UC Berkeley, NKT Photonics, Thorlabs platform sees details of neural activity

22 Nov 2023

Two-photon holographic mesoscope will boost understanding of distributed brain networks.

A microscopy platform developed at the University of California, Berkeley (UC Berkeley) is able to photo-activate spatial and temporal sequences of neurons in one brain area while reading out the downstream effect in several other regions.

The device is built around a NKT Photonics aeroPULSE FS50 ultrafast fiber laser for photostimulation and a modified two-photon mesoscope from Thorlabs with a 5 x 5 millimeter field of view.

"Brain computation depends on intricately connected yet highly distributed neural networks," commented the UC Berkeley team in a preprint of its study.

"Due to the absence of the requisite technologies, causally testing hypotheses on the nature of inter-areal processing has remained largely out of reach. We have developed the first two-photon holographic mesoscope system capable of simultaneously reading and writing neural activity patterns with single cell resolution across large regions of the brain."

The development of mesoscale two-photon microscopes able to sample neural activity with micron precision across relatively large areas of brain tissue has greatly helped investigators wanting to study distributed neural behavior in living animals, according to the project.

But although these systems can monitor cellular activity, they have not also been able to stimulate or perturb that activity in order to see the effects on neural behavior elsewhere, which would reveal causal relationships between different brain areas. Technical challenges relating to numerical aperture and integration of holographic systems have prevented such a platform being assembled until now.

Testing previously untestable theories

To tackle these issues the project assembled a 3D holographic system fully integrated onto a random-access two-photon mesoscope to enable single-cell resolution holographic photo-stimulation of neural ensembles in the brain. In this design the new photostimulation path does not compromise the wide field of view of the mesoscope or its necessary movement capabilities, according to the team.

In trials applying the platform to imaging of tissues in a mouse brain, the holographic mesoscope allowed targeted photostimulation in a 1 × 1 millimeter field of view combined with simultaneous mesoscale imaging across a larger nominal 5 × 5 millimeter imaging field of view.

As well as imaging patterns of neural activity, the UC Berkeley platform could also guide the design of future brain-machine interfaces, where the fine details of the signal flow in neural tissues is a key aspect of coordinating the commands transmitted to devices outside the body. Optogenetics in larger brains such as those of primates could also be more easily carried out by this type of device.

"We expect mesoscale two-photon holographic optogenetics to become a key technology in systems neuroscience," commented the team in its paper. "It can establish whole new classes of perturbative experiments to test previously untestable theories of brain function."