(Invited) Near Infrared Optical Probes for Imaging Neuromodulators with High Spatiotemporal Resolution

Abstract

Dopamine neurotransmission plays critical roles in brain function in both health and disease and aberrations in dopamine neurotransmission are implicated in several psychiatric and neurological disorders, including schizophrenia, depression, anxiety, and Parkinson’s disease. Until recently, measuring the dynamics of dopamine and other neurotransmitters of this class could not be achieved at spatiotemporal resolutions necessary to understand how dopamine regulates the plasticity and function of neurons and neural circuits, and how dysfunctions in this regulation lead to disease. Probes that satisfy critical attributes in spatial and temporal resolution, and chemical selectivity are needed to facilitate investigations of brain neurochemistry.To address this need, we developed an ultrasensitive near-infrared “turn-on” nanosensor (nIRCat) for the catecholamines dopamine and norepinephrine and implemented nIRCat to study endogenous dopamine dynamics in brain tissue. nIRCats are synthesized from photostable and near infrared emissive functionalized single wall carbon nanotubes (SWCNT) and exhibit maximal relative change in fluorescence intensity (ΔF/F0) of up to 35-fold, with a dynamic range that spans physiological concentrations of their target brain analytes. We demonstrate that nIRCat can detect electrically and optogenetically evoked release of dopamine in brain tissue, revealing putative hotspots of activity that exhibited a log-normal distribution in size, ranging from 2 – 10 µm for mice brain tissue in the dorsomedial striatum. Furthermore, the synthetic nature of the molecular recognition platform afforded compatibility with dopamine-receptor targeting antipsychotics and psychoactive drugs and permitted studies of how such receptor-targeting drugs modulate evoked dopamine release. This assay revealed presynaptic correlates of drug activity at the level of putative dopamine release sites, which had heretofore been inaccessible to probe with existing tools. Our results suggest that nIRCat technology may uniquely support similar explorations of processes that regulate dopamine neuromodulation at the level of individual synapses, and exploration of the effects of receptor agonists and antagonists that are commonly used as psychiatric drugs as well as drugs that lead to substance use disorder. We conclude that SWCNTs can serve as versatile synthetic optical scaffolds for monitoring interneuronal chemical signaling in the brain extracellular space at spatial and temporal scales pertinent with the encoded neurochemical information.