BICCN

Accessible technologies for high-throughput, whole-brain reconstructions of molecularly characterized mammalian neurons

 

Modern neuroscience seeks to explain behavior, including sensation, cognition and movement, in terms of information processing in neural circuits. Defined cell types are the nodes of neural circuits. Enumerating and characterizing the brain’s cell types and their connectivity is therefore necessary to understand how circuits process information and how they change in brain disorders. The mammalian brain contains astronomic numbers of neurons (mouse, 10⁸; human, 10¹¹), distributed across ~1,000 brain areas, each containing multiple cell types (likely ranging from 1 – 100)¹. It seems clear that classification of cell types will require integrative analysis of at least two data types at the single-cell level: (1) molecular signature (e.g., transcriptome), and (2) anatomy (e.g., location and connectivity).

The major goal of the ‘Brain Light’ project is to build on the expertise of researchers at JHMI/JHU and Janelia to develop efficient and scalable methods to reconstruct the complete morphologies of molecularly characterized neurons. Over the last seven years, the MouseLight project at Janelia has developed semi-automated methods to facilitate the efficient reconstruction of entire individual neurons, including their axonal arbors, based on light microscopy². MouseLight has reconstructed more than 1,000 projection neurons from the motor cortex, thalamus, hippocampus, and hypothalamus (http://ml-neuronbrowser.janelia.org/). The MouseLight data set has already revealed key information about cell types and their connectivity^22,3,4,5,6.

Our research will build on the expertise at JHMI/JHU in neuroscience and neuro-informatics and experience gained with MouseLight to develop methodologies necessary to elevate the morphological reconstruction of molecularly defined neurons from an artisanal method to a technology that is scalable and suitable for the analysis of all neuron types across the mouse brain and, eventually, other mammalian brains. To achieve this goal, we will develop technology for imaging and reconstructing axon arborizations of individual molecularly defined neurons, thereby providing critical information about neuronal structure and connectivity. The data and methods will be made widely available to enable a community-wide effort to map neuronal connectivity at unprecedented scales and depth.

References:

1. Bota, M. & Swanson, L. W. The neuron classification problem. Brain Res Rev 56, 79–88 (2007).
2. Winnubst, J. et al. Reconstruction of 1,000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain. bioRxiv 537233 (2019). doi:10.1101/537233
3. Economo, M. N. et al. Distinct descending motor cortex pathways and their roles in movement. Nature 563, 79 (2018).
4. Economo, M. N. et al. A platform for brain-wide imaging and reconstruction of individual neurons. eLife 5, e10566 (2016).
5. Cembrowski, M. S. et al. Dissociable Structural and Functional Hippocampal Outputs via Distinct Subiculum Cell Classes. Cell 173, 1280-1292.e18 (2018).
6. Hooks, B. M. et al. Topographic precision in sensory and motor corticostriatal projections varies across cell type and cortical area. Nat. Commun. 9, 3549 (2018).

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