Rapid Tagging Method Reveals Psychedelics' Immediate Effects on Neurons
Neuron-tagging method reveals how psychedelic compounds impact individual neurons in the brain.
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Amidst the psychedelic “renaissance”, a prominent challenge somewhat limits the adoption of psychedelic-based compounds in a clinical setting. While a flurry of studies have demonstrated some efficacy using psychedelics for treating psychiatric disorders, how these effects are achieved isn’t so clear.
“It’s important to think about the cellular mechanisms that these psychedelics act upon,” Christina Kim, an assistant professor of neurology at the University of California (UC) Davis Center for Neuroscience and School of Medicine, and an affiliate of the UC Davis Institute for Psychedelics and Neurotherapeutics, said. Equipped with this knowledge, researchers could improve patient outcomes by designing different versions of the compounds that carry fewer side effects.
Kim’s lab at UC Davis develops molecular and optical approaches that aid in the study of neuronal organization and function. In collaboration with David Olson, founding director of the Institute for Psychedelics and Neurotherapeutics and a professor in the departments of Chemistry and Biochemistry and Molecular Medicine, her research group developed a non-invasive protein-based tool capable of tracking neurons and biomolecules that are activated by psychedelic drugs.
Ca2+-activated Split-TurboID, or CaST for short, enables scientists to tag and follow molecular signaling processes in the brain quickly with a run time of 10 to 30 minutes, compared to several hours.
The research is published in Nature Methods
Tagging neurons in brief, user-defined windows
Calcium concentration is a gold-standard marker for tracking activity in neurons. When neurons are highly active, their intracellular calcium concentrations increase.
“We designed an activity-dependent enzyme that can attach a small, biochemical handle to activated cells exhibiting high intracellular calcium. Our strategy was to reengineer and repurpose a proximity-labeling enzyme, split-TurboID16, to report increased intracellular calcium in living cells by tagging proteins with an exogenously delivered biotin molecule,” the researchers described.
Proximity-labeling enzymes like split-TurboID16 have been used to tag proteins for downstream analysis and enrichment over a period of several days. Kim and colleagues engineered this system so that neurons can be enzymatically tagged in brief, user-defined time windows. Once tagged, the neurons can then be detected using existing methods for biotin detection.
“We designed these proteins in the lab that can be packaged into DNA and then put into harmless adeno-associated viruses,” Kim said. “Once we deliver the CaST tool and these proteins into neurons, then they incubate inside the cells and start expressing.”
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Subscribe for FREECaST was used to tag prefrontal cortex neurons in the mouse brain after administering psilocybin. This area of the brain is associated with several brain disorders and also experiences neuronal growth and strengthened connectivity after psychedelic administration.
Mouse neurons treated with the new CaST labeling technique developed at UC Davis. CaST enables rapid labeling of brain cells as they respond to psychedelic drugs such as psilocybin or LSD. Credit: Run Zhang/UC Davis.
Kim and colleagues could measure how psilocybin modulates neuronal activity in this area of the brain while simultaneously measuring a hallucinogenic behavioral correlate of psychedelic drugs in animals, the head-twitch response (HTR).
“What’s nice about CaST is that it can be used in a freely behaving animal,” Kim said. Other tagging techniques require laboratory models’ heads to be stabilized to achieve high-quality images.
She continued, “Biotin is also a great tagging substrate because there are many pre-existing commercial tools that can report whether biotin is present or not just by a simple staining and imaging method.”
How do psychedelics benefit the cellular profiles of people with brain disorders?
The research team is further developing the CaST tool to achieve brain-wide cellular labeling, while also investigating novel ways to enrich proteins that are produced through psychedelics affecting neurons. Overall, they aim to understand why and how psychedelics can be beneficial for individuals with brain disorders and their cellular phenotypes.
“We can send those samples to the UC Davis Proteomics Core Facility and they can give us an unbiased picture of all the proteins we identified,” Kim said. “We want to examine their entire contents in terms of what proteins they express, what genes they express, and try to see what’s different in psilocybin-treated animals versus control animals or animal models of diseases.”
Reference: Zhang R, Anguiano M, Aarrestad IK, et al. Rapid, biochemical tagging of cellular activity history in vivo. Nat Methods. 2024. doi: 10.1038/s41592-024-02375-7
This article is a rework of a press release issued by the University of California Davis. Material has been edited for length and content.
