Acute restraint stress and pain modulation depend on the interaction between the periaqueductal gray and the lateral septum

Acute restraint stress is known to cause analgesia in humans and laboratory animals, but the mechanisms are unknown. Recently, we have shown that a multi-nodal circuitry between the dorsal lateral septum (dLS)-lateral hypothalamic area (LHA)-rostral ventromedial medulla (RVM) plays an instructive role in restraint stress-induced analgesia. We found that the LS neurons are activated when mice struggle to escape the restraint, and we wondered about the origin of the escape signals. Hence, we performed retrograde viral labeling from the LS and found that the ventrolateral periaqueductal gray (vlPAG), a known anatomical substrate for escape behaviors, provides inputs to the LS. Through anatomical, behavioral, and in-vivo fiber photometry, we show that the PAG and LS neurons are synaptically connected; activation of either PAG or the post-synaptic LS neurons is sufficient to cause analgesia and sufficiently cause hyperalgesia. Moreover, we found that the LS neurons that receive inputs from PAG send axonal projections to the LHA. Together, we found that the vlPAG neurons encoding nociceptive and escape behaviors provide synaptic inputs to the dLS-LHA-RVM circuitry to mediate acute restraint stress-induced analgesia.