlie circuit dysfunction in schizophrenia. Thus, resolving the mechanisms that instruct critical period timing is important to our understanding of neurodevelopmental disorders. Control of critical period timing is modulated by neuron-intrinsic cues, yet recent data suggest that some determinants are derived from neighboring glial cells (astrocytes, microglia, and oligodendrocytes). As glia make up 50% of the human brain, understanding how these diverse cells communicate with neurons and with each other to sculpt neural plasticity, especially during specialized critical periods, is essential to our fundamental understanding of circuit development and maintenance.

VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest adhesion G protein-coupled receptor (aGPCR). Mutations in VLGR1/ADGRV1 are associated with human Usher syndrome, the most common form of deaf-blindness, and also with epilepsy in humans and mice. VLGR1 is expressed almost ubiquitously but is mainly found in the CNS and in the sensory cells of the eye and inner ear. Little is known about the pathogenesis of the diseases related to VLGR1. We previously identified VLGR1 as a vital component of focal adhesions (FAs) serving as a metabotropic mechanoreceptor controls cell spreading and migration. FAs are highly dynamic and turnover in response to internal and external signals. Here, we aimed to elucidate how VLGR1 participates in FA turnover. Nocodazole washouts and live cell imaging of paxillin-DsRed2 consistently showed that FA disassembly was not altered, but de novo assembly of FA was significantly delayed in Vlgr1-deficient astrocytes, indicating that VLGR1 is enrolled in FA assembly. In FRAP experiments, recovery rates were significantly reduced in Vlgr1-deficient FAs, indicating reduced turnover kinetics in VLGR1-deficient FAs. We showed that VLGR1 regulates cell migration by controlling the FA turnover during their assembly and expect novel insights into pathomechanisms related to pathogenic dysfunctions of VLGR1.

Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using the Drosophila central nervous system (CNS), where glia are categorised into 5 main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single-cell RNA sequencing data of Drosophila glia in 2 well-characterised tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (VNC) (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the VNC. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia in Drosophila, and our extensive in vivo validation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function.

Living in a globalized world, viral infections such as CHIKV, SARS-COV-2, and ZIKV have become inevitable to also infect the most vulnerable groups in our society. That poses a danger to these populations including pregnant women since the developing brain is sensitive to maternal stressors including viral infections. Upon maternal infection, the viruses can gain access to the fetus via the maternofetal barrier and even to the fetal brain during which factors such as viral receptor expression, time of infection, and the balance between antiviral immune responses and pro-viral mechanisms contribute to mother-to-fetus transmission and fetal infection. Both the direct pro-viral mechanisms and the resulting dysregulated immune response can cause multi-level impairment in the maternofetal and brain barriers and the developing brain itself leading to dysfunction or even loss of several cell populations. Thus, maternal viral infections can disturb brain development and even predispose to neurodevelopmental disorders. In this review, we discuss the potential contribution of maternal viral infections of three relevant relative recent players in the field: Zika, Chikungunya, and Severe Acute Respiratory Syndrome Coronavirus-2, to the impairment of brain development throughout the entire route.

After the generation, differentiation and integration into functional circuitry, post-mitotic neurons continue to change certain phenotypic properties throughout postnatal juvenile stages until an animal has reached a fully mature state in adulthood. We will discuss such changes in the context of the nervous system of the nematode C. elegans, focusing on recent descriptions of anatomical and molecular changes that accompany postembryonic maturation of neurons. We summarize the characterization of genetic timer mechanisms that control these temporal transitions or maturational changes, and discuss that many but not all of these transitions relate to sexual maturation of the animal. We describe how temporal, spatial and sex-determination pathways are intertwined to sculpt the emergence of cell-type specific maturation events. Finally, we lay out several unresolved questions that should be addressed to move the field forward, both in C. elegans and in vertebrates.

Glia comprise a heterogeneous group of cells involved in the structure and function of the central and peripheral nervous system. Glial cells are found from invertebrates to humans with morphological specializations related to the neural circuits in which they are embedded. Glial cells modulate neuronal functions, brain wiring and myelination, and information processing. For example, astrocytes send processes to the synaptic cleft, actively participate in the metabolism of neurotransmitters, and release gliotransmitters, whose multiple effects depend on the targeting cells. Human astrocytes are larger and more complex than their mice and rats counterparts. Astrocytes and microglia participate in the development and plasticity of neural circuits by modulating dendritic spines. Spines enhance neuronal connectivity, integrate most postsynaptic excitatory potentials, and balance the strength of each input. Not all central synapses are engulfed by astrocytic processes. When that relationship occurs, a different pattern for thin and large spines reflects an activity-dependent remodeling of motile astrocytic processes around presynaptic and postsynaptic elements. Microglia are equally relevant for synaptic processing, and both glial cells modulate the switch of neuroendocrine secretion and behavioral display needed for reproduction. In this chapter, we provide an overview of the structure, function, and plasticity of glial cells and relate them to synaptic maturation and modulation, also involving neurotrophic factors. Together, neurons and glia coordinate synaptic transmission in both normal and abnormal conditions. Neglected over decades, this exciting research field can unravel the complexity of species-specific neural cytoarchitecture as well as the dynamic region-specific functional interactions between diverse neurons and glial subtypes.

CHARGE syndrome is a multiple anomaly developmental disorder characterized by a variety of sensory deficits, including sensorineural hearing loss of unknown etiology. Most cases of CHARGE are caused by heterozygous pathogenic variants in CHD7, the gene encoding Chromodomain DNA-binding Protein 7 (CHD7), a chromatin remodeler important for the development of neurons and glial cells. Previous studies in the Chd7^Gt/+ mouse model of CHARGE syndrome showed substantial neuron loss in the early stages of the developing inner ear that are compensated for by mid-gestation. In this study, we sought to determine if early developmental delays caused by Chd7 haploinsufficiency affect neurons, glial cells, and inner hair cell innervation in the mature cochlea. Analysis of auditory brainstem response recordings in Chd7^Gt/+ adult animals showed elevated thresholds at 4 kHz and 16 kHz, but no differences in ABR Wave I peak latency or amplitude compared to wild type controls. Proportions of neurons in the Chd7^Gt/+ adult spiral ganglion and densities of nerve projections from the spiral ganglion to the organ of Corti were not significantly different from wild type controls. Inner hair cell synapse formation also appeared unaffected in mature Chd7^Gt/+ cochleae. However, histological analysis of adult Chd7^Gt/+ cochleae revealed diminished satellite glial cells and hypermyelinated Type I spiral ganglion axons. We characterized the expression of CHD7 in developing inner ear glia and found CHD7 to be expressed during a tight window of inner ear development at the Schwann cell precursor stage at E9.5. While cochlear neurons appear to differentiate normally in the setting of Chd7 haploinsufficiency, our results suggest an important role for CHD7 in glial cells in the inner ear. This study highlights the dynamic nature of CHD7 activity during inner ear development in mice and contributes to understanding CHARGE syndrome pathology.

One of the most intriguing dogmas in neurosciences-the empirical lack of brain neuronal regeneration in adulthood onwards to late life-began to be debunked initially by research groups focused on understanding postnatal (early days/weeks of murine and guinea pigs) neurodevelopmental and neuroplastic events [...].

Cell-cell interactions in the central nervous system are based on the release of molecules mediating signal exchange and providing structural and trophic support through vesicular exocytosis and the formation of extracellular vesicles. The specific mechanisms employed by each cell type in the brain are incompletely understood. Here, we explored the means of communication used by Müller cells, a type of radial glial cells in the retina, which forms part of the central nervous system. Using immunohistochemical, electron microscopic, and molecular analyses, we provide evidence for the release of distinct extracellular vesicles from endfeet and microvilli of retinal Müller cells in adult mice in vivo. We identify VAMP5 as a Müller cell-specific SNARE component that is part of extracellular vesicles and responsive to ischemia, and we reveal differences between the secretomes of immunoaffinity-purified Müller cells and neurons in vitro. Our findings suggest extracellular vesicle-based communication as an important mediator of cellular interactions in the retina.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects motor neurons and causes muscle atrophy, paralysis, and death. While a great deal of progress has been made in deciphering the underlying pathogenic mechanisms, no effective treatments for the disease are currently available. This is mainly due to the high degree of complexity and heterogeneity that characterizes the disease. Over the last few decades of research, alterations to bioenergetic and metabolic homeostasis have emerged as a common denominator across many different forms of ALS. These alterations are found at the cellular level (e.g., mitochondrial dysfunction and impaired expression of monocarboxylate transporters) and at the systemic level (e.g., low BMI and hypermetabolism) and tend to be associated with survival or disease outcomes in patients. Furthermore, an increasing amount of preclinical evidence and some promising clinical evidence suggests that targeting energy metabolism could be an effective therapeutic strategy. This review examines the evidence both for and against these ALS-associated metabolic alterations and highlights potential avenues for therapeutic intervention.

Neurodevelopment and efferocytosis have fascinated scientists for decades. How an organism builds a nervous system that is precisely tuned for efficient behaviors and survival and how it simultaneously manages constant somatic cell turnover are complex questions that have resulted in distinct fields of study. Although neurodevelopment requires the overproduction of cells that are subsequently pruned back, very few studies marry these fields to elucidate the cellular and molecular mechanisms that drive nervous system development through the lens of cell clearance. In this review, we discuss these fields to highlight exciting areas of future synergy. We first review neurodevelopment from the perspective of overproduction and subsequent refinement and then discuss who clears this developmental debris and the mechanisms that control these events. We then end with how a more deliberate merger of neurodevelopment and efferocytosis could reframe our understanding of homeostasis and disease and discuss areas of future study. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.

The Drosophila visual system supports complex behaviors and shares many of its anatomical and molecular features with the vertebrate brain. Yet, it contains a much more manageable number of neurons and neuronal types. In addition to the extensive Drosophila genetic toolbox, this relative simplicity has allowed decades of work to yield a detailed account of its neuronal type diversity, morphology, connectivity and specification mechanisms. In the past three years, numerous studies have applied large scale single-cell transcriptomic approaches to the Drosophila visual system and have provided access to the complete gene expression profile of most neuronal types throughout development. This makes the fly visual system particularly well suited to perform detailed studies of the genetic mechanisms underlying the evolution and development of neuronal systems. Here, we highlight how these transcriptomic resources allow exploring long-standing biological questions under a new light. We first present the efforts made to characterize neuronal diversity in the Drosophila visual system and suggest ways to further improve this description. We then discuss current advances allowed by the single-cell datasets, and envisage how these datasets can be further leveraged to address fundamental questions regarding the regulation of neuronal identity, neuronal circuit development and the evolution of neuronal diversity.

Microglia, the resident immune cells of the central nervous system (CNS), were once considered quiescent cells that sat in readiness for reacting to disease and injury. Over the last decade, however, it has become clear that microglia play essential roles in maintaining the normal nervous system. The retina is an easily accessible part of the central nervous system and therefore much has been learned about the function of microglia from studies in the retina and visual system. Anatomically, microglia have processes that contact all synapses within the retina, as well as blood vessels in the major vascular plexuses. Microglia contribute to development of the visual system by contributing to neurogenesis, maturation of cone photoreceptors, as well as refining synaptic contacts. They can respond to neural signals and in turn release a range of cytokines and neurotrophic factors that have downstream consequences on neural function. Moreover, in light of their extensive contact with blood vessels, they are also essential for regulation of vascular development and integrity. This review article summarizes what we have learned about the role of microglia in maintaining the normal visual system and how this has helped in understanding their role in the central nervous system more broadly.

Glia are present in all organisms with a central nervous system but considerably differ in their diversity, functions, and numbers. Coordinated efforts across many model systems have contributed to our understanding of glial-glial and neuron-glial interactions during nervous system development and disease, but human glia exhibit prominent species-specific attributes. Limited access to primary samples at critical developmental timepoints constrains our ability to assess glial contributions in human tissues. This challenge has been addressed throughout the past decade via advancements in human stem cell differentiation protocols that now offer the ability to model human astrocytes, oligodendrocytes, and microglia. Here, we review the use of novel 2D cell culture protocols, 3D organoid models, and bioengineered systems derived from human stem cells to study human glial development and the role of glia in neurodevelopmental disorders.