In a groundbreaking study published in Nature, researchers have uncovered the profound influence that cold-related memories exert on the regulation of whole-body metabolism and thermogenic responses. By harnessing advanced optogenetic techniques, the team demonstrated that reactivating specific neuronal ensembles in the dentate gyrus (DG) of the hippocampus—cells dedicated to encoding cold experiences—can artificially elevate metabolic rates and stimulate gene expression associated with heat production in brown adipose tissue (BAT). These findings shed light on the neural circuitry underlying environmental adaptation and open new avenues for metabolic therapies.
The central focus of this study was to interrogate whether cold-sensitive engrams—the physical neural substrates of memory formed under cold exposure—play an active, causal role in systemic metabolic regulation. Using transgenic mouse models, the scientists selectively labelled cold-responsive neuronal populations in the DG during cold exposure (termed CL1). Subsequent optogenetic reactivation of these labelled cells in a neutral ambient temperature environment elicited significant increases in oxygen consumption, a robust indicator of metabolic activity. This artificial stimulation thereby mimicked the physiological metabolic boost normally prompted by cold exposure itself.
Detailed temporal analysis revealed that metabolic rate surges occurred specifically during laser-on intervals when cold-sensitive engrams were activated, returning promptly to baseline levels once stimulation ceased. Intriguingly, this effect attenuated upon a third consecutive stimulation session, implying potential habituation within the downstream pathways or limitations inherent to neuronal optogenetic activation. The reproducibility of these outcomes was confirmed across different transgenic systems, including those utilizing the FOS-tTa labelling framework, demonstrating the robustness of cold-engram manipulation in controlling metabolism.
To rigorously validate these observations, the researchers conducted control experiments targeting DG engrams labeled in the absence of cold exposure—termed “no-cold” engrams. Optogenetic activation of these non-cold contextual engrams yielded no significant enhancement in whole-body metabolic rate. In several instances, stimulation of no-cold engrams even elicited slight decreases in oxygen consumption, reinforcing the specificity of cold-sensitive engram activation in driving metabolic changes. Comparative analyses underscored that the pronounced oxygen consumption rise was unique to cold-exposed animals during light-induced reactivation.
Extending beyond the hippocampus, the team probed the downstream brain regions implicated in thermoregulatory control. By combining channelrhodopsin-assisted DG stimulation with brain-wide labelling of engram cells using eYFP fluorescence, they mapped coactivation patterns in hypothalamic nuclei. Significant increases in co-labelled neurons occurred in the lateral hypothalamic area (LHA) and medial preoptic (MPO) hypothalamic regions, but not in the lateral preoptic area (LPO). This selective regional involvement suggests that the DG’s cold-sensitive engrams interface functionally with specific hypothalamic circuits orchestrating systemic metabolic output.
Moreover, a compelling positive correlation emerged between oxygen consumption and the extent of artificial engram activity within the LHA, highlighting this region’s pivotal role in mediating learned thermoregulatory responses. These data intimate a circuit architecture whereby cold memory engrams in the hippocampus transmit signals to hypothalamic hubs, ultimately governing metabolic rate adjustments to optimize energy expenditure following environmental challenges.
To translate these neural manipulations into peripheral metabolic outcomes, the investigators evaluated thermogenesis gene expression profiles within BAT—an organ central to heat generation and energy homeostasis. Reactivation of cold-sensitive hippocampal engrams markedly elevated expression of Ucp1 and Cpt1a, key genes implicated in mitochondrial uncoupling and fatty acid oxidation, respectively. These molecular changes mirror physiological cold adaptation where BAT activity is upregulated to maintain core temperature. Notably, no alterations were observed in other thermogenic markers such as Hsl, Atgl, or Ppargc1a, indicating a targeted transcriptional response.
Together, the findings establish a paradigm wherein cold exposure leaves persistent neuronal “imprints” in the hippocampus that can be recalled to activate systemic thermogenic mechanisms even in the absence of external cold stimuli. This neural ‘memory’ of cold effectively modulates hypothalamic circuits and peripheral metabolic tissues to orchestrate complex physiological responses critical for survival. The precise manipulation of these engrams reveals the power of memory traces not only in cognition but in whole-body energy balance.
The attenuation of metabolic responses upon repeated engram stimulations observed in the study also prompts intriguing questions about neural plasticity and adaptation in this pathway. It may reflect synaptic fatigue, recruitment of inhibitory feedback loops, or homeostatic mechanisms limiting overstimulation of thermogenic systems to prevent adverse effects. Future research will be necessary to dissect these mechanisms and determine how persistent or flexible the memory-driven thermoregulatory system is.
This work elegantly combines cutting-edge optogenetics, genetic labelling strategies, and metabolic phenotyping to bridge the gap between experiential memory and physiological regulation. By identifying the hippocampus, a region typically associated with declarative memory, as a key player in energy balance, the research challenges classical circuit models of thermoregulation and opens new landscapes for exploring memory-dependent metabolic control.
Applications of this knowledge could extend to novel interventions in metabolic diseases such as obesity or hypothermia, whereby targeted activation or repression of memory engrams might recalibrate energy expenditure. Moreover, understanding the neurobiology of environmental memory could have broad implications for adaptation to climate variability or seasonal changes.
The integration of behavioral neuroscience with whole-body physiology marks a transformative approach, illustrating how experiential neural circuits transcend cognitive roles to govern vital homeostatic functions. As such, these insights are poised to stimulate cross-disciplinary research efforts and inspire new conceptual frameworks in neuro-metabolism.
Ultimately, the demonstration that “cold memories” exert causal control over metabolism underscores the elegance of adaptive biological systems: encoding not just the past, but banking on experience to anticipate physiological needs. This innovative research not only deciphers the neural codes of environmental adaptation but also paves the way for harnessing memory circuits to modulate somatic health.
Subject of Research: Memory engrams and their role in regulating whole-body metabolism and thermogenesis.
Article Title: Cold memories control whole-body thermoregulatory responses.
Article References:
Muñoz Zamora, A., Douglas, A., Conway, P.B. et al. Cold memories control whole-body thermoregulatory responses. Nature (2025). https://doi.org/10.1038/s41586-025-08902-6
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