MerQuaCo: a computational tool for quality control in image-based spatial transcriptomics.

Image-based spatial transcriptomics platforms are powerful tools often used to identify cell populations and describe gene expression in intact tissue. Spatial experiments return large, high-dimension datasets and several open-source software packages are available to facilitate analysis and visualization. Spatial results are typically imperfect.

The commitment of the human cell atlas to humanity.

The Human Cell Atlas (HCA) is a global partnership "to create comprehensive reference maps of all human cells-the fundamental units of life - as a basis for both understanding human health and diagnosing, monitoring, and treating disease." ( https://www.humancellatlas.

Distinctive physiology of molecularly identified medium spiny neurons in the macaque putamen.

The distinctive physiology of striatal medium spiny neurons (MSNs) underlies their ability to integrate sensory and motor input. In rodents, MSNs have a hyperpolarized resting potential and low input resistance. When activated, they have a delayed onset of spiking and regular spike rate.

Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies.

SEA-AD is a multimodal cellular atlas and resource for Alzheimer's disease.

The Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) is a multifaceted open data resource designed to identify cellular and molecular pathologies that underlie Alzheimer’s disease. Integrating neuropathology, single cell and spatial genomics, and longitudinal clinical metadata, SEA-AD is a unique resource for studying the pathogenesis of Alzheimer’s and related dementias.

Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits.

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos.

Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons.

Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas.

B-BIND: Biophysical Bayesian Inference for Neurodegenerative Dynamics.

Throughout an organism's life, a multitude of complex and interdependent biological systems transition through biophysical processes that serve as indicators of the underlying biological states. Inferring these latent, unobserved states is a goal of modern biology and neuroscience. However, in many experimental setups, we can at best obtain discrete snapshots of the system at different times and for different individuals.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.

Morpho-electric diversity of human hippocampal CA1 pyramidal neurons.

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery.

Mapping human tissues with highly multiplexed RNA in situ hybridization.

In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections.

Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer's disease microglia.

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-β and tau. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases.

Connecting single-cell transcriptomes to projectomes in mouse visual cortex.

The mammalian brain is composed of diverse neuron types that play different functional roles. Recent single-cell RNA sequencing approaches have led to a whole brain taxonomy of transcriptomically-defined cell types, yet cell type definitions that include multiple cellular properties can offer additional insights into a neuron's role in brain circuits. While the Patch-seq method can investigate how transcriptomic properties relate to the local morphological and electrophysiological properties of cell types, linking transcriptomic identities to long-range projections is a major unresolved challenge.

AAV-mediated interneuron-specific gene replacement for Dravet syndrome.

Dravet syndrome (DS) is a devastating developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10-20% rate of premature death. Most DS patients harbor loss-of-function mutations in one copy of , which has been associated with inhibitory neuron dysfunction. Here we developed an interneuron-targeting AAV human gene replacement therapy using cell class-specific enhancers.

Conserved and divergent gene regulatory programs of the mammalian neocortex.

Divergence of cis-regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes.

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus.

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei.

Single-cell DNA methylation and 3D genome architecture in the human brain.

Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures.

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex.

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1.