Novel Approaches to High Speed Imaging of Neural Activity in the Behaving Brain

Could you figure out how a computer works by just switching it off and disassembling it? To understand the brain we need both knowledge of its structure, and a view of how the living brain’s components work together while it is actively computing, awake and intact – a significant technical challenge. The BRAIN Initiative is addressing this urgent need for innovation, to help us better understand how the brain works, and how to detect and repair disease and injury.

The Hillman lab at Columbia University is receiving BRAIN funding to develop imaging methods that use light and lasers to read-out brain activity. Leveraging parallel improvements in fluorophores that can make neurons to flash when firing, our technologies focus on reading this neural information at very high speeds, in 3D or over large areas of the intact brain. One technology, Swept Confocally Aligned Planar Excitation (SCAPE) microscopy delivers video-rate, 3D imaging in a versatile, free-space imaging geometry. Although SCAPE’s 1 mm field of view is small compared to a human brain, this system can image every neuron in the brains of small organisms such as fruit flies and larval zebrafish. Being able to image the activity of every neuron in the brain gives us a critical new view of how the brain’s cells work together in a living animal. In fruit flies, SCAPE can image the whole brain while also letting the fly engage in a wide range of behaviors such as walking, sensing odors and even flying – providing an essential connection between behavior and the neural activity in the brain that controls it. SCAPE can also be used to image the mouse brain, providing a 3D view of activity in different layers of the brain’s cortex in parallel, allowing new analysis of the way signals travel through the brain.

Zooming out, I will also show results from another technique, wide-field optical mapping (WFOM), which can image neural activity over very large areas of the awake, behaving mouse brain. Whereas many investigations of brain activity focus on small clusters of cells, or regions of brain known to control specific functions, WFOM provides a parallel view of neural activity in over 15 bilateral brain regions while the mouse can engage in a wide range of behaviors. Using WFOM, we recently characterized patterns of symmetric spontaneous neural activity that appear to represent the neural underpinnings of resting-state functional magnetic resonance imaging (rs-fMRI). These results are helping us to better understand rs-fMRI measurements in the human brain. Latest results will be presented.