See how ketamine acts as a ‘switch’ in the brain — ScienceDaily

Ketamine, an established anesthetic and increasingly popular antidepressant, dramatically reorganizes activity in the brain, as if a switch has been flipped on its active circuits, according to a new study by researchers at Penn Medicine. In a Natural Neuroscience In a paper released this month, the team described dramatically altered neuronal activity patterns in the cerebral cortex of animal models following ketamine administration – observing normally active neurons being silenced and another set that was normally silent suddenly springing into action. This ketamine-induced activity change in key brain regions associated with depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry.

“Our surprising results reveal two distinct populations of cortical neurons, one involved in normal waking brain function, the other linked to the ketamine-induced brain state,” said co-lead and co-senior author Joseph Cichon, MD, PhD, an assistant professor of anesthesiology and critical care and neuroscience at the Perelman School of Medicine at the University of Pennsylvania. “It’s possible that this new network, triggered by ketamine, is enabling dreams, hypnosis, or some sort of unconscious state. And if this is found to be true, it could also signal that it’s where the therapeutic effects of ketamine are taking place. take place.”

Anesthesiologists routinely provide anesthetics for surgery to reversibly alter activity in the brain so that it enters the unconscious state. Since its synthesis in the 1960s, ketamine has been a mainstay in anesthetic practice due to its reliable physiological effects and safety profile. One of the distinctive properties of ketamine is that it maintains certain states of activity across the surface of the brain (the cortex). This is in contrast to most anesthetics, which work by completely suppressing brain activity. It is these preserved neuronal activities that are believed to be important for the antidepressant effects of ketamine in key brain regions associated with depression. But to date, it remains mysterious how ketamine exerts these clinical effects.

In their new study, the researchers analyzed the behavior of mice before and after they were given ketamine, and compared them to control mice that were given a placebo saline solution. One key observation was that those given ketamine showed behavioral changes consistent with what is seen in people taking the drug within minutes of injection, including decreased mobility, decreased responses to sensory stimuli, collectively referred to as “dissociation.”

“We hoped to pinpoint exactly which parts of the brain circuitry ketamine affects when it is administered, so that we can open the door for better study of it and, in the future, for more beneficial therapeutic uses,” said co-lead and co senior author Alex Proekt, MD, PhD, an associate professor of anesthesiology and critical care at Penn.

Two-photon microscopy was used to image cortical brain tissue before and after ketamine treatment. By tracking individual neurons and their activity, they found that ketamine turned on silent cells and turned off previously active neurons.

The neuronal activity observed was traced to ketamine’s ability to block the activity of synaptic receptors – the connection between neurons – called NMDA receptors and ion channels called HCN channels. The researchers found that they could recreate the effects of ketamine without the drugs by simply inhibiting these specific receptors and channels in the cortex. The scientists showed that ketamine weakened several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally silent neurons, which were usually suppressed in the absence of ketamine, to become active.

The study showed that this drop in inhibition was necessary for the activity change in excitatory neurons – the neurons that form communication highways and the main target of commonly prescribed antidepressants. More research will be needed to determine whether the ketamine-driven effects in excitatory and inhibitory neurons are the cause of ketamine’s rapid antidepressant effects.

“While our study relates directly to basic neuroscience, it does point to ketamine’s greater potential as a fast-acting antidepressant, among other uses,” said co-author Max Kelz, MD, PhD, a distinguished professor of anesthesiology and vice chair. of research in anesthesiology and critical care. “Further research is needed to fully investigate this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric conditions.”

The study was supported by the Foundation for Anesthesia Education and Research and the National Institutes of Health (T32NS091006, R01GM124023-01A1, R01GM088156-08, R01 EY020765).

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