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Gene expression in primate postnatal brain through lifespan - cerebellar cortex

ABSTRACT: We investigated molecular changes during human, chimpanzee, and rhesus macaque postnatal brain development at the transcriptome, proteome, and metabolome levels in two brain regions: the prefrontal cortex (PFC) that is involved in several human-specific cognitive processes, and the cerebellar cortex (CBC) that may be functionally more conserved. We find a nearly three-fold excess of human-specific gene expression changes in PFC compared to CBC. The most prominent human-specific mRNA expression pattern in the PFC is a developmental delay of approximately 5 years in the expression of genes associated with learning and memory, such as synaptic transmission and long-term potentiation. This pattern is supported by correlated changes in concentrations of proteins and the respective neurotransmitters and its magnitude is beyond the shift expected from the life-histories of the species. Mechanistically, it might be driven by change in timing of expression of four or more transcription factors. We speculate that delayed synaptic maturation in PFC may play a role in the emergence of human-specific cognitive abilities. Keywords: Age series

ORGANISM(S): Pan troglodytes Homo sapiens Macaca mulatta

PROVIDER: GSE22569 | GEO | 2011/12/09

SECONDARY ACCESSION(S): PRJNA129099

REPOSITORIES: GEO

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Gene expression in primate postnatal brain through lifespan - cerebellar cortex

Project description:We investigated molecular changes during human, chimpanzee, and rhesus macaque postnatal brain development at the transcriptome, proteome, and metabolome levels in two brain regions: the prefrontal cortex (PFC) that is involved in several human-specific cognitive processes, and the cerebellar cortex (CBC) that may be functionally more conserved. We find a nearly three-fold excess of human-specific gene expression changes in PFC compared to CBC. The most prominent human-specific mRNA expression pattern in the PFC is a developmental delay of approximately 5 years in the expression of genes associated with learning and memory, such as synaptic transmission and long-term potentiation. This pattern is supported by correlated changes in concentrations of proteins and the respective neurotransmitters and its magnitude is beyond the shift expected from the life-histories of the species. Mechanistically, it might be driven by change in timing of expression of four or more transcription factors. We speculate that delayed synaptic maturation in PFC may play a role in the emergence of human-specific cognitive abilities. Keywords: Age series Human, chimpanzee and rhesus macaque post-mortem brain samples from the cerebellar cortex were collected. The age ranges of the individuals in all three species covered the respective species' postnatal maturation period from infancy to old adulthood. RNA extracted from the dissected tissue was hybridized to Affymetrix® Human Gene 1.0 ST arrays. CBC samples.

2011-12-09 | E-GEOD-22569 | biostudies-arrayexpress

Gene expression in primate postnatal brain through lifespan - prefrontal cortex

Project description:We investigated molecular changes during human, chimpanzee, and rhesus macaque postnatal brain development at the transcriptome, proteome, and metabolome levels in two brain regions: the prefrontal cortex (PFC) that is involved in several human-specific cognitive processes, and the cerebellar cortex (CBC) that may be functionally more conserved. We find a nearly three-fold excess of human-specific gene expression changes in PFC compared to CBC. The most prominent human-specific mRNA expression pattern in the PFC is a developmental delay of approximately 5 years in the expression of genes associated with learning and memory, such as synaptic transmission and long-term potentiation. This pattern is supported by correlated changes in concentrations of proteins and the respective neurotransmitters and its magnitude is beyond the shift expected from the life-histories of the species. Mechanistically, it might be driven by change in timing of expression of four or more transcription factors. We speculate that delayed synaptic maturation in PFC may play a role in the emergence of human-specific cognitive abilities. Keywords: Age series Human, chimpanzee and rhesus macaque post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. The age ranges of the individuals in all three species covered the respective species' postnatal maturation period from infancy to old adulthood. RNA extracted from the dissected tissue was hybridized to Affymetrix® Human Gene 1.0 ST arrays. PFC samples.

2011-12-09 | E-GEOD-22521 | biostudies-arrayexpress

Gene expression in primate postnatal brain through lifespan - prefrontal cortex

2011-12-09 | GSE22521 | GEO

The mRNA expression patterns in macaque brains from prenatal to neonatal

Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. To distinguish whether the human specific developmental pattern represent novel human-specific developmental patterns or a shift in the timing of the existing patterns, we measured mRNA expression patterns in macaque brains from prenatal to neonatal. Our results show that the major human-specific developmental patterns identified in the PFC reflects an extreme shift in timing of synaptic development. Rhesus macaque post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. Six fetal and six newborn samples were used. RNA extracted from the dissected tissue was hybridized to Affymetrix® Human Gene 1.0 ST arrays.

2012-02-02 | E-GEOD-29138 | biostudies-arrayexpress

Disruption of human-specific synaptogenesis program in autism [RNA-seq]

Project description:To test the connection between the molecular mechanisms underlying autistic disorder and human cognitive evolution, we analyzed the gene expression changes taking place during prefrontal cortex development in autism patients and healthy controls, as well as non-human primates. We found the genes with expression changes in autism are significantly overlapped with genes showing human-specific developmental profile. A major pattern of the overlapped genes reflects the aberrant acceleration of synaptogenesis and synaptic maturation followed by premature synaptic pruning in the prefrontal cortex of autism patients. This pattern involves the same developmental program that controls human-specific extension of cortical synaptogenesis in healthy individuals. Taken together, these findings shed light on the molecular mechanisms underlying autistic phenotype and provide potential targets for clinical intervention.

2016-08-12 | GSE59288 | GEO

The mRNA expression patterns in macaque brains from prenatal to neonatal

2012-02-02 | GSE29138 | GEO

Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

Project description:The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.

2020-07-27 | GSE155131 | GEO

Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory

Project description:Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

2016-10-06 | GSE87675 | GEO

Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

Project description:The role of transfer (t)RNA cytosine methyl-transferases as epitranscriptomic regulators of brain proteomes remains unexplored. We report that fear memory and antidepressant-like behaviors are highly sensitive to bi-directional changes in Nsun2 tRNA methyltransferase activity in prefrontal cortex (PFC) neurons. Nsun2-deficient mutant cortex showed a selective deficit in multiple glycine tRNAs, resulting in codon-specific shifts in translational efficiencies and a distorted proteomic landscape with deficits in glycine-rich neuronal proteins impacting synaptic signaling and behavior.

2021-07-02 | PXD023437 | Pride

Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes [RNA-Seq]

Project description:Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA- and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.

2023-02-21 | GSE220745 | GEO

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