Researchers have discovered that the CA1 and CA2 areas of the brain encode information about locations and people associated with threatening situations. Their findings indicate that CA2 goes beyond just recognizing individuals; it also helps store more intricate details of social memory, particularly regarding whether a person is safe or poses a risk.
How do we recognize what is safe and what is threatening? This question is crucial not only in everyday life but also in the context of mental health disorders associated with fear of others, such as social anxiety and post-traumatic stress disorder (PTSD). A microscope image from Steven A. Siegelbaum, PhD, at Columbia’s Zuckerman Institute, highlights an advanced method utilized by scientists to explore this issue.
The research focused on the hippocampus, a brain region essential for memory in both humans and mice. The team zoomed in on the CA2 area, recognized for its role in social memory—remembering other people—and the CA1 area, which is vital for remembering locations.
In this breakthrough study, researchers have shown for the first time that the CA1 and CA2 areas specifically encode locations and individuals associated with a threatening experience. The study reveals that CA2 not only helps identify people but also captures more nuanced aspects of social memory—specifically, whether another individual is perceived as safe or dangerous. These findings were published on October 15 in the journal Nature Neuroscience.
“Social memories are crucial for all species that live in communities, including mice and humans. They help us avoid harmful encounters while remaining open to beneficial ones,” stated Pegah Kassraian, PhD, a postdoctoral fellow in the Siegelbaum lab and lead author of the study. “Memories of fear are vital for survival and contribute to our safety.”
To explore how fearful social memories are formed in the brain, Dr. Kassraian and her team gave mice a choice: They could go to a certain area, meet an unfamiliar mouse, and receive a mild foot shock (similar to a static electricity jolt from touching a doorknob after walking on carpet). Alternatively, they could run in the opposite direction to meet another stranger without any associated threat. Typically, the mice quickly learned to steer clear of both the strangers and locations tied to the shocks, retaining those memories for at least 24 hours.
To identify where in the hippocampus these memories were stored, the researchers genetically modified the mice to selectively shut down the CA1 or CA2 regions. Interestingly, silencing each region had distinct outcomes. When CA1 was turned off, the mice forgot where they had been shocked yet still remembered which stranger was tied to the danger. In contrast, when CA2 was silenced, the mice recalled the location of the shocks but developed a generalized fear of both strangers.
This study reveals that CA2 enables mice to differentiate between past interactions with others that were either safe or threatening. These results align with earlier research showing that CA1 contains place cells crucial for location encoding.
Previous studies have suggested a link between CA2 and various neuropsychiatric disorders, including schizophrenia and autism. This new research indicates that further exploration of CA2 may contribute to a deeper understanding of conditions like social anxiety and PTSD, which can result in social withdrawal.
“It’s likely that symptoms of social withdrawal stem from an inability to differentiate between threats and safe individuals,” noted Dr. Siegelbaum, who is also a professor and department chair at Columbia’s Vagelos College of Physicians and Surgeons. “Focusing on CA2 could be a valuable approach for diagnosing or treating disorders associated with fear of others.”
The article, titled “The hippocampal CA2 region discriminates social threat from social safety,” was published online in Nature Neuroscience on October 15, 2024.
The complete 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 declare that they have no conflicts of interest.
