June 8, 2021

Study reveals brain cells that sustain or suppress fearful memories

At a Glance

  • Researchers identified clusters of brain cells that compete to promote either the persistence or disappearance of fearful memories.
  • The findings could give insight into post-traumatic stress disorder (PTSD) and anxiety disorders.
Person in shadow running through creepy underpass When fearful memories persist, they can lead to harmful mental health conditions. Suteishi / E+ via Getty Images

Remembering a threat is key for survival. Fearful memories help people and animals respond to potential dangers. But having these memories fade when they’re no longer useful is important to avoid undue stress and anxiety. When traumatic memories persist, they can lead to conditions like PTSD, anxiety disorders, and related problems like alcohol use disorder.

In past studies, researchers identified specialized circuits in the brain that preserve fearful memories or, in a process called extinction, suppress them. Rather than erasing the fearful memory, a new memory is formed that coexists in opposition. But while the neural circuits involved in this process are known, the interactions between them aren’t well understood.

A team led by Dr. Andrew Holmes of NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Andreas Lüthi of the Friedrich Miescher Institute for Biomedical Research investigated how certain brain cells interact to preserve or suppress traumatic memories. Their findings appeared in Nature on May 26, 2021.

The research team conducted studies in mice to examine clusters of neurons known as intercalated cells, or ITCs. These neurons are packed tightly around the amygdala, a brain region known for processing fear and anxiety. Previous studies suggested that certain ITCs play a role in fear extinction, but their small size and location deep in the brain have made them hard to study.

To better understand the role of ITCs, researchers used calcium imaging to study their activity in mice. The team tracked which cells were activated as mice learned to associate a cue (e.g., a sound) with a fear-inducing event (a mild foot shock). They then tracked the cells’ activity as they extinguished the association by no longer pairing the cue with a foot-shock.

The researchers found that two distinct ITC clusters underlie the fear response and its extinction. These clusters compete with one another to determine the relative strength of each memory. The balance of activity between the clusters was correlated with a shift in the animals’ behavior from fearful to less fearful, as measured by their willingness to explore protected and unprotected areas of a maze.

The study also showed that the ITC clusters have long-range connections to separate brain regions known to regulate fear in the midbrain and prefrontal cortex.

“The persistence of disturbing memories of a traumatic event are one of the hallmarks of PTSD and some anxiety disorders,” Holmes says. “Our findings identify a neural circuit within the amygdala that orchestrates activity across a broad brain network to exert a powerful influence over the ability to switch between high and low fear states.

“This finding now raises interesting questions about whether dysfunction of this brain system could contribute to the marked individual differences in risk for trauma-related psychiatric disorders,” he adds.

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References: Intercalated amygdala clusters orchestrate a switch in fear state. Hagihara KM, Bukalo O, Zeller M, Aksoy-Aksel A, Karalis N, Limoges A, Rigg T, Campbell T, Mendez A, Weinholtz C, Mahn M, Zweifel LS, Palmiter RD, Ehrlich I, Lüthi A, Holmes A. Nature. 2021 May 26. doi: 10.1038/s41586-021-03593-1. Online ahead of print. PMID: 34040259.

Funding: NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA); European Research Council (ERC); Swiss National Science Foundation; German Research Foundation; Novartis Research Foundation.