Rostral ventromedial medulla (RVM) projects to the lateral hypothalamic area (LHA) to drive aversion and anxiety

Neurons in the LHA are critical drivers of behavioral and physiological responses to acute and chronic stress. However, the roles of the specific pre-synaptic inputs to the LHA in driving stress and resultant physiological effects are yet to be fully understood. Here, taking advantage of mouse viral genetics, rabies tracing, optogenetics, chemogenetics, and fiber photometry, we show that the excitatory projections from the RVM to LHA drive stress-induced anxiety. This is a surprising finding since, traditionally, RVM has been studied in the context of opioidergic pain modulation through its inhibitory projections to the spinal cord. We find that the LHA neurons receiving inputs from the RVM, when activated, do not alter the nociceptive thresholds yet are sufficient to drive anxiety-like behaviors. These LHA neurons are recruited by acute restraint, which is known to cause stress. On the other hand, the LHA-projecting RVM neurons are responsive to both noxious thermal stimuli and acute restraint, promoting stress-induced anxiety, yet with no effect on pain thresholds. Together, we found an ascending neural pathway between RVM and LHA that mediates stress-induced anxiety. Significance statement There is a strong correlation between pain and anxiety. However, the underlying neural mechanisms are poorly understood. Here, we reveal a novel neural pathway between the rostral ventromedial medulla (RVM) and lateral hypothalamus (LHA) that can potentially convert painful experiences into stress and anxiety. The traditional role of RVM is opioidergic modulation of pain. However, here we show that in addition to nociception, RVM neurons can play an essential role in the affective-motivational components of pain.