New tools for dynamic analysis and molecular mapping of the brain

Boyden lab develops technology for application in DS research
red and blue jagged lines from a cell recording

Dr. Ed Boyden’s lab has been building tools for the dynamic analysis and molecular mapping of the brain for all Alana Center groups to better understand the differences present in Down syndrome.

Imaging neurons as they fire

In a first line of work, the Boyden Lab has been developing imaging tools to characterize brain activity in Down syndrome model mice at the high speeds necessary to understand the mechanisms underlying the Tsai lab’s 40 Hz sensory stimulation protocol, GENUS. To do so, the lab has been identifying and developing new voltage indicators and creating new microscope architectures. The lab identified an excellent voltage indicator for in-animal neuron voltage imaging. To make high-speed, 3D imaging possible in the brains of freely moving mice, they are designing a miniaturized light-field endoscope that will allow simultaneous recording of neural activity in a 3-D volume at exceptionally high imaging rates. They have fabricated customized components, are working to finalize its construction, and are planning to apply it to studying Down syndrome mouse models in collaboration with the Tsai lab.

green, purple, yellow, cyan and blue cells in a grid
Imaging of many dynamic signals in a living cell is possible by using distinct clocklike fluorophores to represent the activity of each signal.

As part of this work, the Boyden lab recently identified sets of fluorescent probes that could be utilized simultaneously to do massively parallel imaging of many signals at once in a living cell, which is key to understanding how cells compute.

Expanding brains to see more clearly

Down syndrome involves changes in the organization of neural connections called synapses, which are too small scale to be imaged. In a second line of work, the Boyden Lab is refining its technology of expansion microscopy (ExM), which physically enlarges objects so they can be imaged with nanoscale precision on ordinary lab equipment.

A highly magnified cellular structure with expansion microscopy (A) and the improved method (B)

They are developing a more powerful chemical method that locks proteins in place while enabling them to be cleanly separated from each other. The team is also creating a freezing protocol that uses cold temperatures to lock molecules in place while the aforementioned process is fixing them. The result is better preservation of delicate nanostructures. As part of this work, the team was able to publish their procedure on expanding proteins away from each other to greater extents than previously possible (see article on MIT news).