Measuring large-scale brain circuit dynamics

Yaroslav Sych from the Helmchen group at the Brain Research Institute of UZH has developed a method to measure brain-wide calcium dynamics with miniaturized arrays of optical fibers. In their paper, published in Nature Methods, they demonstrate the versatility of this novel approach and how it can be applied to study the complex functional organization of the mammalian brain.

Animal behavior originates from neuronal activity distributed across brain-wide networks. However, techniques for assessing large-scale neural dynamics in behaving animals remain limited. One way of recording from deeper areas in the brain is to implant optical fibers that conduct light. In combination with fluorescent calcium indicators these fibers can be used to excite fluorescence signals with a blue laser while collecting back the green indicator fluorescence that reports changes in neuronal activity. Optical fibers are also useful for optogenetic perturbations, where light-sensitive proteins are turned on or off with light to manipulate neural activity with high specificity. Until now, only a handful of these fibers have been applied simultaneously so that measurements remained rather local.

Yaroslav Sych, the lead author of the study, recalls: “We tried several designs to use a larger number of fibers, including packing fibers into standard housing rods. But the bulk material around these rods did not allow to interface with all desired brain areas. We needed a much denser configuration of fibers; the inspiration came from the telecommunication industry where optical fiber cables cross continents creating the internet network. Some of these networks multiplex optical signals with the help of dense fiber arrays. We thought “why not do the same in the brain?”.

Brain-wide measurements and manipulations

Using dense arrays of optical fibers, the researchers could measure activity (in the form of calcium indicator fluorescence recordings) from up to 48 different brain regions of mice engaged in a texture discrimination task using their whiskers. Interestingly, mice recruited brain-wide circuits including striatal, thalamic, hippocampal and cortical areas far beyond the specific sensory areas typically studied with such tasks.

Importantly, the array of optical fibers did not only allow them to observe brain region activity but also to actively manipulate selected regions by optogenetic perturbations. The technique can therefore be used to first identify relevant active regions in a network and then specifically study how perturbation of these regions affects neural communication across brain regions and animal behavior.

A further important advance is the possibility to do multi-fiber experiments in freely behaving animals (see Figure) which opens new opportunities to study brain dynamics during naturalistic behaviors. The paper describes a proof of concept recording in freely moving animals, including simultaneous recordings from two mice during social interaction.

The authors conclude that high-density multi-fiber arrays are versatile tools to study large-scale brain dynamics during normal behavior and may also help to discover areas affected in neurological or psychiatric disorders.

High-density multi-fiber photometry for studying large-scale brain circuit dynamics. Sych Y, Chernysheva M, Sumanovski LT, Helmchen F. Nature Methods. 2019 Jun;16(6):553-560. PubMed Abstract

Image:  Top left: Histology and schematic of 12 optical fibers implanted in a mouse brain, each targeting a different region. Lower left: Measurements with multi-fiber arrays can be performed in freely behaving and socially interacting mice. Right: Example data of brain dynamics across many regions in two mice when the animals approached each other and interacted (12 and 36 fibers in mouse 1 and 2, respectively; targeted areas listed on the left; pseudocolor intensity low (blue) and high (red) activity).