Dopamine neurotransmission plays critical roles in brain function in both health anddisease and aberrations in dopamine neurotransmission are implicated in severalpsychiatric and neurological disorders, including schizophrenia, depression, anxiety, andParkinson’s disease. Until recently, measuring the dynamics of dopamine and otherneurotransmitters of this class could not be achieved at spatiotemporal resolutionsnecessary to study how dopamine regulates the plasticity and function of neurons and neuralcircuits, and how dysfunctions in this regulation lead to disease. Probes that satisfy criticalattributes in spatiotemporal resolution and chemical selectivity are needed to facilitateinvestigations of dopamine neurochemistry.To address this need, this dissertation describes the synthesis and implementation ofan ultrasensitive near-infrared “turn-on” nanosensor (nIRCat) for the catecholamineneuromodulators dopamine and norepinephrine. To guide probe development, we presentresults from a computational model that offers insight into the spatiotemporal dynamics ofdopamine in the striatum, a subcortical structure that is enriched in dopamine. With thismodel, we elucidated the kinetic requirements for a prototypical optical indicator as well asoptimal imaging frame rates needed for measuring dopamine neurochemical dynamics.Stochastic modeling of dopamine dynamics, driven by kinetic phenomena of vesicularrelease, diffusion and clearance, provide a platform to evaluate dopaminergic volumetransmission arising from a single terminal or ensemble terminal activity. With this work,we illustrate that only probes with kinetic parameters in a particular range are feasible fordopamine imaging at spatiotemporal scales likely to be encountered in brain tissue.In two subsequent chapters, we describe the development and in vitrocharacterization of nIRCats, synthesized from functionalized single wall carbon nanotubes(SWCNT) that fluoresce in the near infrared range of the spectrum. We show that nIRCatsexhibit maximal relative change in fluorescence intensity (ΔF/F0) of up to 35-fold inresponse to catecholamines and have optimal dynamic range that span physiologicalconcentrations of their target brain analytes. Through a combination of experimental andmolecular dynamics approaches, we elucidate the photophysical principles and intermolecularinteractions that govern the molecular recognition and fluorescence modulation of nIRCats by dopamine.Finally, we demonstrate that nIRCat can be used to measure electrically andoptogenetically evoked release of dopamine in striatal brain slices, revealing hotspots ofactivity with a median size of 2 μm, and exhibiting a log-normal size distribution that extendsup to 10 μm. Moreover, nIRCats are shown to be compatible with dopamine pharmacologyand permit studies of how receptor-targeting drugs modulate evoked dopamine release. Ourresults suggest nIRCats may uniquely support similar explorations of processes that regulatedopamine neuromodulation at the level of individual synapses, and exploration of the effectsof receptor agonists and antagonists that are commonly used as psychiatric drugs andpsychoactive molecules that modulate the release and clearance profiles of dopamine. Weconclude that nIRCats and other nanosensors of this class can serve as versatile syntheticoptical tools to monitor interneuronal chemical signaling in the brain extracellular space atspatial and temporal scales pertinent to the encoded information
