Biology subjects

Maat, C. A.

Publications and source records attributed to Maat, C. A..

5 recordsLinked to original sources

bioRxiv2026

Spatially resolved transcriptomic identification of thousands of neurons recorded in vivo.

Transcriptomics has transformed our understanding of the brain, but assigning transcriptomic identities to neurons recorded in vivo remains challenging at scale. Existing platforms can pair transcriptomic identity with two-photon calcium imaging in small populations of approximately 100 neurons, but they require recorded cells to be sparse and therefore cannot be applied to large population recordings. Here, we present coppaFISH 3D, a spatially resolved transcriptomics method, and CASTalign, an in silico alignment framework, which together enable transcriptomic identification of thousands of simultaneously recorded cells. coppaFISH 3D detects hundreds of genes in thick 50m fixed sections while preserving tissue integrity, enabling both 3D registration to in vivo imaging and integration with immunofluorescence labelling. The platform is fully powered by open chemistry and open source software, runs on commodity hardware, and can be performed at very low cost per section. It therefore enables transcriptomic identification of recorded neurons at scale, making it possible to study how transcriptomic identity shapes activity in neural populations.

neuroscience↗

bioRxiv2021

A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk

The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms--the blood-brain barrier--impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimers disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

neuroscience↗

bioRxiv2021

Molecular roadmap of the healthy stress response in the mouse hippocampus

The acute stress response mobilizes energy to meet situational demands and re-establish homeostasis. However, little is known about the nature and dynamics of the underlying molecular cascades. We used a brief forced swim exposure to trigger a strong stress response in mice, which transiently increases anxiety, but does not lead to lasting maladaptive behavioral changes. Using multiomic profiling we characterize the stress-induced molecular events in the hippocampus over time, across molecular scales, and down to the level of cell types and single cells. Our results unveil the complexity and specificity of the healthy stress response, with widespread changes in protein phosphorylation and gene transcription, but tightly regulated protein translation. All observed molecular events resolve efficiently within 4 hours after initiation of stress. The data are accessible through an interactive web portal, creating an extensive molecular resource that will help understand how stress impacts brain function in health and disease.

neuroscience↗

bioRxiv2020

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity1-3. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans4--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.

neuroscience↗

bioRxiv2018

Detailed structural orchestration of Lewy pathology in Parkinson’s disease as revealed by 3D multicolor STED microscopy

Post-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinsons disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

neuroscience↗