A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.

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The Steroidogenic Acute Regulatory Protein Is Expressed in Steroidogenic Cells of the Day-Old Brain

Endocrinology ◽

10.1210/en.2003-1740 ◽

2004 ◽

Vol 145 (10) ◽

pp. 4775-4780 ◽

Cited By ~ 20

Author(s):

Steven R. King ◽

Stephen D. Ginsberg ◽

Tomohiro Ishii ◽

Roy G. Smith ◽

Keith L. Parker ◽

...

Keyword(s):

De Novo ◽

Metastatic Lymph Node ◽

Regulatory Protein ◽

Cell Types ◽

Adult Brain ◽

Peripheral Tissues ◽

Cytochrome P450scc ◽

Star Protein ◽

Steroidogenic Acute Regulatory ◽

The Brain

Abstract Although recent research has focused on the fundamental role(s) of steroids synthesized de novo in the brain on development, the mechanism by which production of these neurosteroids is regulated remains unclear. Steroid production in peripheral tissues is acutely regulated by the steroidogenic acute regulatory (StAR) protein, which mediates the rate-limiting step in steroid biosynthesis: the intramitochondrial delivery of cholesterol to cytochrome P450scc for conversion to steroid. We recently demonstrated that StAR is present in discrete cell types in the adult brain, suggesting that neurosteroid production is mediated by StAR. Nevertheless, little is known regarding the presence of StAR in the developing brain. In the present study, the presence of StAR and for the first time, its homolog, the putative cholesterol transport protein metastatic lymph node 64 (MLN64), were defined in the neonatal mouse brain using immunocytochemical techniques. Both StAR and MLN64 were found to be present in the brain with staining patterns characteristic to each protein, indicating the authenticity of StAR and MLN64 immunoreactivity. Furthermore, we found MLN64 to be expressed in the adult brain as well, apparently at higher levels than StAR. Importantly, StAR protein is present in cells that also express P450scc. These data suggest that, as with the adult, neurosteroid production during development occurs through a StAR-mediated pathway.

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Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

10.1101/756635 ◽

2019 ◽

Author(s):

Soumya Korrapati ◽

Ian Taukulis ◽

Rafal Olszewski ◽

Madeline Pyle ◽

Shoujun Gu ◽

...

Keyword(s):

Single Cell ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Stria Vascularis ◽

Cell Types ◽

Cellular Heterogeneity ◽

Genetic Mechanisms ◽

Single Nucleus ◽

Gene Regulatory

AbstractThe stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

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Astrocytes are necessary for blood-brain barrier maintenance in the adult mouse brain

10.1101/2020.03.16.993691 ◽

2020 ◽

Cited By ~ 2

Author(s):

Benjamin P. Heithoff ◽

Kijana K. George ◽

Aubrey N. Phares ◽

Ivan A. Zuidhoek ◽

Carmen Munoz-Ballester ◽

...

Keyword(s):

Blood Brain Barrier ◽

Glucose Transporter ◽

Morphological Changes ◽

Cell Types ◽

Adult Brain ◽

Brain Barrier ◽

Glucose Transporter 1 ◽

Blood Brain ◽

Junction Protein ◽

The Brain

AbstractIn the adult brain, multiple cell types are known to produce factors that regulate blood-brain barrier properties, including astrocytes. Yet several recent studies disputed a role for mature astrocytes at the blood-brain barrier. To determine if astrocytes contribute a non-redundant and necessary function in maintaining the adult blood-brain barrier, we used a mouse model of tamoxifen-inducible astrocyte ablation. In adult mice, tamoxifen induction caused sparse apoptotic astrocyte cell death within 2 hours. Indicative of BBB damage, leakage of the small molecule Cadaverine and the large plasma protein fibrinogen into the brain parenchyma indicative of BBB damage was detected as early as astrocyte ablation was present. Vessels within and close to regions of astrocyte loss had lower expression of the tight junction protein zonula occludens-1 while endothelial glucose transporter 1 expression was undisturbed. Cadaverine leakage persisted for several weeks suggesting a lack of barrier repair. This is consistent with the finding that ablated astrocytes were not replaced. Adjacent astrocytes responded with partial non-proliferative astrogliosis, characterized by morphological changes and delayed phosphorylation of STAT3, which restricted dye leakage to the brain and vessel surface areas lacking coverage by astrocytes one month after ablation. In conclusion, astrocytes are necessary to maintain blood-brain barrier integrity in the adult brain. Blood-brain barrier-regulating factors secreted by other cell types, such as pericytes, are not sufficient to compensate for astrocyte loss.Main PointsMature astrocytes are necessary for maintenance of endothelial tight junctions in the adult brain. Ablated astrocytes are not replaced by proliferation or process extension of neighboring astrocytes resulting in long-term blood-brain barrier damage.

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DNA Methylation Abnormality and Brain Dysfunction of Neural Stem Cells Caused by Chronic Inflammation by Nanoparticle Exposure

Impact ◽

10.21820/23987073.2020.7.28 ◽

2020 ◽

Vol 2020 (7) ◽

pp. 28-30

Author(s):

Ken Tachibana

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neural Development ◽

Broad Class ◽

Cell Types ◽

Associate Professor ◽

Adult Brain ◽

Wide Range ◽

The Creation ◽

The Brain

The biological development of a human is an extremely complex and delicate process. It starts from fertilisation and continues until long after birth. The creation and development of the brain is particularly complicated and susceptible to disruptions to its progression. The primary cells responsible for the development of the brain are the neural stem cells. These are a broad class of cells that can differentiate into the wide range of cell types that form the adult brain. To achieve this complex process, different cells need to undergo a range of gene expression changes at the right time. This is delicate and its disturbance is a key cause of pathology in a wide range of diseases. There are many external factors that are known to disrupt neural development however, there are several common chemicals whose effects remain largely unknown. One such group are broadly described as nanoparticles. These are small particles that are being increasingly used by many industries as they can help in the creation of products with better properties. However, their effect on the environment and the human body – particularly that of a developing brain – have been largely unexamined. Associate Professor Ken Tachibana of the Division of Hygienic Chemistry, Sanyo-Onoda City University, Japan is researching the effects of nanoparticles on neural development.

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Inter-individual body mass variations relate to fractionated functional brain hierarchies

Communications Biology ◽

10.1038/s42003-021-02268-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Bo-yong Park ◽

Hyunjin Park ◽

Filip Morys ◽

Mansu Kim ◽

Kyoungseob Byeon ◽

...

Keyword(s):

Young Adults ◽

Body Mass ◽

Functional Organization ◽

Cell Types ◽

Modular Architecture ◽

Brain Organization ◽

Genome Wide ◽

Learning Techniques ◽

Cerebellar Cell ◽

The Brain

AbstractVariations in body mass index (BMI) have been suggested to relate to atypical brain organization, yet connectome-level substrates of BMI and their neurobiological underpinnings remain unclear. Studying 325 healthy young adults, we examined associations between functional connectivity and inter-individual BMI variations. We utilized non-linear connectome manifold learning techniques to represent macroscale functional organization along continuous hierarchical axes that dissociate low level and higher order brain systems. We observed an increased differentiation between unimodal and heteromodal association networks in individuals with higher BMI, indicative of a disrupted modular architecture and hierarchy of the brain. Transcriptomic decoding and gene enrichment analyses identified genes previously implicated in genome-wide associations to BMI and specific cortical, striatal, and cerebellar cell types. These findings illustrate functional connectome substrates of BMI variations in healthy young adults and point to potential molecular associations.

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Shaking hands is a putative terminal selector and controls axon outgrowth of central complex neurons in the insect model Tribolium

10.1101/2020.11.24.393207 ◽

2020 ◽

Author(s):

Natalia Carolina Garcia-Perez ◽

Gregor Bucher ◽

Marita Buescher

Keyword(s):

Cell Types ◽

Axon Outgrowth ◽

Central Complex ◽

The Subject ◽

Neuronal Subtype ◽

Gene Regulatory ◽

Motor Actions ◽

Developmental Dynamics ◽

The Brain ◽

Command Center

AbstractIndividual cell types are specified by transcriptional programs which act during development. Gene regulatory mechanisms which specify subtype identity of central complex (CX) neurons are the subject of intense investigation. The CX is a compartment within the brain common to all insect species. The CX functions as a “command center” by initiating motor actions in response to incoming information. The CX is made up of several thousand neurons with more than 60 morphologically distinct identities. Accordingly, transcriptional programs must effect the specification of at least as many neuronal subtypes. Here we demonstrate a role for the transcription factor Shaking hands (Skh) in the specification of embryonic CX neurons in Tribolium. The developmental dynamics of Tc-skh expression are characteristic for terminal selectors of neuronal subtype identity. In the embryonic brain Tc-skh expression is restricted to a subset of neurons, many of which survive to adulthood and contribute to the mature CX. Tc-skh expression is maintained throughout the lifetime of the respective CX neurons. Tc-skh knock-down results in severe axon outgrowth defects thus preventing the formation of an embryonic CX primordium. The as yet unstudied Drosophila skh shows a similar embryonic expression pattern suggesting that subtype specification of CX neurons may be conserved.

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A single-cell catalogue of regulatory states in the ageing Drosophila brain

10.1101/237420 ◽

2017 ◽

Cited By ~ 5

Author(s):

Kristofer Davie ◽

Jasper Janssens ◽

Duygu Koldere ◽

Uli Pech ◽

Sara Aibar ◽

...

Keyword(s):

Single Cell ◽

Regulatory Networks ◽

Neuronal Cell ◽

Cell Types ◽

Disease Mutations ◽

Drosophila Brain ◽

Gene Regulatory ◽

Cell Transcriptome ◽

Single Cell Transcriptome ◽

The Brain

SummaryThe diversity of cell types and regulatory states in the brain, and how these change during ageing, remains largely unknown. Here, we present a single-cell transcriptome catalogue of the entire adult Drosophila melanogaster brain sampled across its lifespan. Both neurons and glia age through a process of “regulatory erosion”, characterized by a strong decline of RNA content, and accompanied by increasing transcriptional and chromatin noise. We identify more than 50 cell types by specific transcription factors and their downstream gene regulatory networks. In addition to neurotransmitter types and neuroblast lineages, we find a novel neuronal cell state driven by datilografo and prospero. This state relates to neuronal birth order, the metabolic profile, and the activity of a neuron. Our single-cell brain catalogue reveals extensive regulatory heterogeneity linked to ageing and brain function and will serve as a reference for future studies of genetic variation and disease mutations.

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5-Lipoxygenase DNA Methylation and mRNA Content in the Brain and Heart of Young and Old Mice

Neural Plasticity ◽

10.1155/2009/209596 ◽

2009 ◽

Vol 2009 ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Svetlana Dzitoyeva ◽

Marta Imbesi ◽

Louisa W. Ng ◽

Hari Manev

Keyword(s):

Dna Methylation ◽

Brain Aging ◽

Cell Types ◽

Brain Regions ◽

Dna Methyltransferases ◽

Tissue Samples ◽

Tissue Specific ◽

Mrna Content ◽

Old Mice ◽

The Brain

The expression of 5-lipoxygenase (5-LOX) is affected by aging and regulated by epigenetic mechanisms including DNA methylation. We used methylation-sensitive restriction endonucleases (AciI, BstUI, HpaII, and HinP1I) to assess 5-LOX DNA methylation in brain and heart tissue samples from young (2 months) and old (22 months) mice. We also measured mRNA content for 5-LOX and the DNA methyltransferases DNMT1 and DNMT3a. In young mice, the 5-LOX mRNA content was significantly greater in the heart compared to the brain; 5-LOX DNA methylation was lower, except in the AciI assay in which it was higher in the heart. Aging decreased 5-LOX mRNA content in the heart and increased it in the brain. Aging also increased 5-LOX DNA methylation and this effect was site- (i.e., enzyme) and tissue-specific. Generally, DNMT1 and DNMT3a mRNA content was lower in the brain regions compared to the heart; the only effect of aging was observed in the mRNA content of DNMT3a, which was decreased in the heart of old mice. These results indicate a complex tissue-specific and aging-dependent interplay between the DNA methylation system and 5-LOX mRNA content. Interpretation of this data must take into account that the tissue samples contained a mixture of various cell types.

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Systematic investigation of imprinted gene expression and enrichment in the mouse brain explored at single-cell resolution

10.1101/2020.07.27.222893 ◽

2020 ◽

Author(s):

M. J. Higgs ◽

M. J. Hill ◽

R. M. John ◽

A. R. Isles

Keyword(s):

Gene Expression ◽

Single Cell ◽

Gene Networks ◽

Cell Types ◽

Brain Regions ◽

Systematic Investigation ◽

Adult Brain ◽

Imprinted Genes ◽

Imprinted Gene ◽

The Brain

AbstractAlthough a number of imprinted genes are known to be highly expressed in the brain, and in certain brain regions in particular, whether they are truly over-represented in the brain has never been formally tested. Using fifteen single-cell RNA sequencing datasets we take a systematic approach to investigate imprinted gene over-representation at the organ, brain region, and cell-specific levels. We establish that imprinted genes are indeed over-represented in the adult brain, and in neurons particularly compared to other brain cell-types. We then examine brain-wide datasets to examine enrichment within distinct regions of the brain and demonstrate over-representation of imprinted genes in the hypothalamus, ventral midbrain, pons and medulla. Finally, using datasets focusing on these regions of enrichment, we were able to identify hypothalamic neuroendocrine populations and the monoaminergic hindbrain neurons as specific hotspots of imprinted gene expression. These analyses provide the first robust assessment of the neural systems on which imprinted genes converge. Moreover, the unbiased approach, with each analysis informed by the findings of the previous level, permits highly informed inferences about the functions on which imprinted genes converge. Our findings indicate the neuronal regulation of motivated behaviours such as feeding, parental behaviour and sleep as functional hotspots for imprinting, thus adding statistically rigour to prior assumptions and providing testable predictions for novel neural and behavioural phenotypes associated with specific genes and imprinted gene networks. In turn, this work sheds further light on the potential evolutionary drivers of genomic imprinting in the brain.

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Stem cells in stroke management

Reviews in Clinical Gerontology ◽

10.1017/s0959259810000390 ◽

2010 ◽

Vol 21 (2) ◽

pp. 125-140

Author(s):

Keith W Muir

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tissue Regeneration ◽

Clinical Studies ◽

Cell Types ◽

Adult Brain ◽

Permanent Disability ◽

Ischaemic Injury ◽

Cell Therapies ◽

The Brain

SummaryStem cells are a potential means of tissue regeneration in the brain that hold promise for treatment of the large number of stroke survivors who have permanent disability. Animal studies with stem cells derived from many different sources indicate that cells can migrate to the site of ischaemic injury in the brain, and that some survive and differentiate into neurones and glia with evidence of electrical function. Cells additionally promote endogenous repair mechanisms, including mobilization of neural stem cells resident within the adult brain. Whether the behavioural benefits seen with stem cell administration in rodent models reflect enhanced endogenous recovery or tissue regeneration is unclear. Production of stem cells to clinical standards and in quantities required for clinical studies is technically challenging. To date only a handful of patients have been involved in preliminary clinical studies of cell therapies for stroke, and there are therefore insufficient data to draw conclusions about either safety or efficacy. Further trials with several cell types are ongoing or planned, including neural stem cells, and bone marrow-derived stem cells and endothelial progenitor cells.

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