António Pinto‐Duarte
A5073864690- Single-cell and spatial transcriptomics
- Epigenetics and DNA Methylation
- Neuroscience and Neuropharmacology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Neural dynamics and brain function
- Tryptophan and brain disorders
- Gene Regulatory Network Analysis
- Adenosine and Purinergic Signaling
- Genetics and Neurodevelopmental Disorders
- Cell Image Analysis Techniques
- Mitochondrial Function and Pathology
- Nerve injury and regeneration
- Memory and Neural Mechanisms
- Neurogenesis and neuroplasticity mechanisms
- Receptor Mechanisms and Signaling
- Neurological and metabolic disorders
- Neuroscience of respiration and sleep
- Amino Acid Enzymes and Metabolism
- Adipose Tissue and Metabolism
- Nicotinic Acetylcholine Receptors Study
- Alzheimer's disease research and treatments
- Nuclear Receptors and Signaling
- Neurological Complications and Syndromes
Salk Institute for Biological Studies
2012-2023
Ionis Pharmaceuticals (United States)
2022
University of Maryland, Baltimore
2020
University of California, San Diego
2018-2019
Howard Hughes Medical Institute
2012-2018
University of Lisbon
2005-2014
Hospital de Egas Moniz
2008
Abstract The primary motor cortex (M1) is essential for voluntary fine-motor control and functionally conserved across mammals 1 . Here, using high-throughput transcriptomic epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys mice, we demonstrate a broadly cellular makeup this region, with similarities that mirror evolutionary distance are consistent between the transcriptome epigenome. core molecular identities neuronal non-neuronal cell types allow us to...
Here we report the generation of a multimodal cell census and atlas mammalian primary motor cortex as initial product BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved morphological electrophysiological properties cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance collective knowledge...
Abstract Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in brain 1–3 . With proliferation multi-omics datasets, a major challenge is to validate and integrate results into biological understanding cell-type organization. Here we generated transcriptomes epigenomes from more than 500,000 individual cells mouse primary motor cortex, structure that has an evolutionarily conserved role locomotion. We developed...
Significance Astrocytes are well placed to modulate neural activity. However, the functions typically attributed astrocytes associated with a temporal dimension significantly slower than timescale of synaptic transmission neurons. Consequently, it has been assumed that do not play major role in modulating fast network dynamics known underlie cognitive behavior. By creating transgenic mouse which vesicular release from can be reversibly blocked, we found necessary for novel object recognition...
Abstract Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of epigenomes mouse cell types by applying single-nucleus methylation sequencing 1,2 to profile 103,982 nuclei (including 95,815 neurons 8,167 non-neuronal cells) from 45 regions cortex, hippocampus, striatum, pallidum olfactory areas. We identified 161...
Abstract Single-cell DNA methylome profiling has enabled the study of epigenomic heterogeneity in complex tissues and during cellular reprogramming. However, broader applications method have been impeded by modest quality sequencing libraries. Here we report snmC-seq2, which provides improved read mapping, reduced artifactual reads, enhanced throughput, as well increased library complexity coverage uniformity compared to snmC-seq. snmC-seq2 is an efficient strategy suited for large-scale...
Abstract The mammalian cerebrum performs high-level sensory perception, motor control and cognitive functions through highly specialized cortical subcortical structures 1 . Recent surveys of mouse human brains with single-cell transcriptomics 2–6 high-throughput imaging technologies 7,8 have uncovered hundreds neural cell types distributed in different brain regions, but the transcriptional regulatory programs that are responsible for unique identity function each type remain unknown. Here...
Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within human brain. However, regulatory programs governing identity function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open landscapes across 1.1 million cells 42 brain regions from three adults. Integrating this data unveiled 107 distinct their specific utilization of 544,735 candidate cis-regulatory DNA...
Cytosine DNA methylation is essential in brain development and implicated various neurological disorders. Understanding diversity across the entire a spatial context fundamental for complete molecular atlas of cell types their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) multi-omic (snm3C-seq)
Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of physiological changes that occur in brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify unique molecular pathway shared between aging AD. J147 reduced cognitive decline as well metabolic transcriptional markers when administered rapidly SAMP8 mice. Both compounds preserved mitochondrial homeostasis by...
Abstract Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution characterization of type diversity the brain 1 , neuronal often studied out context anatomical properties. To improve our understanding relationship between features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing link neural epigenomic...
Abstract Recent advances in single-cell technologies have led to the discovery of thousands brain cell types; however, our understanding gene regulatory programs these types is far from complete 1–4 . Here we report a comprehensive atlas candidate cis -regulatory DNA elements (cCREs) adult mouse brain, generated by analysing chromatin accessibility 2.3 million individual cells 117 anatomical dissections. The includes approximately 1 cCREs and their across 1,482 distinct populations, adding...
Abstract Single-cell analyses parse the brain’s billions of neurons into thousands ‘cell-type’ clusters residing in different brain structures 1 . Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific types. Here we used epi-retro-seq 2 to link single-cell epigenomes and for 33,034 dissected from 32 regions projecting 24 targets (225 source-to-target combinations) across whole mouse brain. We highlight uses these data...
Abstract Single cell transcriptomics has transformed the characterization of brain identity by providing quantitative molecular signatures for large, unbiased samples populations. With proliferation taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningful types. We used battery single-cell transcriptome epigenome measurements generated BRAIN Initiative Cell Census Network (BICCN) comprehensively assess types in...
Abstract We previously reported that adenosine, through A 2A receptor activation, potentiates synaptic actions of brain‐derived neurotrophic factor (BDNF) in the hippocampus infant (3–4 weeks) rats. Since ‐receptor‐mediated are more evident old than young rats and since therapeutic potential for BDNF‐based strategies is greater subjects, we now evaluated BDNF levels TrkB receptors adenosine three groups adult rats: adults (10–16 weeks), (36–38 aged (70–80 as well one group (20 ng/ml)...
The second messenger inositol 1,4,5-trisphosphate (IP3 ) is paramount for signal transduction in biological cells, mediating Ca2+ release from the endoplasmic reticulum. Of three isoforms of IP3 receptors identified nervous system, Type 2 R2) main isoform expressed by astrocytes. complete lack R2 transgenic mice was shown to significantly disrupt signaling astrocytes, while leaving neuronal intracellular pathways virtually unperturbed. Whether and how this predominantly nonneuronal receptor...
Abstract Adenosine, a neuromodulator of the CNS, activates inhibitory‐A 1 receptors and facilitatory‐A 2A receptors; its synaptic levels are controlled by activity bi‐directional equilibrative nucleoside transporters. To study relationship between extracellular formation/inactivation adenosine activation receptors, we investigated how A receptor modifies transport in hippocampal synaptosomes. The agonist, CGS 21680 (30 n m ), facilitated uptake through PKC‐dependent mechanism, but had no...
Cytosine DNA methylation is essential in brain development and has been implicated various neurological disorders. A comprehensive understanding of diversity across the entire context brain's 3D spatial organization for building a complete molecular atlas cell types their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) multi-omic (snm3C-seq
Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development function. However, their respective contributions brain maturation unknown. We found that conditional loss the de novo methyltransferase Dnmt3a in mouse excitatory neurons altered expression synapse-related genes, stunted synapse maturation, impaired working memory social interest. At genomic level, abolished postnatal accumulation CG...
Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory constitute a significant therapeutic target for many neurodegenerative, neurological, psychiatric disorders. Here, we report that brain-derived neurotrophic factor (BDNF) (1–100 ng/ml), member of neurotrophin gene family, rapidly decreases α7 nicotinic acetylcholine receptor responses in interneurons hippocampal CA1 stratum radiatum. Such effect is dependent activation TrkB involves actin cytoskeleton;...
Single-cell sequencing could help to solve the fundamental challenge of linking millions cell-type-specific enhancers with their target genes. However, this task is confounded by patterns gene co-expression in much same way that genetic correlation due linkage disequilibrium confounds fine-mapping genome-wide association studies (GWAS). We developed a non-parametric permutation-based procedure establish stringent statistical criteria control risk false-positive associations enhancer-gene...
It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as exacerbation of symptoms in response to NMDAR antagonists. Abnormal signaling presumably contributes cognitive deficits which substantially contribute functional disability schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms hypoglutmatergic neurotransmission Here, we examined the responses Sp4 hypomorphic mice antagonists...