Sickness engrams modulate anticipatory immune responses

A threat to survival in the wild is vulnerability to infection. The immune system is essential for defence against foreign species which cause sickness. During infection the brain triggers conserved behaviors, including fever, tiredness and anorexia that support immunity. The immune system stores infection information via adaptive immunity, however it remains unclear whether the brain stores immune-related information as long-term memory engrams. Here we demonstrate that mice form contextual memories for sickness events. Upon sickness-memory recall mice lower whole-body metabolism, and increase coactivation between the hippocampus and sickness regions such as the central amygdala, alongside elevated engram activation. Optogenetic reactivation of sickness engrams decreases metabolism, similar to natural recall. Finally, natural recall and artificial reactivation of a sickness-memory increased genes associated with the acute phase response in the liver. These findings suggest that sickness experiences are encoded as engrams, which upon reactivation trigger coordinated metabolic and innate immune responses.