Neuroscience

Optogenetics: Illuminating When Brain Cells Switch Off

Landmark study uses optogenetics with proteomics to track neural dynamics.

Posted February 7, 2024 | Reviewed by Kaja Perina

Rauschenberger/Pixabay

Scientists at Scripps Research Institute have created a groundbreaking method to track when brain cell activity decreases or switches off after a burst of activity using a combination of optogenetics and proteomics.

“Neuronal dynamics involve both the increase and decrease of activities; yet, for a long time, there have only been trackable histological markers for the former,” wrote corresponding author and neuroscientist Li Ye in collaboration with twenty co-authors.

Optogenetics is an innovative technique that combines optics with genetic engineering in order to control the activity of neurons with light activation. It is a method of activating brain cells or proteins by shining a light on photosensitive proteins.

The history of optogenetics is a modern one. Neuroscientist, molecular biologist and biophysicist Francis Crick (1916-2004), co-discoverer of DNA’s double helix structure, recipient of the Nobel Prize for Physiology or Medicine in 1962 and the Copley Medal in 1975, identified one of the top neuroscience challenges as the need to control specific classes of neurons without altering others. Crick subsequently put forth the notion that light might be a candidate control tool due to the ability to precisely administer timed pulses in contrast to electrical stimuli via electrodes or drugs.

In 2003, German biophysicists Georg Nagel, Peter Hegemann, and their co-authors published their research that demonstrates how an opsin from the green alga Chlamydomonas reinhardtii called channelrhodopsin-2 (ChR2) may be used to depolarize cell membranes and increase cytoplasmic calcium ion concentration via light activation.

Two years later, American psychiatrist and bioengineer Karl Deisseroth and American neuroscientist Edward Boyden introduced the use channelrhodopsin-2 to activate neurons with light in the 2005 publication of Millisecond-timescale, genetically targeted optical control of neural activity along with co-authors Feng Zhang, Ernst Bamberg, and Georg Nagel. Deisseroth et al. introduced the term optogenetic in 2006.

In the current study, researchers at the Scripps Research Institute set out with the aim of finding a way to track brain inhibition, when brain cells shut off after an activity burst.

“Neuronal dynamics involve both the increase and decrease of activities; yet, for a long time, there have only been trackable histological markers for the former,” wrote the researchers.

The researchers used optogenetics to conduct analysis of protein phosphorylation sites (phosphoproteomics) on neurons in the search for a reverse marker of brain activity. Primary cortical neurons were transduced with light-activated channelrhodopsin-2 and electrophysiological recordings helped to quantify the firing of action potentials under various light conditions. Using this methodology, the researchers discovered that a phosphorylated form of the protein pyruvate dehydrogenase (pPDH) can serve as an inverse activity marker to indicate brain inhibition in lab mice.

With this proof-of-concept, scientists have a new method to help spot and understand the neural dynamics of mood disorders, depressive disorder, post-traumatic stress disorder, trauma and stress related disorders, nervous system diseases, neurodegenerative disorders, Alzheimer's disease, and more ailments related to the brain in the future.