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In December of 2022, researchers at Penn Medicine published a paper that gives healthcare professionals a glimpse into the way that ketamine can be used to dramatically reorganize neural pathways in the brain to help alleviate symptoms of depression.

The study was published in Nature Neuroscience and studied may have advanced our understanding of how ketamine infusions affect the brain.

Ketamine has been around since the 1960s but has only recently gained credibility among healthcare professionals as a viable treatment option for people suffering from depression.

The study found that there were starkly changed neuronal patterns of activity in the cerebral cortex of animal models after ketamine was administered. They observed normally active neurons that were silenced and another set that was normally quiet suddenly springing to action.

The ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry. This could also signal that it is the place where ketamine’s therapeutic effects take place.

In the study, the researchers analyzed mouse behaviors before and after they were administered ketamine, comparing them to control mice who received placebo saline. They observed that those given ketamine exhibited behavioral changes consistent with what is seen in humans on the drug, including reduced mobility, and impaired responses to sensory stimuli, which are collectively termed “dissociation.”

The researchers used two-photon microscopy to image cortical brain tissue before and after ketamine treatment. By following individual neurons and their activity, they found that ketamine turned on silent cells and turned off previously active neurons. They traced the neuronal activity observed to ketamine’s ability to block the activity of synaptic receptors — the junction between neurons — called NMDA receptors and ion channels called HCN channels.

The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons, allowing the normally quiet neurons, which are usually being suppressed when ketamine isn’t present, to become active.

The study showed that this dropout in inhibition was necessary for the activity switch in excitatory neurons, which are the neurons forming communication highways and the main target of commonly prescribed antidepressant medications. More work will need to be undertaken to determine whether the ketamine-driven effects in excitatory and inhibitory neurons are the ones behind ketamine’s rapid antidepressant effects.

Overall, the study’s findings could help in the development of future treatments for neuropsychiatric disorders by providing a better understanding of how ketamine works in the brain. The researchers hope that this could lead to better and more beneficial therapeutic use of ketamine in the future.