Investigation of neural ensembles driving pain chronification

PROJECT SUMMARY The unpleasantness, or negative affective component, of pain perception is an emotional phenomenon distinct from the perceptive sensory qualities. This affective dimension of pain underlies the suffering and motivational deficits of chronic pain patients. However, similar cellular-resolution mechanisms within brain networks is lacking relative to the intricate nociceptive detail in the peripheral and spinal circuits. Thus, a key step toward accelerating the development of effective pain treatments must be the discovery of the specific neural circuits in the brain that are responsible for the aversive and unpleasant quality of pain perception. We recently reported the discovery and characterization of a basolateral amygdalar (BLA) neural ensemble, at single neuron resolution, that transforms nociceptive information in affective-motivational behavior in both acute and chronic pain conditions. While these studies provide a critical point of entry into the complex affective circuits of pain, it is not clear how the BLA nociceptive ensemble connects with other parts of the larger affective brain circuitry. Our goal here is to provide a systems-level understanding of the nociceptive cortical brain networks involved in the affective perception of pain by integrating multimodal data from pain-experience-dependent transcriptomics, activity based whole-brain circuit tracing, and precision chemogenetic control—anchored in motivational behavior-based classifications—throughout the transition from acute to chronic pain. Thus, to discover this nociceptive brain network, in AIM 1 we will use a rabies viral-genetic strategy combined with immediate early gene mapping in cleared, intact brain tissue to locate key neuronal populations whose activity is altered by chronic neuropathic pain. In AIM 2, we will employ single-nuclei RNA sequencing to link transcriptomic identity and change in cellular states during pain chronification in defined nociceptive input cells to the BLA noci- ensemble. In AIM 3, we will chemogenetically manipulate nociceptive cell-types projecting to the BLA to mitigate pain affective-motivational behaviors with locally infused microsphere drug-delivery. The cellular and functional identification of these fundamental nociceptive circuits should open new avenues for developing precision therapeutics to combat different dimensions of pain experiences, including the unpleasant affective component. Such circuit-targeted therapies could selectively diminish the suffering of pain patients, regardless of etiology and without influencing reward, while preserving necessary sensory discriminative processes for protective pain sensation.