A Midbrain Circuit that Mediates Headache Aversiveness in Rats

Abstract

Summary: Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness. : Migraine headache is a common and debilitating disorder, yet its brain-activation patterns are poorly understood. Waung et al. discover that headache activates a connection between the periaqueductal gray and the ventral tegmental area in rats. Turning off this connection has no effect normally but decreases unpleasantness during headaches. Keywords: headache, migraine, periaqueductal gray, ventral tegmental area, ventrolateral PAG