Mammalian brains are plastic and able to rewire themselves, sometimes dramatically, as organisms mature, learn, or recover from injuries. But there are periods in a person’s or animal’s development where the brain is especially plastic, and after which it is not. Visual learning is an example of just such a “critical period,” where a young brain learns how to make sense of the stimuli entering the visual cortex from its eyes and optic nerves.
However, new preclinical research by a team at the Institute of Science and Technology in Klosterneuburg, Austria suggests there may be relatively safe methods of temporarily restoring the plasticity seen during critical periods. In a study published in July in the journal Cell Reports, the researchers showed that both anesthetic doses of ketamine and exposure to lights flickering at 60 cycles per second, 60 hertz, could restore neural plasticity in the visual systems of mice.
According to Sandra Siegert, an assistant professor of life sciences at the institute and the primary investigator on the study, her research team has primarily been interested in the active immune cells of the central nervous system, microglia. “We are focusing on the fundamentals of the microglia-neuron interaction as well as how disease factors — environment, genes — influence this balance,” she said. In the study, “our initial objective was to understand whether ketamine anesthesia would have an impact on microglia.”
Ketamine, it turns out, has a large impact on microglia, and the extracellular environment around certain neurons.
In the study, researchers gave mice either anesthetic doses of ketamine or saline injections every three days for up to six injections in total. The ketamine dosing was 100mg of ketamine per kilogram of mouse body weight. Researchers collected the brains of the mice and looked for changes in “perineuronal nets” (PNNs) in their visual systems. PNNs are a type of extracellular matrix coating certain neurons in the brain that keep neural connections stable in the adult brains. However, that same stability prevents adult neurons from rewiring with the same plasticity seen in young animals, and the formation of the PNN is thought to close out critical periods of learning.
The study found that ketamine exposure caused microglia to remodel the PNNs in the mice, loosening them for around seven days, and allowing the mice to recover the neural plasticity of their youth. “PNN loss provides an opportunity to overwrite previous learned information and to save this newly learned information,” Siegert said. “We see this kind as a ‘window of opportunity.’”
In addition to examining mouse brain tissue, the researchers demonstrated this restored plasticity through a monocular deprivation procedure, covering one of the animals’ eyes for three days. In young mice still in the critical period for visual system development, this procedure will lead to neuronal changes favoring the uncovered eye. So shining light in both eyes and measuring neural activity in the visual cortex reveals more activity in the circuitry processing information from the uncovered eye than from the covered eye. This change does not normally occur to the same degree, or in such a short time, in adults.
But the adult mice treated with ketamine showed exactly this effect after monocular deprivation. The saline-treated mice did not.
Interestingly, the study also showed similar microglia-driven dissolution of the PNN by exposing mice to light flickering at 60 hertz, but not eight or 40 hertz, for two hours a day for five days. In past research, microglia were shown to respond to external lights flickering in the gamma range — 25 to 100 hertz — with light flickering at 40 hertz causing microglia to remove the amyloid plaques seen in Alzheimer’s disease. These earlier results, along with the knowledge that ketamine itself impacts gamma frequency brainwaves, is what led the researchers to experiment with light stimulation. However, further research is needed to understand why microglia responded specifically to light flickering at 60 hertz in this study.
Together, the two findings suggest ketamine and flickering light could be used to safely treat conditions such as amblyopia, where “one eye has reduced vision causing poor alignment of the input from both eyes to the brain resulting in vision loss,” Siegert said. Current treatments for amblyopia require a person to wear an eye patch over the stronger eye for several weeks, she said, and are most effective during early childhood when the brain is more plastic.
Restoring youth-like plasticity temporarily in adults could therefore improve amblyopia treatment in older patients, but other methods previously understood to dissolve the PNN, such as the applications of certain enzymes, cause long-term PNN loss that is detrimental. “Long term loss of PNN would cause the brain to be ‘instable’ and be sensitive to all kinds of information coming in without filtering out the relevant information,” Siegert said. “We could imagine that a combination of both ketamine and light could be a new therapeutic angle.”
Evidence for ketamine’s effectiveness as a treatment for major depression and other psychiatric conditions is mounting, but which of the drug’s many mechanisms of action drives these therapeutic effects remains unclear. Siegert and her team are actively researching whether or not ketamine’s effects on the PNN could be an important part of that mechanism. Whether or not ketamine and/or flickering light could enable temporary neural plasticity in other parts of the brain, perhaps to treat language disorders or learning disabilities, is also “an intriguing possibility and would need further experiments,” Siegert added.
The immediate next steps for Siegert and her team will be refining their understanding of the present study. Siegert noted they used an anesthetic dose of ketamine to ensure an effect, given that mice metabolize ketamine faster than humans. In the future, they would like “to reduce the dosage in mice and see at which dosage and regime this effect could be replicated with lower dosage,” she said.