Cell type-specific dissection of sensory pathways involved in descending modulation

The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are critically important hubs in the endogenous analgesia pathway.Technological and conceptual advances have permitted the identification and targeting of neural ensembles in the PAG and RVM during complex behaviors, revealing that they divergently modulate distinct components of somatosensation.In vivo imaging, viral tracing, and molecular genetic manipulations have afforded a new layer of insight by characterizing the function of genetically defined neuronal populations within the PAG and RVM.How these identified pathways coordinate other autonomic, motivational, and defensive responses during ongoing nociception remains to be addressed in greater detail.Further investigations into the PAG and RVM in the descending modulation of nociception, itch, and other complex behaviors are ongoing. Decades of research have suggested that stimulation of supraspinal structures, such as the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), inhibits nocifensive responses to noxious stimulation through a process known as descending modulation. Electrical stimulation and pharmacologic manipulations of the PAG and RVM identified transmitters and neuronal firing patterns that represented distinct cell types. Advances in mouse genetics, in vivo imaging, and circuit tracing methods, in addition to chemogenetic and optogenetic approaches, allowed the characterization of the cells and circuits involved in descending modulation in further detail. Recent work has revealed the importance of PAG and RVM neuronal cell types in the descending modulation of pruriceptive as well as nociceptive behaviors, underscoring their roles in coordinating complex behavioral responses to sensory input. This review summarizes how new technical advances that enable cell type-specific manipulation and recording of neuronal activity have supported, as well as expanded, long-standing views on descending modulation.