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Scientific Reports Jun 2024Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and...
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.
Topics: Animals; Hernias, Diaphragmatic, Congenital; Neurons; Oligodendroglia; Rats; Humans; Brain; Female; Stem Cells; Fetus; Disease Models, Animal; Pregnancy; Male
PubMed: 38871804
DOI: 10.1038/s41598-024-64412-x -
Brain and Behavior Jun 2024In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to...
INTRODUCTION
In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants.
METHODS
Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio.
RESULTS
Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function.
CONCLUSIONS
The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.
Topics: Humans; Male; Female; Magnetic Resonance Imaging; Aged; Middle Aged; Myelin Sheath; Autism Spectrum Disorder; Adult; Cerebral Cortex; Neuropsychological Tests; Aging
PubMed: 38849980
DOI: 10.1002/brb3.3594 -
Neurobiology of Disease Aug 2024Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of...
Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.
Topics: alpha-Synuclein; Multiple System Atrophy; Humans; Oligodendroglia; Inclusion Bodies; Aged; Female; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Aged, 80 and over
PubMed: 38839023
DOI: 10.1016/j.nbd.2024.106551 -
Immunity Jun 2024Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia...
Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER, that targets PAMs and DAMs in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several disease models, uncovering convergence and context-dependent differences in PAM and DAM gene expression. Through long-term tracking, we demonstrated microglial state plasticity. Lastly, we specifically depleted DAMs in demyelination, revealing their roles in disease recovery. Together, we provide a versatile genetic tool to characterize microglial states in CNS development and disease.
Topics: Microglia; Animals; Mice; Remyelination; Cell Plasticity; Demyelinating Diseases; Mice, Inbred C57BL; Mice, Transgenic; Disease Models, Animal; Brain; Myelin Sheath; White Matter
PubMed: 38821054
DOI: 10.1016/j.immuni.2024.05.005 -
Gut Microbes 2024Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating...
Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating a deeper understanding of early life factors on children's brain development. This study introduces a mouse model, knockout mice, to investigate the relationship between breast milk, the gut microbiome, and brain development. The results reveal that breast milk's reactive oxygen species (ROS) are vital in shaping the neonatal gut microbiota. Decreased hydrogen peroxide (HO) levels in milk disrupt the gut microbiome and lead to abnormal metabolite production, including D-glucaric acid. This metabolite inhibits hippocampal myelin formation during infancy, potentially contributing to behavioral abnormalities observed in adulthood. These findings suggest that HO in breast milk is crucial for normal gut microbiota formation and brain development, with implications for understanding and potentially treating neurodevelopmental disorders in humans.
Topics: Animals; Gastrointestinal Microbiome; Myelin Sheath; Mice; Animals, Newborn; Mice, Knockout; Milk, Human; Humans; Female; Hydrogen Peroxide; Brain; Reactive Oxygen Species; Hippocampus; Male; Mice, Inbred C57BL
PubMed: 38816999
DOI: 10.1080/19490976.2024.2359729 -
Nature Communications May 2024Lipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52...
Lipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52 neocortical ones. The lipidome composition varies greatly among the brain regions, affecting 93% of the 419 analyzed lipids. These differences reflect the brain's structural characteristics, such as myelin content (345 lipids) and cell type composition (353 lipids), but also functional traits: functional connectivity (76 lipids) and information processing hierarchy (60 lipids). Combining lipid composition and mRNA expression data further enhances functional connectivity association. Biochemically, lipids linked with structural and functional brain features display distinct lipid class distribution, unsaturation extent, and prevalence of omega-3 and omega-6 fatty acid residues. We verified our conclusions by parallel analysis of three adult macaque brains, targeted analysis of 216 lipids, mass spectrometry imaging, and lipidome assessment of sorted murine neurons.
Topics: Humans; Lipidomics; Animals; Brain; Mice; Adult; Lipids; Male; Lipid Metabolism; Macaca; Neurons; Female; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Myelin Sheath; Middle Aged
PubMed: 38796479
DOI: 10.1038/s41467-024-48734-y -
International Journal of Molecular... May 2024In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial...
In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as , , and . The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as and . Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.
Topics: MicroRNAs; Animals; Exosomes; Hypothalamus; Aging; Neural Stem Cells; Gene Regulatory Networks; Cellular Senescence; Brain; Mice; Parabiosis; Oligodendroglia; Transcriptome; Gene Expression Regulation; Gene Expression Profiling
PubMed: 38791505
DOI: 10.3390/ijms25105467 -
International Journal of Molecular... May 2024The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire...
The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.
Topics: Schwann Cells; SOXE Transcription Factors; Cell Differentiation; Animals; Co-Repressor Proteins; Rats; Mice; Feedback, Physiological; Myelin Sheath; Gene Expression Regulation; Humans; Transcription Factor HES-1
PubMed: 38791273
DOI: 10.3390/ijms25105234 -
Molecular Brain May 2024The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that...
The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.
Topics: Animals; alpha-Synuclein; Oligodendroglia; Multiple System Atrophy; Mice, Transgenic; Inclusion Bodies; Humans; Disease Models, Animal; Protein Aggregates; Green Fluorescent Proteins; Cytoplasm; Mice; Brain; Protein Aggregation, Pathological
PubMed: 38790036
DOI: 10.1186/s13041-024-01104-7 -
Cell Death & Disease May 2024Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe...
Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.
Topics: Animals; GTP-Binding Protein gamma Subunits; Cell Differentiation; Mice; Oligodendrocyte Precursor Cells; Myelin Sheath; Cognitive Dysfunction; Lipid Metabolism; Oligodendroglia; Mice, Inbred C57BL; PPAR gamma; Mice, Knockout; Male; Rosiglitazone
PubMed: 38773070
DOI: 10.1038/s41419-024-06737-z