(467f) Near-Infrared Catecholamine Nanosensors Reveal Disruptions in Dopamine Release in Huntington’s Disease Mouse Models

Dopamine neuromodulation of neurotransmitter signaling is a critical process that facilitates learning, motivation, and motor control. Disruption of these processes has been implicated in a number of neurological and psychiatric disorders including Huntington’s Disease (HD), a neurodegenerative disorder characterized by the production of mutated huntingtin protein and a triad of motor, behavioral, and cognitive symptoms. Despite the established clinical relationship between HD and dopamine, the exact mechanisms through which disease develops and progresses is not fully understood. Similarly, though present treatments for HD symptom management often broadly target dopamine neuromodulation, their exact mechanism of action remains elusive owing to challenges in studying dopaminergic neuromodulation. In contrast to classical neurotransmitter signaling, dopamine neuromodulation exerts it influence by diffusing beyond the synaptic cleft to influence the excitability of neighboring neurons. As such, studying the release and spread of dopamine at the spatio-temporal resolution of single dopamine release sites (µm, ms) and beyond is critical to not only understanding HD disease mechanisms but also understanding how to best develop novel therapies (RNAi, cell replacement) to target HD affected neural circuits.

To this end, we employ near-infrared fluorescent catecholamine nanosensors (nIRCats) to image dopamine release within the brain striatum of R6/2 Huntington’s Disease Model (R6/2) mice. We have previously shown that these near-infrared fluorescent, polymer-functionalized semiconducting single wall carbon nanotubes serve as adept dopamine sensors in the basal ganglia, exhibiting ΔF/F of up to 24-fold in the fluorescence emission window of 1000-1300 nm, a wavelength ideal for imaging in optically scattering brain tissue¹. In this study, we find that stimulated dorsal striatal dopamine release decreases with progressive degeneration of motor ability, consistent with previous trends identified through microdialysis and Fast Scan Cyclic Voltammetry. Notably, nIRCats’s high spatial resolution allows further elucidation of this process, revealing that these decreases are primarily driven by a decrease in the number of dopamine releasing sites rather than a decrease in individual release site performance. We further interrogate this late disease state, by examining the external calcium sensitivity of these dopamine release sites and utilizing nIRCats’ compatibility with dopamine pharmacology to assess changes in Dopamine D2 Receptors (D2R) expression. These findings, enabled by nIRCats, provide a more detailed look into how dopamine release is disrupted and dysregulated during Huntington’s Disease. Furthermore, they provide a framework to understand the brain during disease and underscore the utility of nIRCats as a versatile new optical tool for dopamine detection in the brain.

1. Beyene, A. G., Delevich, K., Yang, S.J. et al. Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor. Science Advances (2019).