Neurobehavioral Analysis After Spinal Cord Injury: Exploring the Relationship Between Altered Motor Behavior and Dopamine Transients in the Dorsolateral Striatum - Spinal cord injury (SCI) leads to severe sensorimotor deficits, often requiring rehabilitation to relearn motor actions. Dopamine (DA) signaling in the dorsolateral striatum (DLS) plays a critical role in motor actions, motor learning, and action selection. The DLS also receives direct input from sensorimotor cortices, circuits which are modulated by exercise (a necessary therapy post-SCI). Together, this makes the DLS a compelling target for studying its potential role in driving motor relearning post-SCI. However, despite evidence linking DLS DA to motor actions, its role in recovery remains completely unexplored. Thus, this proposal sits at an exciting intersection of post-SCI motor behavior and the striatal biology involved in driving motor behavior. The central hypothesis of this proposal is that distinct DLS DA dynamics underlie motor recovery following SCI, with changes in DA release corresponding to specific motor behaviors. To test this, I aim to: (1) establish baseline DLS DA transients during recovery, (2) define DLS DA transients in specific post-SCI behaviors, (3) evaluate sensory-based exercise's effect on DLS DA and behavior, and (4) assess real-time modulation of DLS DA in motor action selection and sequencing post-SCI. Training potential: This proposal combines sophisticated tools including photometry in awake behaving mice, AI-driven behavioral characterization, mouse molecular genetics, AAV tracing, and optogenetics to test the role of DLS DA in post-SCI motor actions. Complementing my previous expertise in AI-driven behavioral analysis, I propose to expand my skills by learning how supraspinal signals contribute to motor recovery. I will gain training in photometry to measure DLS DA release, linking DA signals to post-SCI behavior, and supraspinal anatomical mapping. Using a moderate contusion SCI model, I will apply photometry and AI-driven behavioral analysis to sync real-time DLS DA activity during spontaneous behaviors (Aim 1), with and without exercise (Aim 2), and with real-time optogenetic modulation (Aim 3). Advisors: During the mentored K99 phase, my career development and training will be supervised by expert Advisors (grouped by expertise), including: Sponsor, Dr. Abraira (Rutgers); Co-sponsor/co-mentor, Dr. Datta (Harvard); Preclinical SCI scientists, Drs. McTigue (Ohio State) and Cafferty (Yale); SCI Clinician, Dr. Forrest (Kessler); Expert in career development and neuromodulatory systems, Dr. Aston-Jones (Rutgers), and Experts in photometry and striatal biology, Drs. Markowitz (Georgia Tech) and Tischfield (Rutgers). Independent R00 phase, I will use real-time optogenetic modulation of DLS DA Research impact: During the to examine its effects on post-SCI behavior. Completing the proposed aims will provide fundamental insight into how DLS DA dynamics and supraspinal circuits contribute to motor recovery. The training provided by the K99/R00 will prepare me to transition to independence and lay the foundation for my R01 proposal focused on understanding how sensory- based interventions, detailed behavioral analysis, and supraspinal dynamics integrate across the neuroaxis.
