The scientists were investigating the hippocampus, a brain area that plays a key role in memory in humans and mice. Specifically, they focused on the CA2 region, which is significant for social memory, the ability to remember other individuals, and the CA1 region, which is important for remembering places.

In this new study, the researchers for the first time reveal that CA1 and CA2 respectively encode the locations and individuals linked with a threatening experience. The results show that, beyond simply recognizing individuals, CA2 helps record more complex aspects of social memory: in this case, whether another individual is safe or risky. The scientists published their findings on October 15 in the journal Nature Neuroscience.

“It’s vital to all species that live in social communities, including mice and humans, to have social memories that can help one avoid future experiences with others that might prove harmful while keeping ourselves open to individuals who may be beneficial,” saidPegah Kassraian, PhD, a postdoctoral research fellow in the Siegelbaum lab and lead author of the new study. “Fearful memories are important for survival and help to keep us safe.”

To investigate where fearful social memories originate in the brain, Dr. Kassraian and her colleagues gave individual mice a choice. They could scamper to one place, meet another mouse that was unknown to them, and receive a mild foot shock (much like a static electricity zap people might get after walking on a carpet and touching a doorknob). Scurrying in the opposite direction to meet a different stranger was safe. Normally, the mice quickly learned to avoid the strangers and locations that were associated with the shocks, and these memories lasted for at least 24 hours.

To determine where in the hippocampus these memories were stored, the researchers genetically altered the mice to enable them to selectively suppress the CA1 or CA2 regions. Surprisingly, turning off each region had very different effects. When the scientists silenced CA1, the mice could no longer remember where they were zapped, but they could still remember which stranger was associated with the threat. When they silenced CA2, the mice remembered where they were shocked, but became indiscriminately afraid of both strangers they met.

These new findings reveal that CA2 helps mice remember whether past encounters with others were threatening or safe. The results also are consistent with prior research detailing how CA1 is home to place cells, which encode locations.

Previous research has implicated CA2 in various neuropsychiatric conditions such as schizophrenia and autism. The new study suggests that further investigating CA2 might help scientists better understand social anxiety, post-traumatic stress disorder and other conditions that can lead to social withdrawal.

“It’s possible that social withdrawal symptoms are related to an inability to discriminate between who is a threat and who is not,” said Dr. Siegelbaum, who is also a professor and chair of the department of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons. “Targeting CA2 could be a useful way of diagnosing or treating disorders linked with a fear of others.”

The paper, “The hippocampal CA2 region discriminates social threat from social safety,” was published online in Nature Neuroscience on October 15, 2024.

The full list of authors includes Pegah Kassraian, Shivani K. Bigler, Diana M. Gilly, Neilesh Shrotri, Anastasia Barnett, Heon-Jin Lee, W. Scott Young, and Steven A. Siegelbaum.

The authors report no conflicts of interest.

The first human case of mpox was recorded in 1970 in the Democratic Republic of the Congo (DRC). Two types of the virus that causes mpox have been identified. Clade I is endemic in Central Africa and can cause severe illness. Clade II, endemic in West Africa, caused the global mpox outbreak that began in 2022 and tends to result in milder illness. People with compromised immune systems, children, and those who are pregnant are especially vulnerable to severe mpox regardless of the virus clade. A large proportion of people affected in the current Clade I outbreak in the DRC and other African countries are adolescents and children. The modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine is approved in several countries for the prevention of mpox and smallpox in adults, but insufficient data are available to support licensure for people younger than 18 years.

NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring a mid-stage study in the United States to evaluate the safety and immune response generated by two doses of MVA-BN in adolescents aged 12-17 years, comparing outcomes to those in adults aged 18-50 years. In a planned interim analysis, study investigators measured antibody levels two weeks after the second dose (study day 43) and monitored safety through 180 days after the second dose (study day 210). The analysis showed that the MVA-BN vaccine generated antibody levels in adolescents equivalent to those observed in adults at day 43 and found that the vaccine was well tolerated through study day 210. The overall frequency of adverse events was comparable between the study groups. Reports of dizziness were more common in adolescents than adults, but similar to the frequency of dizziness reported when other vaccines are administered in adolescents.

According to the study team, the interim data support the safety and quality of the immune response generated by the MVA-BN vaccine in adolescents, findings relevant to the United States and other areas where mpox cases have occurred. The authors underscored the need to evaluate the MVA-BN vaccine in younger children to extend the evidence base to all people affected by mpox.

NIH is grateful to the research sites and volunteers who participate in studies to improve the mpox response.

For more information about this study, please visit ClinicalTrials.gov and use the identifier NCT05512949.