Allen Mouse Brain Atlas
Defining Neurons in Technicolor
Posted on by Dr. Francis Collins
Can you identify a familiar pattern in this image’s square grid? Yes, it’s the outline of the periodic table! But instead of organizing chemical elements, this periodic table sorts 46 different types of neurons present in the visual cortex of a mouse brain.
Scientists, led by Hongkui Zeng at the Allen Institute for Brain Science, Seattle, constructed this periodic table by assigning colors to their neuronal discoveries based upon their main cell functions . Cells in pinks, violets, reds, and oranges have inhibitory electrical activity, while those in greens and blues have excitatory electrical activity.
For any given cell, the darker colors indicate dendrites, which receive signals from other neurons. The lighter colors indicate axons, which transmit signals. Examples of electrical properties—the number and intensity of their “spikes”—appear along the edges of the table near the bottom.
To create this visually arresting image, Zeng’s NIH-supported team injected dye-containing probes into neurons. The probes are engineered to carry genes that make certain types of neurons glow bright colors under the microscope.
This allowed the researchers to examine a tiny slice of brain tissue and view each colored neuron’s shape, as well as measure its electrical response. They followed up with computational tools to combine these two characteristics and classify cell types based on their shape and electrical activity. Zeng’s team could then sort the cells into clusters using a computer algorithm to avoid potential human bias from visually interpreting the data.
Why compile such a detailed atlas of neuronal subtypes? Although scientists have been surveying cells since the invention of the microscope centuries ago, there is still no consensus on what a “cell type” is. Large, rich datasets like this atlas contain massive amounts of information to characterize individual cells well beyond their appearance under a microscope, helping to explain factors that make cells similar or dissimilar. Those differences may not be apparent to the naked eye.
Just last year, Allen Institute researchers conducted similar work by categorizing nearly 24,000 cells from the brain’s visual and motor cortex into different types based upon their gene activity . The latest research lines up well with the cell subclasses and types categorized in the previous gene-activity work. As a result, the scientists have more evidence that each of the 46 cell types is actually distinct from the others and likely drives a particular function within the visual cortex.
Publicly available resources, like this database of cell types, fuel much more discovery. Scientists all over the world can look at this table (and soon, more atlases from other parts of the brain) to see where a cell type fits into a region of interest and how it might behave in a range of brain conditions.
 Classification of electrophysiological and morphological neuron types in the mouse visual cortex. N Gouwens NW, et al. Neurosci. 2019 Jul;22(7):1182-1195.
 Shared and distinct transcriptomic cell types across neocortical areas. Tasic B, et al. Nature. 2018 Nov;563(7729):72-78.
Brain Basics: The Life and Death of a Neuron (National Institute of Neurological Disorders and Stroke/NIH)
Cell Types: Overview of the Data (Allen Brain Atlas/Allen Institute for Brain Science, Seattle)
Hongkui Zeng (Allen Institute)
NIH Support: National Institute of Mental Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development
Mapping the Brain’s Memory Bank
Posted on by Dr. Francis Collins
There’s a lot of groundbreaking research now underway to map the organization and internal wiring of the brain’s hippocampus, essential for memory, emotion, and spatial processing. This colorful video depicting a mouse hippocampus offers a perfect case in point.
The video presents the most detailed 3D atlas of the hippocampus ever produced, highlighting its five previously defined zones: dentate gyrus, CA1, CA2, CA3, and subiculum. The various colors within those zones represent areas with newly discovered and distinctive patterns of gene expression, revealing previously hidden layers of structural organization.
For instance, the subiculum, which sends messages from the hippocampus to other parts of the brain, includes several subregions. The subregions include the three marked in red, yellow, and blue at about 23 seconds into the video.
How’d the researchers do it? In the new study, published in Nature Neuroscience, the researchers started with the Allen Mouse Brain Atlas, a rich, publicly accessible 3D atlas of gene expression in the mouse brain. The team, led by Hong-Wei Dong, University of Southern California, Los Angeles, drilled down into the data to pull up 258 genes that are differentially expressed in the hippocampus and might be helpful for mapping purposes.
Some of those 258 genes were generally expressed only in previously defined portions of the hippocampus. Others were “turned on” only in discrete portions of known hippocampal domains, leading the researchers to define 20 distinct subregions that hadn’t been recognized before.
Combining these data, sophisticated analytical tools, and plenty of hard work, the team assembled this detailed atlas, together with connectivity data, to create a detailed wiring diagram. It includes about 200 signaling pathways that show how all those subregions network together and with other portions of the brain.
What’s really interesting is that the data also showed that these components of the hippocampus contribute to three relatively independent brain-wide communication networks. While much more study is needed, those three networks appear to relate to distinct functions of the hippocampus, including spatial navigation, social behaviors, and metabolism.
This more-detailed view of the hippocampus is just the latest from the NIH-funded Mouse Connectome Project. The ongoing project aims to create a complete connectivity atlas for the entire mouse brain.
The Mouse Connectome Project isn’t just for those with an interest in mice. Indeed, because the mouse and human brain are similarly organized, studies in the smaller mouse brain can help to provide a template for making sense of the larger and more complex human brain, with its tens of billions of interconnected neurons.
Ultimately, the hope is that this understanding of healthy brain connections will provide clues for better treating the brain’s abnormal connections and/or disconnections. They are involved in numerous neurological conditions, including Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder.
 Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks. Bienkowski MS, Bowman I, Song MY, Gou L, Ard T, Cotter K, Zhu M, Benavidez NL, Yamashita S, Abu-Jaber J, Azam S, Lo D, Foster NN, Hintiryan H, Dong HW. Nat Neurosci. 2018 Nov;21(11):1628-1643.
Mouse Connectome Project (University of Southern California, Los Angeles)
Human Connectome Project (USC)
Allen Brain Map (Allen Institute, Seattle)
The Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
NIH Support: National Institute of Mental Health; National Cancer Institute