The experience of cold temperatures leaves a lasting impression on the brain, according to a new study published April 23, 2025 in the journal Nature. The study was conducted through a collaborative effort between Princeton researcher Lydia Lynch and Tomás Ryan from Trinity College Dublin.

See the Nature "News & Views" article about this paper.

When you get caught out in the cold, you can take several measures to improve your chances of survival. First, you can enact behavioral changes such as putting on an extra layer of clothing or searching out a cozy space where you can huddle to conserve heat. Your body will also mobilize fuel reserves in brown adipose tissue (also known as brown fat, or BAT), increasing metabolism to generate heat. Hopefully this will be enough to see you through, and more drastic adaptations such as cutting off circulation to the extremities or shivering will not be necessary. But what about the next time? Does having experienced cold prepare you for subsequent encounters?

“We set out to test whether mammals can form memories of cold experiences,” said Dr. Lydia Lynch, a Professor in the Princeton Department of Molecular Biology.

Lynch, whose lab studies interactions between the immune system and metabolism, came to Princeton from Dublin. While there, she’d struck up a collaboration with Ryan. The pair wanted to investigate whether animals can form memories about temperature that allow them to anticipate the need for adaptations to cold, and whether such memories can affect metabolism.

“Tomás is a neuroscientist [and he] really wanted to apply some of our techniques in immunology and whole body metabolism to memory formation, which is his specialty,” said Lynch.

The team’s studies were led by graduate student Andrea Muñoz Zamora and postdoctoral researcher Aaron Douglas, whose work was mentored by both Lynch and Ryan.

To determine whether mice are able to form memories about temperature, Muñoz Zamora and colleagues employed a modern twist on methods initially pioneered by Ivan Pavlov more than a century ago. Animals were first housed at normal temperatures in cages decorated with a specific color scheme, wall pattern, and scent, then transferred to cages with different visual and scent cues that were maintained at cold temperatures. The cages were equipped with instruments to remotely monitor the changes in oxygen consumption and carbon dioxide exhalations that accompany increases in metabolic activity, and cameras to observe the animals’ body temperature, activity levels, and posture.

As expected, mice exposed to cold temperatures showed changes in behavior as they sought to adapt. They also showed signs of increased metabolism, such as increased body temperatures and altered respiratory rates, until they were returned to their home cages. The researchers showed that these external signs of increased metabolism were accompanied by changes in BAT gene expression consistent with metabolic adaptation.

Next, the animals were rested for a few days and then placed in cages decorated like the cold cages but kept at normal temperature. This setup tested whether, like Pavlov’s famous dogs, the mice had been conditioned to remember and expect a certain experience—in this case, cold temperatures—in this setting. In fact, the mice exhibited behavioral, metabolic and BAT gene expression changes similar to those observed under actual cold conditions, showing that they had formed memories of the cold environment and were anticipating the need for these adaptions. Next, the team investigated how these memories are formed.

“Memories are stored as ensembles of cells, termed engrams,” said Ryan. So, the team investigated whether they could identify engrams associated with memories about cold.

Scientists have already mapped the brain regions and structural circuits responsible for behavioral responses to cold in laboratory mice, so the researchers examined whether similar engrams are involved in forming memories that can affect metabolism. They found that the hypothalamus and the hippocampus are both involved in cold memory formation, and identified a brain circuit that houses these memories. Crucially, having identified this engram, the researchers then showed that stimulating it using implanted lasers causes increased metabolic activity in BAT. Animals in which these circuits were chemically deactivated could not form memories about cold temperature or enact anticipatory changes to metabolism. Put together, these observations demonstrate that cold temperatures engender memories in the brain that can control BAT metabolism.

“This is an example of inter-disciplinary science,” said Ryan. “It was the collaboration with Lydia that allowed the integration of engram work with metabolism research.” 

Already, this work has opened several avenues for further research touching on topics ranging from metabolic and neurodegenerative disorders to aging.

“In the future, we will be looking at whether the manipulation of cold memories in humans may provide novel avenues for manipulating metabolism for therapeutic purposes,” said Lynch.

Citation: Andrea Muñoz Zamora, Aaron Douglas, Esteban Urrieta, Taylor Moniz, James D. O’Leary, Lydia Marks, Christine A. Denny, Clara Ortega-de San Luis, Lydia Lynch, and Tomás J. Ryan. Cold memories control whole-body thermoregulatory responses. Nature. 2025. DOI: 10.1038/s41586-025-08902-6

Funding: The work described here was funded by the Air Force Office of Scientific Research (FA9550-24-1-0258), European Research Council (715968), Irish Research Council (GOIPG/2020/913), Science Foundation Ireland (15/YI/3187), the National Institute of Health (1R01NS121316) and Trinity College Dublin.