Learn about and access data from the network of BICCN centers and laboratories. Data spans multiple species, modalities, and techniques.

Retrograde tracers injected into the mouse brain backfill the cell bodies of their input projections and fluoresce, as shown here. A combination of classical tracing techniques combined with novel rabies methods allows for the systematic elucidation of specific neuronal circuits, anatomy, and morphology. By injecting several different tracers into a single subject, the projections from the cortex can be shown with precise spatial relativity, further enriching the data that can be captured from each subject.

Regulatory elements controlling gene expression can be detected by identification of regions of open chromatin (scATAC-seq), or changes in the level of cytosine methylation (scmC-seq) in the genomes of single cells. Applying these complementary state-of-the-art DNA sequencing techniques to record the pattern in individual brain cell nuclei generates an epigenetic fingerprint for each cell. These fingerprints can be used to classify unique cell types and, when linked to specific neuronal circuits across brain regions, lead to the discovery of new genetic determinants of neuronal cell function.

Three cell-type specific axon projection patterns from motor cortex using multiplexed anterograde cre/flp-dependent viral tracers mapped to the common coordinate framework.

To help fill the evolutionary gap in knowledge between rodents and humans, high-throughput single-cell RNA sequencing will be used to identify cell types across 16 regions of the adult marmoset brain. Spatially mapping of these cell types in the brain will be performed using multiplexed fluorescent in situ hybridization. By combining viral expression we will also correlate cell morphology with this genetic information. Altogether these efforts will produce a census of cell types in the marmoset brain.

Photo primary slice culture tissue stained to show fiber architecture (green), progenitor cells (red), and neurons (blue). Understanding human brain development is crucial to understanding stem cell function, how neurons and glia are made, and as a foundation for potential regeneration medicine therapies. The structure of a cortical brain slice, shown here, shows a sliver of the dynamic cell types, behaviors, and organization that emerges during brain development.

Triple modality Patch-seq experiment on a human layer 2 pyramidal neuron in temporal cortex (left). Triple modality Patch-seq experiment on a human layer 3 fast-spiking interneuron in temporal cortex (right). These examples demonstrate the successful recovery of detailed cellular morphology (a,d), electrophysiology (b,e), and single nucleus transcriptome (c,f) from human neocortical neurons. The single nucleus RNA-seq data from each Patch-seq experiment is used to map the experimental sample to a reference dendrogram of human middle temporal gyrus transcriptomic cell types.

Brain wide spatial distribution of neuronal cell types.

Whole brain morphology reconstruction demonstrating multiple cell types in the isocortex. Two distinct cell types were identified based on their whole brain projection patterns. One type has projections restricted to ipsilateral cortex, while the other type sends projections to the homotypic region of the contralateral cortex.

An example of a genetically sparse-labeled D2-medium spiny neurons (MSN) imaged from a MORF (Mosaicism with Repeat Frameshift) mouse developed by the Yang lab.

AV1-Cre (Schematic of the proposed study (left). Anterograde transsynaptic labelling of spinal cord neurons with Aright).

Example of transfer of information from micron-scale imaging to in vivo studies. Five cortical areas were manually labeled in the OCT AIP image (1), then registered to ex vivo MRI of the hemisphere that it was taken from (2). The areas were sampled onto an ex vivo surface model for that subject (3). Surface-based registration is then used to map these labels to models derived from in vivo ADNI subjects (4). This approach, when enabled by our proposed technology, will allow us and others to carry out morphometry studies in these predicted regions (5) revealing disease effects on laminar structure, cell density and myelin content.

Proteomic reconstruction of the human brain: integrated mapping of many cell-types in human visual cortex using the SWITCH technology (Murray, Cell, 2015)

Single-cell analyses to resolve cellular diversity in the adult human brain. Brain tissues are imaged and spatially registered using MRI, and sampling regions (visual cortex or BA17) are processed for single cell assays. Gene expression and chromatin accessible site mapping permits unbiased clustering of nuclei (visualized using t-SNE) and cell type annotation. Integration of these expression and regulation profiles provides more detailed molecular annotation of the cell types that can then be spatially mapped to the brain tissue sections using DART-FISH.

Epigenomic profiling of human brain cells identifies cell-type specific gene regulatory regions. Analysis of the unique genetic profile of individual cell types supports the discovery of genetic variants associated with brain health and disease at the cellular level.

Single cell transcriptomic and epigenomic data will directly inform the distribution and function of key cell types across the lifespan of a close non-human primate relative—the rhesus macaque. These lifespan atlases will support the development of molecular interventions that empower the study, and potentially treatment, of myriad brain disorders.

Overlay of multi-round immunostained images registered based on preserved YFP signals. YFP: green, NeuN: red; Neurofilament-H: white; Calretinin: dark blue; Calbindin: light blue; GFAP: dark purple; Parvalbumin: light blue; SMI-32: yellow.

Neurons in the adult mouse cortex expressing DNA barcodes developed in the Nowakowski lab. Cells will be sequenced and lineages reconstructed based on shared barcodes, which are inherited from their radial glia progenitors.

Manual annotation remains the bottleneck in morphological studies of projection neurons in mammalian brains (Winnubst et. al., 2019, Cell). Principled, open-source computer vision techniques will be developed to accelerate neuron segmentation in sub-micron resolution images, producing traces like those shown here.

A composite imaging transcriptomic measurement of gene expression in mouse cortex. The expression levels of multiple genes are measured simultaneously in each color channel. When a small series of such image composites are acquired, the expression levels of a larger complement of genes in each cell may be inferred computationally.

Distinct neuronal types labeled in the mouse brain via an enhancer-driven Flp recombinase delivered by retroorbital injection of adeno-associated virus to a transgenic reporter mouse. The bright tdTomato fluorescent reporter molecule fills the virally transduced cells, revealing the full neuronal architecture.

DANDI is a Web platform for scientists to share, collaborate, and process data from cellular neurophysiology experiments. DANDI works with BICCN and other BRAIN Initiative awardees to curate data using community data standards such as NWB and BIDS, and to make data and software for cellular neurophysiology FAIR (Findable, Accessible, Interoperable, and Reusable). DANDI will store electrical and optical cellular neurophysiology recordings and associated MRI and/or optical imaging data.