Neurons communicate through chemical neurotransmitter signals that either terminate at the postsynaptic process (“wired transmission”) or diffuse beyond the synaptic cleft to modulate the activity of larger neuronal networks (“volume transmission”). Molecules such as dopamine belong to the latter class of neurotransmitters, for which real-time imaging of the signal’s spatial propagation would constitute a major advance in neurochemical imaging. To this end, we present a nanoscale near-infrared fluorescent sensor for dopamine and demonstrate its efficacy for imaging dopamine volume transmission in the extracellular space of the brain striatum and prefrontal cortex. The sensor is developed from polymers pinned to the surface of single wall carbon nanotubes (SWNT) in which the surface-adsorbed polymer is the recognition moiety and the carbon nanotube the fluorescence transduction element. Using this paradigm, we describe the design, characterization, and implementation of polymer-functionalized SWNT nanosensors and present recent progress in imaging the dynamics of evoked and spontaneous dopamine release in mouse acute brain slices.

Fluorescence imaging of dopamine volume transmission with our probes provides much needed spatial information and high resolution of dopamine dynamics in contrast with traditional electrochemical dopamine measurements obtained with fast scan cyclic voltammetry (FSCV). Whereas FSCV measures dopamine concentration at a single point arising from the activity of a large number of dopamine terminals, our probes capture local release arising from single and multiple terminals within the imaging field of view. From imaging data, we can describe localized release and clearance kinetics of dopamine neuromodulation. In the brain striatum, the nanosensors record spatially and temporally resolved dynamic behavior of dopamine on length scales that encompass single terminals and inter-terminal distances, and enable investigation of the effect of antidepressant drugs such as Nomifensine on dopamine dynamics. In the prefrontal cortex (PFC), an area of sparse dopaminergic innervation, dopamine nanosensors capture dynamics elicited by single terminals. In both the striatum and PFC, optogenetics enables selective stimulation of dopaminergic terminals to evoke dopamine release.

We further describe how nanoparticle exciton engineering can be used to tune sensor performance and design sensors best suited for in vivo experimentation. Molecular dynamics modeling elucidates the physicochemical phenomena underlying the dopamine sensing process and stochastic simulations reveal that optical nanosensors can capture millisecond-scale changes during phasic and tonic firing of dopaminergic neurons. Combining our experimental and computational work, we outline the functional range of this technology for imaging dopamine neuromodulation in biologically complex and optically dense live brain. Our experimental and theoretical results show that near-infrared (nIR) neurotransmitter nanosensor constructs can relay information about neuronal signaling in the tissue-compatible nIR optical window, with spatiotemporal scales that capture both single synaptic release events and ensemble terminal behavior suitable for in vivo behavioral experimentation.