The Role of Distinct Dorsal Column Nuclei Outputs in Persistent Pain

Project Summary/Abstract Touch-evoked pain is a hallmark of persistent pain, making it crucial to understand how supraspinal touch pathways contribute to the different aspects of pain. The dorsal column nuclei (DCN) in the brainstem receives direct input from touch sensory neurons. Various non-specific manipulations such as ablation, electrical stimulation, and pharmacology, have implicated the DCN in both transmitting and reducing touch-evoked pain. While these manipulations highlight 2 opposing roles for the DCN, as a mediator or inhibitor of touch-evoked pain, the mechanisms underlying these opposing roles remain unknown. The functional relevance of touch processing by the DCN is defined by its output connectivity with effector structures throughout the brain. Two important regulators of pain behavior, the ventral posterolateral thalamus (VPL) and ventrolateral periaqueductal gray (vlPAG), receive input from the DCN. The VPL plays an important role in touch and pain perception, while the vlPAG is part of a descending pain suppression circuit. My central hypothesis is that the dorsal column nuclei (DCN) shape our central representation of touch through two functionally distinct pathways to the thalamus and the periaqueductal gray. Disruption of the balance between these pathways following injury allows touch stimuli to engage ‘pain’ pathways and promote touch-evoked pain. To test this hypothesis, I will employ a powerful combination of tools to determine the mechanisms underlying altered touch signaling following neuropathic injury and simultaneously image Ca2+ activity and optogenetically manipulate distinct neural populations to determine how divergent projections to the VPL and vlPAG uniquely contribute to the sensory, affective, and motivations components of pain behavior. During the mentored K99 phase, my career development and training will be supervised by my mentors Drs. Abraria (Rutgers), Aston-Jones (Rutgers), and Stuber (University of Washington). I will also receive additional support from Drs. Basbaum (UCSF), Abdus-Saboor (Columbia), Tao (Rutgers), Margolis (Rutgers), and Azim (Salk). These mentors possess expertise in viral and optogenetic circuit mapping, in-vivo Ca2+ imaging in freely behaving mice, machine-vision behavioral approaches to define how neural networks encode different aspects of behavior in health and disease. During the independent R00 phase, I will examine the postsynaptic targets of DCN projections within the VPL and vlPAG, studying how neural ensembles in these regions encode the many facets of persistent pain behavior. Completing the proposed aims will provide fundamental insight into how the DCN encodes tactile information and elucidate the circuits that promote touch-evoked pain in persistent pain states. This career development award will provide conceptual and technical training, as well as mentorship from renowned experts in the field of circuit neuroscience. The training opportunities provided by the K99/R00 will prepare me to lead an independent research program and serve as a foundation for future NIH grant applications focused on the supraspinal circuits that encode touch-evoked pain.