Cold memories cue our bodies to warm up

Our brains use associations to guide our bodily states – as anyone who has ever salivated at the sight of a slice of cake can attest. Now, research in Nature shows that mice that have learned to expect to become cold in a particular environment hike their metabolic rate, generating heat, when they're put back into that environment, even if it's actually warm. If the same thing happens in people, it might be possible to manipulate memories to help to treat conditions including obesity and certain cancers, the researchers suggest.

Andrea Muñoz Zamora at Trinity College Dublin first trained mice to associate cold, 4°C temperatures with being in a cage that was different to their standard home cage. It had brighter lights, patterns on the wall and floor, different bedding, and three drops of acetic acid, creating a vinegary odour. In total, the mice spent six hours over three days in this cage, at 4°C.

A few days later, they were put back in this cage, but at a room temperature of 21°C. The team found that though it was warm, the mice's metabolic rate and core body temperature increased. This showed that they had learned to 'expect' to be cold in this cage, and that their brains had automatically initiated a response to warm them up.

The researchers then looked for the 'engram' for this cold experience in the brain. An engram is an inter-connected group of neurons that have undergone physical changes as a result of an instance of learning, so encoding a memory. Reactivation of an engram leads to the retrieval of a specific memory.

Earlier work has identified engrams for various bodily representations, including inflammation and pain, the team notes. They found that cold-sensitive memory engrams form in the hippocampus and specific regions of the hypothalamus — a region of the brain important for regulating body temperature.

The researchers also found that when they artificially activated these cold-sensitive memory engrams, the metabolic rate of the mice increased. Conversely, when these engrams were inhibited, the mice no longer reacted to the 'cold' environment with a hike in their metabolic rate. This showed that these engrams play a crucial role in the warming up of the mice's bodies in a situation in which they were previously cold.

The research also revealed that a large part of the learned control of body temperature seemed to be due to increased activity of brown adipose tissue — or brown fat — which can be controlled by signals starting in the brain, commented co-author Lydia Lynch, in a press release. "Our brain must learn from the bodily experiences of cold, but then feeds back to control how our fat cells respond to cold," she said.

One approach to addressing obesity and related metabolic disorders is to stimulate activity of brown fat. Changes to brown fat have also been implicated in weight loss in cancer patients, which can interfere with treatment. The team would now like to see research to explore whether manipulating cold memories might help to change metabolic activity in people, and provide assistance (however slight that assistance may be) in treating certain diseases.

Read the paper in full:
Muñoz Zamora, A., Douglas, A., Conway, P. B., Urrieta, E., Moniz, T., O'Leary, J. D., Marks, L., Denny, C. A., Ortega-de San Luis, C., Lynch, L., & Ryan, T. J. (2025). Cold memories control whole-body thermoregulatory responses. Nature. https://doi.org/10.1038/s41586-025-08902-6

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