Locus coeruleus microcircuitry processes periaqueductal gray inputs into distinct outputs for regulation of pain and anxiety

The locus coeruleus (LC) is a modularly organized heterogeneous structure that projects to various CNS regions to modulate a range of physiological and pathophysiological processes, including anxiety and pain. However, there are conflicting results on the role of LC activity in pain states. In particular, how the LC integrates inputs from upstream structures such as the ventrolateral periaqueductal gray (vlPAG) to regulate descending control of peripheral pain signals remains to be elucidated. Here, we used genetic cell-type-specific targeting of vlPAG to LC projections, optogenetics, electrophysiology, calcium imaging, and behavior assessment to define how this pathway modulates pain and anxiety-like behavior in mice with neuropathic pain. We show that glutamatergic and GABAergic vlPAG inputs into the LC differentially regulate pain and anxiety-like behavior through specific processing in the LC and the surrounding peri-LC region. Our results provide key insights into how the LC modulates critical behavioral outputs.