By Pooja Toshniwal PahariaReviewed by Lexie CornerMay 6 2025A recent study published in Nature reveals that recalling cold experiences can trigger significant physiological responses in the body, boosting metabolism, thermogenesis in brown adipose tissue (BAT), and the breakdown of glucose and lipids.
This memory-induced thermoregulation suggests potential applications for treating metabolic conditions like diabetes and obesity. The findings also hint at possible therapeutic approaches for conditions like Raynaud’s disease, where enhanced thermogenesis could offer relief.
How the Brain Regulates Body Temperature
The brain maintains homeostasis through a complex network of cells and signaling pathways that connect it to the rest of the body. Learned associations can influence peripheral immune and neuroendocrine responses, and mental states can directly impact physical functions.
In the context of temperature regulation, environmental cues trigger the brain to coordinate behavioral and autonomic responses aimed at restoring optimal body temperature. Behavioral adaptations might include nest building or migrating to warmer areas, while autonomic responses include vasoconstriction, shivering, and non-shivering thermogenesis.
Despite this understanding, the mechanisms by which the brain encodes, stores, and retrieves temperature-related information remain largely unknown. How these stored memories influence physiological changes is still not fully understood. This study set out to explore that connection.
Study Overview
In this study, researchers examined how memory recall can influence physiological function, specifically looking at whether recalling a cold experience could alter metabolism in mice.
To explore this, they used a combination of Pavlovian conditioning, engram labeling, chemogenetics, and optogenetics. In the conditioning experiments, mice were trained at 4 °C to associate a particular environment with cold exposure, allowing the researchers to test whether the animals could later recall temperature-related experiences. A separate set of experiments tested whether mice developed an aversion to cold by comparing those trained at 4 °C and 21 °C.
The team labeled specific memory engrams—neural circuits responsible for encoding cold-related experiences—to monitor their activation during memory recall. Using optogenetic and chemogenetic tools, they artificially reactivated these cold-associated engrams and measured the resulting physiological responses. Metrics such as oxygen consumption, energy expenditure, and core body temperature were used to assess metabolic changes during memory recall.
To further understand the metabolic effects, the researchers analyzed the expression of thermogenesis-related genes in brown adipose tissue. They also conducted control experiments to determine whether these effects were specific to cold memory recall or could result from generalized stress. This included comparing tissue from mice subjected to contextual fear conditioning using mild foot shocks and from mice exposed to a predator odor (trimethylthiazoline, TMT).
Finally, they examined FOS protein expression—a marker of neuronal activity—in several brain regions involved in memory processing. By correlating these patterns with metabolic changes, they aimed to better understand how the brain encodes and retrieves cold-related experiences and how this recall can influence the body’s physiological state.
Key Findings
The study showed that recalling cold experiences—either naturally or through artificial stimulation—provoked clear physiological responses in mice. These included increased body temperature, carbon dioxide production, glucose and lipid metabolism, energy expenditure, and mobility. Importantly, these responses occurred even in a warm environment, indicating that the memory itself, not the external temperature, triggered the changes.
The team identified significant upregulation of thermogenesis-related genes in brown adipose tissue during cold memory recall. These included:
- UCP1 (uncoupling protein 1) – essential for heat generation in BAT
- CPT1A (carnitine palmitoyltransferase 1A) – regulates mitochondrial fatty acid uptake
- CACT (carnitine-acylcarnitine translocase) – facilitates mitochondrial transport
- ATGL and HSL (adipose triglyceride lipase and hormone-sensitive lipase) – involved in lipid mobilization
These molecular signatures support the idea that recalling cold experiences primes the body for thermogenesis by initiating lipid and glucose breakdown, offering a non-invasive strategy for metabolic regulation.
The researchers also mapped the neural circuits involved. Cold-associated memory engrams were located in both the hypothalamus and hippocampus. Activation of these circuits triggered the physiological responses. Notably, the CA1 and CA3 regions of the hippocampus showed elevated FOS protein expression—an indicator of neuronal activity—during memory recall, suggesting these subregions play a key role in encoding cold experiences.
Functional connectivity between the dentate gyrus of the hippocampus and the lateral hypothalamic area (LHA) was critical for triggering thermogenic responses. The findings confirm that memory recall alone, independent of physical cold exposure, can initiate metabolic adaptation via these brain networks.
Interestingly, stress alone did not replicate these effects. Neither fear-conditioned mice nor those exposed to predator odors showed similar thermogenic gene expression or hypothalamic-hippocampal activity, underscoring the specificity of the cold-memory-driven mechanism. Additionally, inhibiting cold-sensing hippocampal neurons disrupted both memory recall and the associated physiological response.
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Conclusion
This study provides compelling evidence that recalling cold-related experiences can initiate real physiological changes, including elevated body temperature, increased metabolism, and activation of thermogenic pathways in brown adipose tissue. These effects are not general stress responses but are specific to the memory of cold exposure, mediated by neural circuits connecting the hippocampus and hypothalamus.
The findings open up new possibilities for memory-based interventions in metabolic health. Therapeutic strategies that stimulate cold-related memory circuits could one day support treatments for obesity, diabetes, and temperature regulation disorders.
Journal Reference
Muñoz Zamora, A., . et al. Cold memories control whole-body thermoregulatory responses. Nature (2025), DOI: 10.1038/s41586-025-08902-6, https://www.nature.com/articles/s41586-025-08902-6
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