Tomer lab maps impact of Ketamine on brain-wide neural circuits

December 04, 2023

Ketamine is having a moment. Widely used as a recreational drug, ketamine is increasingly appearing in clinical settings. While originally used as an anesthetic, lower sub-anesthetic doses of ketamine have become more common as a painkiller and an antidepressant. The drug has most recently made headlines because of Elon Musk. When Don Lemon asked Musk about his ketamine use in an interview, Lemon’s new show, which was set to premier on X (formerly Twitter), was cancelled. 

In a clinical setting, the effects of ketamine are quickly seen and quickly abate, which means that continued, long-term use is necessary to manage chronic symptoms. However, the long-term effects of many medications on the brain after decades of use are still not well understood. Dr. Raju Tomer and his lab have published the first high-resolution map of a brain with long-term exposure to the clinical drug ketamine. “We were very interested in understanding if and how drugs change brain-wide networks with repeated usage,” says Dr. Tomer. “Most studies examine acute effects of drugs on brain activity, but we wanted to better understand how, over time, that leads to reconfiguration of our very plastic brains.” 

The Tomer Lab investigated ketamine's impact on the entire dopamine system, which is known to modulate activity across the brain. Their study in mice revealed a widespread, differential impact of ketamine across the entire brain. For instance, they observed increased dopaminergic innervation of areas in the prefrontal cortex involved in executive functions and decision making, and decreased connections to sensory brain regions involved in auditory and visual information processing. This unexpected differential impact on sensory and associative pathways parallels the known behavioral impact of ketamine in causing hallucinations—detaching sensory reality from cognitive faculty. The study further demonstrates that the same types of neurons located in different brain regions can be impacted differently by the same drug, underscoring the importance of developing targeted drug delivery approaches for neurological disorders. 

In addition, this study introduces efficient tools for systematic, unbiased brain-wide mapping of various drugs' effects on the brain at a sub-cellular level. The experimental and computational pipeline that the Tomer lab has developed is precedent-setting in the field of drug testing. “At the broad level this study is an elegant technical demonstration that it is possible to pick up fine changes in brain networks as a result of repeated exposure to a drug. I hope this study inspires more of such systematic investigation of how repeated exposure to a drug or medicine can reconfigure very plastic brains,” says Dr. Tomer. “I would like to see this done systematically for many types of drugs, to develop a sort of brain plasticity map. The technology is mature enough now for that.” 


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