Understanding the biological basis of pain-related behaviors is essential for the development of improved therapeutic options for chronic pain. The main goal of our research program is to identify brain mechanisms underlying maladaptive changes in pain-related behaviors in chronic pathological pain states. We have focused on the central amygdala (CeA), a structure in the limbic brain system that modulates pathological pain and affective behaviors. Previous studies have demonstrated that CeA neurons are morphologically, electrophysiologically and molecularly diverse. More importantly, modulation of emotional behaviors in the CeA has been shown to be both cell-type and circuit-specific. The contribution of different CeA cell types and circuits to the modulation of pain-related behaviors, however, has not been established. Our overarching hypothesis is that modulation of pain-related behaviors in chronic pathological states is encoded by plastic changes in distinct CeA cell types and by alterations in the functional connectivity between the CeA and other brain regions. Since joining the NIH, we have successfully built a multidisciplinary research program that uses state-of-the-art molecular genetics, ex-vivo electrophysiological and in-vivo mouse behavioral approaches to begin to address these ambitious but also fundamentally important questions in the field. Our experiments identified two functionally distinct populations of nociceptive neurons in the CeA that have opposing electrophysiological phenotypes and bidirectionally modulate pain-related behaviors. Our findings reveal previously underappreciated complexities of pain modulation in the CeA and provide the first causal evidence for endogenous bidirectional, cell-type-specific modulation of pain-related behaviors in the CeA in models of persistent pain. Ongoing experiments aim at elucidating the cellular and circuit-level mechanisms underlying the opposing functions of these two subpopulations of cells in the modulation of maladaptive changes in pain-related behaviors.
