Dopamine neuromodulation is a critical process that facilitates learning, motivation, and movement. Disruption of these processes has been implicated in several neurological and psychiatric disorders including Huntington’s Disease (HD). While many treatments for physical and psychiatric HD symptoms target dopaminergic neuromodulation, the mechanism by which dopaminergic dysfunction occurs during HD is unknown. This is partly due to limited capability to visualize dopamine release at the spatiotemporal resolution of both neuromodulator release (ms) and dopaminergic boutons (µm). We have designed a synthetic, optical probe for catecholamines that utilizes near-infrared (nIR) fluorescent, polymer-functionalized single wall carbon nanotubes to report dopamine dynamics within striatal brain tissue. These nIR catecholamine sensors (nIRCats) show a strong response to dopamine within the near-infrared wavelengths ideal for imaging in optically scattering brain tissue. Furthermore, the chemically synthetic molecular recognition elements of nIRCats allow for expression-free imaging of dopamine in the presence of dopamine receptor pharmacology. These characteristics of nIRCat imaging make it a powerful tool uniquely suited for the study of dopamine release in diseased tissues.

In this dissertation I develop methods to utilize nIRCat imaging for the study of dopamine release within R6/2 Huntington’s Disease Model mice (R6/2). Using nIRCat’s high spatial resolution, I show that dopamine release in R6/2 HD mice decreases with progressive motor degeneration and that these decreases are primarily driven by a decrease in the number of dopamine hotspots combined with decreased release intensity. I adapt this analytical framework towards elucidating how dopamine release sensitivity to extracellular calcium concentration and D2-autoreceptor modulation is affected over the course of HD. In contrast to findings from spatially diffuse dopamine recordings, nIRCat imaging in ex vivo R6/2 HD slices indicates that calcium signaling within dopamine hotspots is altered late in disease and D2-autoreceptor signaling is altered early in disease. Lastly, I utilize nIRCat's ability to track individual dopamine hotspots over repeated stimulations and pharmacological washes to measure the release fidelity of dopamine hotspots in late disease. Compellingly, I demonstrate that antagonism of D2-autoreceptors using Sulpiride and direct blocking of Kv1.2 channels using 4-Aminopyradine (4-AP) increases the fidelity of dopamine hotspot activity in the striatum of WT slices, but not in the striatum of late HD slices. Altogether, these findings --- enabled by nIRCats --- provide a deeper look into how dopamine release is disrupted and dysregulated during Huntington’s Disease to alter the coverage of dopamine modulation across the dorsal striatum.