(22e) Imaging Healthy and Diseased Striatal Dopamine Release with Near-Infrared Catecholamine Nanosensors

Neuromodulators such as dopamine and serotonin and play a critical role in healthy brain function, and their disruption has been implicated in a number of neurological and psychiatric disorders. In particular, the neuromodulator dopamine is thought to facilitate learning, motivation, and motor control. Disruption of dopamine signaling plays a crucial role in a number of neurological and psychiatric disorders, including Parkinson’s Disease, Huntington’s Disease, and Schizophrenia. Present treatments for these disorders often broadly target dopamine neuromodulation, and many novel therapies (RNAi, cell replacement) target circuits that participate or are affected by dopaminergic systems within the brain. However, despite the established relationship between these disorders and dopamine, the exact mechanisms through which these diseases progress, and their therapies act, is unknown. This is in part because our ability to study dopaminergic modulation in healthy and diseased tissue has been limited. Unlike classical neurotransmission, dopamine exerts it influence by diffusing beyond the synaptic cleft to influence the excitability of neighboring neurons. As such, being able to study the release and spread of dopamine at the spatio-temporal resolution of single dopamine release sites (µm, ms) is critical.

Here, we implement the 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. Furthermore, the chemically synthetic molecular recognition elements of nIRCats readily allows imaging of dopamine dynamics in diseased tissues or tissues that have undergone treatment via novel therapy without the need for additional genetic manipulation or mouse-line development. These unique properties of nIRCat make it an ideal tool to study the dysregulation of dopamine over the course of Huntington’s Disease and subsequent treatment. We demonstrate that nIRCats imaging in R6/2 Mice ex vivo brain slices before and after the onset of motor symptoms reveal insights into possible mechanisms of dopamine decrease with Huntington’s Disease motor symptom development. These findings provide a framework to understand how the diseased brain adapts to disease progression and subsequent treatment, and underscore the utility of nIRCats as a versatile new optical tool for dopamine detection in the brain.

1. Beyene, A. G., Delevich, K. et al. "Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor." Science Advances, 5 (7) (2019).