MIT engineers have developed a microscope that can image electrical activity across the entire brain of a larval zebrafish with millisecond temporal resolution. The system adapts a light-sheet microscope using faster camera acquisition and a remote-refocusing technique to scan the whole brain volume 200 times per second, or once every five milliseconds. Senior author Ed Boyden says the advance allows researchers to observe how distributed neurons coordinate as a network, a prerequisite for understanding how brain-wide activity underlies behavior and cognition.
The work appears in Nature Methods. Lead authors are Zeguan Wang, a former J. Douglas Tan Postdoctoral Fellow, and Jie Zhang, a former MIT postdoc. The team included researchers from the McGovern Institute, Picower Institute, Koch Institute, and Boston College. Funding came from the National Institutes of Health, the BRAIN Initiative, several MIT centers, and private donors including the Howard Hughes Medical Institute.
Conventional calcium imaging tracks neural activity on the order of seconds to minutes, too slow to resolve individual electrical spikes. Voltage imaging uses genetically encoded fluorescent proteins that light up when a neuron fires, providing a direct readout of electrical impulses. Until now, voltage imaging has been limited to small brain regions because scanning a large volume at the required speed was not feasible.
The researchers engineered larval zebrafish to express a voltage indicator called Positron2-Kv. The indicator produced usable signals in roughly one quarter of neurons distributed throughout the brain. Even with this partial coverage, the microscope captured single voltage spikes and rapid burst patterns during spontaneous activity.
When the fish were exposed to ultraviolet light, activity appeared first in the optic tectum, which processes visual input, and propagated from one side of the tectum to the other. Stimulus-independent sequences of activity were also observed in the cerebellum and hindbrain. These observations demonstrate that the system can track both evoked and ongoing brain-wide dynamics.
The team aims to increase the fraction of neurons imaged, improve the microscope's speed and resolution, and extend the technique to other model organisms such as mice. Boyden suggests the method could help generate hypotheses about how neural networks produce specific behaviors or brain states such as daydreaming.
The study represents a methodological advance in neuroscience instrumentation rather than a biological discovery per se. By enabling simultaneous voltage imaging across a whole vertebrate brain at the timescale of neural computation, it provides a tool for future investigations of brain-wide circuit function.
High-speed microscopy reveals electrical activity across the brain
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