Rice University neuroscientist Valentin Dragoi and collaborator Ariana Andrei from the Houston Methodist Research Institute developed a detailed, step-by-step guide for deploying optogenetics in nonhuman primates. The experimental protocol, documented in a paper published in Nature Protocols, provides critical guidance for researchers working to advance understanding of the brain’s complex networks and their relationship with behavior.
Until the mid-2000s, the knowledge on how the brain works in real time was largely based on lessons derived from how injuries or lesions to specific brain regions impacted the overall functioning of this complex organ.
Optogenetics ⎯ a technique that uses gene delivery vectors to enable specific neurons to produce light-responsive proteins ⎯ has since had a transformative impact on neuroscience, enabling researchers to activate or deactivate target neurons in real time without causing tissue damage. However, the technique poses unique technical challenges that have so far limited its use in larger animal models.
“This technique is powerful but extremely challenging,” said Dragoi, a professor of electrical and computer engineering at Rice, the Rosemary and Daniel J. Harrison III Presidential Distinguished Chair in Neuroprosthetics at Houston Methodist and professor of neuroscience at Weill Cornell Medical College. “If you have multiple steps, each with a 90% success rate, by the end you’re down to a 10% success rate overall — we hope our ‘recipe’ for carrying out these experiments can help improve those odds.”
Dragoi’s lab is one of the few in the world to have successfully deployed optogenetics in nonhuman primates to study brain circuits in real time.
“We want to share our expertise to empower and inspire other researchers to pursue what we believe is one of the most promising research directions in neuroscience,” said Dragoi, who is also a core member of the Rice Neuroengineering Initiative and scientific director of the Rice-Houston Methodist Center for Neural Systems Restoration.
Dragoi explained that neurons communicate through electrical impulses regulated by the flow of ions ⎯ such as sodium, potassium, calcium and chloride ⎯ across their membranes. This flow is controlled by specialized proteins known as ion channels embedded in neuron’s cell membranes.
Optogenetics is a way to make specific neurons produce light-responsive responses by opening and closing specific ion channels, thus rendering neuronal tissue responsive to light of particular wavelengths. Compared to lesion-based methods that involve physically removing parts of the brain to study their function, optogenetics is both far more precise in the temporal and spatial domains and also reversible.
“Unlike traditional methods, it allows real-time activation and inactivation of neurons,” said Andrei, a postdoctoral researcher at the Houston Methodist Research Institute. “It’s the interaction between networks that defines who we are, our behavior, and optogenetics is a great way to study neural circuits with great spatiotemporal resolution.”
Understanding brain function is the first critical step toward developing therapies for neurological disorders, and optogenetics could prove useful not only as a tool for research but also as the basis for future therapies for conditions such as epilepsy, neuropathic pain and vision impairment.
Dragoi said the next step is making optogenetics work in freely moving animals rather than in controlled, head-fixed conditions.
“Wireless, real-time control of brain circuits could open new doors for understanding natural behavior,” Dragoi said.
Another goal is to use optogenetics to study deep brain structures like the thalamus and its cortical interactions, which regulate attention and sensory information ⎯ a prospect that Andrei called “tantalizing.”
“It’s not enough to describe methods in a research paper; you need a dedicated protocol with step-by-step instructions,” Dragoi said.
The research was supported by the National Institutes of Health (K99EY034699, R01EY026156, R34NS116829). The content herein is solely the responsibility of the authors and does not necessarily represent the official views of the funders.