Cold memories control whole-body thermoregulatory responses

Abstract

Environmental thermal challenges trigger the brain to coordinate both autonomic and behavioural responses to maintain optimal body temperature1–4. It is unknown how temperature information is precisely stored and retrieved in the brain and how it is converted into a physiological response. Here we investigated whether memories could control whole-body metabolism by training mice to remember a thermal challenge. Mice were conditioned to associate a context with a specific temperature by combining thermoregulatory Pavlovian conditioning with engram-labelling technology, optogenetics and chemogenetics. We report that if mice are returned to an environment in which they previously experienced a 4 °C cold challenge, they increase their metabolic rates regardless of the actual environmental temperature. Furthermore, we show that mice have increased hypothalamic activity when they are exposed to the cold, and that a specific network emerges between the hippocampus and the hypothalamus during the recall of a cold memory. Both natural retrieval and artificial reactivation of cold-sensitive memory engrams in the hippocampus mimic the physiological responses that are seen during a cold challenge. These ensembles are necessary for cold-memory retrieval. These findings show that retrieval of a cold memory causes whole-body autonomic and behavioural responses that enable mice to maintain thermal homeostasis. Cold-sensitive engrams contribute to learned thermoregulation in mice that are returned to an environment in which they previously experienced a cold challenge, through a network formed between the hippocampus and hypothalamus that enables the recall of cold-related memories.