Something positive about Norwegian winter? Cold memories control whole-body thermoregulatory responses
by Ulrik Larsen
Exposure to cold induces long-lasting changes in physiology that persist beyond the cold period itself. This study investigates the cellular and molecular mechanisms of this phenomenon, termed “cold memory”, focusing on specific neural activation and downstream metabolic effects.
Through a combination of TRAP2-based activity-dependent cell labeling (a tracing method to trace neurons that are active, in this case when the mice are exposed to the cold, to permanently tag them using tamoxifen) and whole-brain mapping, researchers identified a cold-activated neuronal population in the hypothalamus. These neurons were reactivated when the mice were placed back in the cold chamber even at room temperature, suggesting a memory trace.
Chemogenetic (DREADDs) and optogenetic (Channelrhodopsin or Halorhodopsin) activation or inhibition of these cold-memory engram neurons demonstrated their ability to reactivate a thermogenic and metabolic state mimicking cold exposure. Reactivation of these engram neurons led to increased sympathetic tone, elevated body temperature, enhanced brown adipose tissue activity, and improved systemic glucose metabolism, without external cold stimulus. These changes were confirmed to not be due to increased activity level of the mice. Additionally, molecular profiling of these neurons showed a gene expression signature enriched in neuropeptides and cold-responsive pathways.
The results indicate a mechanism wherein environmental history can be embedded in neural engram cells and influence systemic physiology, including energy balance and glucose handling. This neural mechanism could have implications for understanding adaptive thermogenesis and metabolic disease modulation. However, this activation may also affect immune function, blood pressure regulation, and stress levels.
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Muñoz Zamora A, Douglas A, Conway PB, Urrieta E, Moniz T, O’Leary JD, Marks L, Denny CA, Ortega-de San Luis C, Lynch L, Ryan TJ. Cold memories control whole-body thermoregulatory responses Nature. 2025 Apr 23. doi: 10.1038/s41586-025-08902-6