Closed-loop optogenetic neuromodulation based brain-machine interfaces dissecting dopaminergic reinforcement learning circuits of the basal ganglia and developing translational therapies for ALS-related dysphagia
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[EMBARGOED UNTIL 12/01/2026] This dissertation presents an integrated framework that bridges systems neuroscience and translational bioengineering to advance closed-loop optogenetic neuromodulation. The objective was to dissect cell-type-specific corticostriatal dopaminergic mechanisms of reinforcement learning and develop a translational approach to delay bulbar motor function degeneration in amyotrophic lateral sclerosis (ALS) related dysphagia. The work begins with the design and validation of two open-source engineering platforms that enable precise, accessible experimentation: (i) AROMATS (Arduino-based Rodent Olfactory Manipulation and Training System), a fully programmable behavioral interface that delivers millisecond-synchronized stimuli during Go/No-Go and reinforcement tasks, and (ii) a low-cost optoelectronic fiber-electrode assembly, optimized for simultaneous optical stimulation and neural recording in freely behaving mice. Together, these tools form the technical foundation for the experimental and translational studies that follow. Using these platforms, the first research component delineates how D1- and D2-expressing medium spiny neuron (MSN) pathways in the dorsomedial and dorsolateral striatum differentially shape reinforcement learning, motivation, and motor vigor. Optogenetic activation of D1-MSNs promoted persistent approach behavior, increased response rates, and enhanced reward engagement, whereas D2-MSN stimulation induced behavioral inhibition and slowed action initiation without disrupting task accuracy. Together, these findings reveal a functional gradient across striatal subregions that governs the balance between flexible and habitual control. The second research component translates this mechanistic insight to therapy, using targeted optogenetic excitation of hypoglossal motor units to counteract tongue weakness in ALS. Anesthetized strain gauge recordings confirmed robust, light-evoked mechanical contractions of the tongue in symptomatic and end-stage mice, establishing proof-ofconcept for preserving bulbar motor function through minimally invasive, light-based neuromodulation. Collectively, this work advances our mechanistic understanding of reinforcement learning circuits while pioneering adaptive, closed-loop neuromodulation strategies that connect computational theory with clinically relevant neural engineering.
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Ph. D.