A corticothalamic circuit modulates pain sensitivity and mediates innate fear-induced analgesia in male mice

Abstract Fear and pain are two frequently co-occurring states that mammals need to orchestrate to ensure survival. Nevertheless, how the brain dynamically prioritizes between them remains poorly understood. Here, we demonstrate that innate fear suppresses both acute and chronic pain, whereas pain does not reciprocally modulate fear responses in male mice. Using fiber photometry, virus tracing, and electrophysiological approaches, we show that exposure to a fear-inducing odor activates GABAergic neurons in the anterior piriform cortex (APC), which subsequently attenuates pain-associated hyperactivity in the downstream mediodorsal thalamus (MD). Crucially, inhibiting either APCGABA neurons or the APCGABA-MD circuit enhances pain sensitivity and abolishes fear-induced analgesia. Conversely, activation of APCGABA neurons or the APCGABA-MD circuit induces freezing responses and relieves pain, mimicking fear-induced analgesia. These findings unveil a corticothalamic circuit that bidirectionally regulates pain processing and underlies fear-provoked analgesia, offering potential therapeutic avenues for pain management.