Recording from one million neurons

Brain function is organized through the collective activity of a myriad neurons: about 10 million of them in a mouse brain, and about 90 billion in our brain. This collective activity is called the neural code. Our ability to decipher this code is very limited, largely because we have been able to access only small fragments of it. The best technologies available today allow us to read at most the activity of a few thousand neurons at a time.

A new technology that appeared in the USA this year, the Light Beads Microscope, allows for a major increase in the number of neurons that we can record at the same time: one million neurons. This microscope was developed at Rockefeller University in New York, and will next be deployed in key laboratories across the United States. Thanks to our close collaboration with the inventors, we have the opportunity to deploy the first such device outside the USA.

We will install it in our laboratory in London, where we will provide ample access to colleagues across the United Kingdom to perform, pilot, or observe experiments that would not have been possible even a year ago.

The Light Beads Microscope is a particularly powerful version of a technology called two-photon imaging. A traditional two-photon microscope focuses light from a laser on a single point in the brain and moves this point along a plane, revealing the activity of the neurons in that plane. If a volume is desired, the acquisition must be repeated across multiple planes, greatly limiting the rate of acquisition. Moreover, the time required to move within a plane and across planes is much longer than the time required to image a point, so most of the imaging time is wasted. In a Light Beads Microscope, instead, the light is patterned in a line of beads separated in time by minuscule intervals, so while the microscope is scanning one point, it is imaging an entire line below it. By scanning a single plane, the microscope acquires a whole volume, with no wasted time.

This technology requires a combination of three components. The first is a specialized source of powerful light pulses that are extraordinarily brief and frequent. The second is a module that sequentially focuses these pulses into a line of "light beads" separated in both space and time. The third is a traditional two-photon microscope that scans this line through a horizontal plane. We have already secured the second and third items thanks to separate funding, and are here requesting funds to purchase the first item, the light source.

With this light source, we will obtain a uniquely advanced new microscope that will allow unprecedented measurements of the activity of ~1 million neurons in the living brain. At higher magnification, the microscope will also provide unprecedented measurements of brain activity in smaller structures, for instance to reveal the activity of the entire extent of a single neuron.

A transformative new technology has appeared that allows us to read the activity of unprecedentedly vast populations of individual neurons in the living brain: the Light Beads Microscope (LBM), which allows recordings from ~1 million neurons in the cerebral cortex (Demas et al, Nature Methods, 2021). This feat is unprecedented: the previous record, obtained with standard two-photon microscopy, was 50,000 neurons.

The LBM is a modified two-photon microscope that images an entire volume in the time it takes to scan a plane. It was developed in the laboratory of our collaborator at Rockefeller University and will next be deployed to key laboratories across the United States. Thanks to our close collaboration, we have the opportunity to deploy the first such device outside the USA. We will install it in our laboratory at UCL, where we will provide ample access to UK colleagues to perform, pilot, and observe transformational experiments that would not have been possible even a year ago.

An LBM is a combination of three components: (1) a specialized source of brief, frequent, and strong light pulses; (2) a multiplexing module that sculpts these pulses into a line of beads; (3) a two-photon mesoscope that projects this line vertically and scans a horizontal plane, thus imaging a volume. We have already secured the second and third items, and here request funds to purchase the first item, the light source: a powerful laser feeding into a high-repetition-rate femtosecond Optical Parametric Amplifier (OPCPA) system.

With this light source, we will obtain a transformative new microscope that will allow unprecedented volumetric measurements of the activity of ~1 million neurons in the living brain. At higher magnification, such volumetric measurements will also provide unprecedented measurements at subcellular scale, for instance to reveal the activity of the entire dendritic tree of a single neuron.