Rostral Ventromedial Medulla (RVM) Projects to the Lateral Hypothalamic Area (LHA) to Drive Aversion and Anxiety

Neurons in the lateral hypothalamic area (LHA) are critical drivers of behavioral and physiological responses to acute and chronic stress. However, the roles of the specific presynaptic inputs to the LHA in driving stress and resultant physiological effects are yet to be fully understood. Here, leveraging intersectional viral genetics, optogenetics, chemogenetics, and fiber photometry, we show that the excitatory projections from the rostral ventromedial medulla (RVM) to LHA drive anxiety-like behaviors in male and female mice. 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 and anxiety. On the other hand, the LHA-projecting RVM neurons are responsive to both noxious thermal stimuli and acute restraint, promoting anxiety, yet with no effect on pain thresholds. Our findings provide evidence that a distinct ascending circuitry, from RVM to LHA, is instrumental in driving aversion and anxiety-like behaviors in mice without affecting nociceptive thresholds.