Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 28, 2024

Abstract The ability to spatially map multiple layers of the omics information over different time points allows for exploring mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC–RNA–Protein-seq) CTRP-seq CUT&Tag– RNA–Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) dynamic remodeling development neuroinflammation. A spatiotemporal atlas mouse was obtained at stages from postnatal day P0 P21, compared regions interest human developing brains. Specifically, cortical area, discovered temporal persistence spreading chromatin accessibility layer-defining transcription factors. In corpus callosum, observed priming myelin genes across subregions. Together, it suggests a role layer specific projection neurons coordinate axonogenesis myelination. We further mapped lysolecithin (LPC) neuroinflammation model common molecular programs Microglia, exhibiting both conserved distinct inflammation resolution, are transiently activated not only core LPC lesion, but also distal locations presumably through neuronal circuitry. Thus, this work unveiled differential neuroinflammation, resulting valuable data resource investigate function

Language: Английский

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The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models

Frontiers in Psychiatry, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 15, 2024

Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review collected during the past 40-plus years supporting role dysfunction attention deficit hyperactivity disorder (ADHD). We recapitulate basic components dopaminergic central nervous system, focusing on core enzymes, transporters receptors monoaminergic functions, particularly striatal cortical regions. summarize key human brain imaging genetic studies reporting associations between neurotransmission traits, with an emphasis ADHD. also consider ADHD context animal models single gene, metabolic, neurological established system. Examining this way leads us to conclude there is for involvement but limited a hypo-dopaminergic state per se as component propose path forward increase our understanding traits should focus its clinical subgroups, development how it interacts other neurotransmitter systems.

Language: Английский

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Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 12, 2024

The ability to spatially map multiple layers of the omics information over different time points allows for exploring mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) CTRP-seq CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) dynamic remodeling development neuroinflammation. A spatiotemporal atlas mouse was obtained at stages from postnatal day P0 P21, compared regions interest human developing brains. Specifically, cortical area, discovered temporal persistence spreading chromatin accessibility layer-defining transcription factors. In corpus callosum, observed priming myelin genes across subregions. Together, it suggests a role layer specific projection neurons coordinate axonogenesis myelination. We further mapped lysolecithin (LPC) neuroinflammation model common molecular programs Microglia, exhibiting both conserved distinct inflammation resolution, are transiently activated not only core LPC lesion, but also distal locations presumably through neuronal circuitry. Thus, this work unveiled differential neuroinflammation, resulting valuable data resource investigate function

Language: Английский

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Multiplexed CRISPRi Reveals a Transcriptional Switch Between KLF Activators and Repressors in the Maturing Neocortex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Abstract A critical phase of mammalian brain development takes place after birth. Neurons the mouse neocortex undergo dramatic changes in their morphology, physiology, and synaptic connections during first postnatal month, while properties immature neurons, such as capacity for robust axon outgrowth, are lost. The genetic epigenetic programs controlling prenatal well studied, but our understanding transcriptional mechanisms that regulate neuronal maturation is comparatively lacking. By integrating chromatin accessibility gene expression data from two subtypes neocortical pyramidal neurons neonatal maturing brain, we predicted a role Krüppel-Like Factor (KLF) family Transcription Factors developmental regulation neonatally expressed genes. Using multiplexed CRISPR Interference (CRISPRi) knockdown strategy, found shift KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) early functions ‘switch’ activate, then repress set shared targets with cytoskeletal including Tubb2b Dpysl3 . We demonstrate this switch buffered by redundancy between paralogs, which CRISPRi strategy equipped overcome study. Our results indicate competition within regulates conserved component program may underlie loss intrinsic growth neurons. This could facilitate transition refinement required stabilize mature circuits.

Language: Английский

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Multiplexed CRISPRi Reveals a Transcriptional Switch Between KLF Activators and Repressors in the Maturing Neocortex

Published: April 30, 2025

A critical phase of mammalian brain development takes place after birth. Neurons the mouse neocortex undergo dramatic changes in their morphology, physiology, and synaptic connections during first postnatal month, while properties immature neurons, such as capacity for robust axon outgrowth, are lost. The genetic epigenetic programs controlling prenatal well studied, but our understanding transcriptional mechanisms that regulate neuronal maturation is comparatively lacking. By integrating chromatin accessibility gene expression data from two subtypes neocortical pyramidal neurons neonatal maturing brain, we predicted a role Krüppel-Like Factor (KLF) family Transcription Factors developmental regulation neonatally expressed genes. Using multiplexed CRISPR Interference (CRISPRi) knockdown strategy, found shift KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) early functions ‘switch’ activate, then repress set shared targets with cytoskeletal including Tubb2b Dpysl3 . We demonstrate this switch buffered by redundancy between paralogs, which CRISPRi strategy equipped overcome study. Our results indicate competition within regulates conserved component program may underlie loss intrinsic growth neurons. This could facilitate transition refinement required stabilize mature circuits.

Language: Английский

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Multiplexed CRISPRi Reveals a Transcriptional Switch Between KLF Activators and Repressors in the Maturing Neocortex

Published: April 30, 2025

A critical phase of mammalian brain development takes place after birth. Neurons the mouse neocortex undergo dramatic changes in their morphology, physiology, and synaptic connections during first postnatal month, while properties immature neurons, such as capacity for robust axon outgrowth, are lost. The genetic epigenetic programs controlling prenatal well studied, but our understanding transcriptional mechanisms that regulate neuronal maturation is comparatively lacking. By integrating chromatin accessibility gene expression data from two subtypes neocortical pyramidal neurons neonatal maturing brain, we predicted a role Krüppel-Like Factor (KLF) family Transcription Factors developmental regulation neonatally expressed genes. Using multiplexed CRISPR Interference (CRISPRi) knockdown strategy, found shift KLF activators (Klf6, Klf7) to repressors (Klf9, Klf13) early functions ‘switch’ activate, then repress set shared targets with cytoskeletal including Tubb2b Dpysl3 . We demonstrate this switch buffered by redundancy between paralogs, which CRISPRi strategy equipped overcome study. Our results indicate competition within regulates conserved component program may underlie loss intrinsic growth neurons. This could facilitate transition refinement required stabilize mature circuits.

Language: Английский

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FOXP1 and FOXP2 genes; school absences; Parkinson’s disease

The Transmitter, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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From Songbird to Humans: The Multifaceted Roles of FOXP2 in Speech and Motor Learning

Neuroscience & Biobehavioral Reviews, Journal Year: 2024, Volume and Issue: 167, P. 105936 - 105936

Published: Nov. 6, 2024

Language: Английский

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CtBP1 is essential for epigenetic silencing of μ-opioid receptor genes in the dorsal root ganglion in spinal nerve ligation-induced neuropathic pain

Neurotherapeutics, Journal Year: 2024, Volume and Issue: unknown, P. e00493 - e00493

Published: Nov. 1, 2024

Language: Английский

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