Arlene George F32

PROJECT SUMMARY Chronic pain (>3 months) affects over 50 million Americans, limiting their life and daily activities, creating a public health crisis. Although there are available treatments for those experiencing acute pain, there is a lack of therapeutic intervention for those suffering from chronic pain. One candidate involved in pain is the striatum which is known for sensorimotor integration and facilitating voluntary movement particularly with the interplay between the GABAergic dopamine receptor 1 (D1N) cells and dopamine receptor 2 (D2N) -expressing principal neurons. The striatum can mediate analgesic action in orofacial pain through activation of striatal D2N pathways. However, the striatal mechanisms underlying chronic neuropathic pain and how this affects ongoing, sensory- guided behaviors is largely unknown. The striatum also has inputs from the primary somatosensory cortex (S1) that contribute to pain processing. S1 is known to process somatic sensations including nociception and touch and its activity changes during pain. In addition to the spinothalamic tract, S1 also has direct projections to the striatum and plasticity changes in this pathway could point to a mechanism involved in the transition from acute to chronic pain and affect ongoing behaviors including motivation and motor planning. My overarching hypothesis is that during the transition from acute to chronic pain, overactive striatal D2N populations driven by hyperactivity of S1 lead to the heightened expression of pain-related behaviors and inhibition of motivational behavior. Specific Aim 1 will test the hypothesis that the transition from acute to chronic pain leads to an increase in reflexive and affective pain features and that this neuropathic pain influences sensory- guided behavior associated with higher D2N activity. Aim 1’s training potential is rooted in cutting-edge tools: machine-learning applications for analyzing pain-related behavioral signatures, in vivo chronic optical imaging with fiber photometry, and neurosurgical techniques and viral injections. Specific Aim 2 will test the hypothesis that there are plasticity changes in corticostriatal pathways in which D2N are more potentiated compared to D1N in the transition from acute to chronic pain and modulating striatal cell activity will lead to changes in pain and sensory-guided behavior. Aim 2’s training potential lies in learning electrophysiological techniques, optogenetic techniques, and data coding analysis from these experiments. The collective results will provide an understanding of (1) how pain-related features of pain change from acute to chronic pain and how this transition affects sensory-guided behavior and (2) the functional role of D1N and D2N activity in the transition of acute to chronic pain My research will provide an understanding of striatal pathways that are active in different time periods of pain. The high training potential for these aims is carefully designed to fill my gap-based knowledge in systems neuroscience. The impact of this fellowship will foster my successful, impactful, and enduring independent research career in neurological disorders.