Psychedelics excite cells in hippocampus to reduce anxiety

A classic psychedelic, similar to LSD, psilocybin and mescalin, was found to activate a cell type in the brain that silences other neighboring neurons, a result that provides insight into how such drugs reduce anxiety, according to a new study in mice and rats.

The study by an international team of researchers, including at Cornell and the Tata Institute of Fundamental Research in India, showed that the psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) lessened anxiety in mice and rats while activating the ventral hippocampus and so-called fast-spiking interneurons there.

Psychedelics have shown potential for treating general anxiety and associated panic attacks. Prolonged use of the conventional anxiety therapy, a drug called benzodiazepine, can damage the brain and lead to dependence.

"It hasn't been known what brain areas and cell types are involved when psychedelics suppress anxiety," said Alex Kwan, associate professor of biomedical engineering at Cornell Engineering and a senior author of the study, which published Sept. 24 in the journal Neuron. "The idea is that if we know the neurobiology involved, we can design some better drug that would target these pathways."

"The work provides an understanding of the cellular trigger for the psychedelic-induced relief of anxiety," said Vidita Vaidya, senior professor of biological sciences at the Tata Institute of Fundamental Research in Mumbai, and the paper's corresponding author, along with first author, Praachi Tiwari, a postdoctoral research fellow at Johns Hopkins University, formerly at the Tata Institute.

The pathway in the ventral hippocampus - a brain structure involved in social memory, emotion and affect - does not appear to cause the hallucinations that are a hallmark of DOI, suggesting that some of the therapeutic effects of psychedelics - including reducing PTSD, depression and anxiety - may be isolated within discrete brain circuits, Vaidya said.

"That opens up the possibility to design psychedelic inspired drugs that target anxiety without evoking potent hallucinations," she added.

In the study, the team tested both rats and mice in a maze designed to study anxiety. The maze has two sections, an enclosed area with walls where the rodent may feel safe, and a completely exposed section that is elevated from the ground.

"As one might expect, the animal tends to spend a lot of time in the closed wing," Kwan said. "This is a kind of standard assay to determine how anxious the animal will be and how much it will explore." Researchers can assess anxiety levels based on time spent in each area.

In one experiment, the team injected DOI generally in the blood stream before running the rodents in the maze. They then systematically infused DOI in four different brain areas, one at a time, and tested for changes in anxiety. "Quite surprisingly, only one region - the ventral hippocampus - when we infused it with DOI, was able to retain the psychedelic's effect of reducing anxiety," Kwan said.

Electrical recordings of the brain were measured by co-author Antonio Fernandez-Ruiz, assistant professor of neurobiology and behavior and Nancy and Peter Meinig Family Investigator in the Life Sciences in the College of Arts and Sciences. These recordings identified that the fast-spiking interneurons, which make up only 10% to 15% of cells in the ventral hippocampus, showed increased firing under the influence of DOI. The interneurons are known for silencing other neurons, creating checks so different types of nerve cells aren't all excited at once.

The study builds upon earlier research that identified abnormal hyperactivity in the ventral hippocampus when an animal is anxious, particularly neurons that communicate with the amygdala, the major processing center for emotions.

"There's a hint that in the anxiety state, these cells are active, and maybe the drug works by then silencing some of these," Kwan said.

In future work, the researchers hope to investigate how the amygdala may be involved.

The study took advantage of cross-campus collaborations between Kwan and Fernandez-Ruiz to measure electrical brain signals and an international collaboration with Vaidya's team, which led many of the behavioral aspects of the study. Other co-authors included researchers from Yale University, Columbia University and the New York State Psychiatric Institute.

The study was supported by the Department of Atomic Energy in India, the Sree Padmavathi Venkateswara Foundation, the National Institutes of Health, a Sloan Fellowship, a Whitehall Research Grant, a Klingenstein-Simons Fellowship, a Sackler Institute Award and the National Science Foundation.

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