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    188宝金博页面版: Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent

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    内容提示： Stochastic Simulation of Dopamine Neuromodulation forImplementation of Fluorescent Neurochemical Probes in the StriatalExtracellular SpaceAbraham G. Beyene, ? Ian R. McFarlane, ? Rebecca L. Pinals, ? and Markita P. Landry* ,?,?,§? Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States? California Institute for Quantitative Biosciences, QB3, University of California, Berkeley, California 94720, United States§ Chan Zuckerberg Biohub, San Francisco,...

    文档格式：PDF | 页数：15 | 浏览次数：10 | 上传日期：2020-10-05 12:21:33 | 文档星级：
    Stochastic Simulation of Dopamine Neuromodulation forImplementation of Fluorescent Neurochemical Probes in the StriatalExtracellular SpaceAbraham G. Beyene, † Ian R. McFarlane, † Rebecca L. Pinals, † and Markita P. Landry* ,†,‡,§† Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States‡ California Institute for Quantitative Biosciences, QB3, University of California, Berkeley, California 94720, United States§ Chan Zuckerberg Biohub, San Francisco, California 94158, United States* S Supporting InformationABSTRACT: Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise fromindividual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution ofthese highly stochastic neuromodulatory events requires concurrent advances in the chemical development of opticalnanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecondneurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in theextracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of f l uorescent neurochemicalprobes that record neurotransmitter dynamics in the ECS. Our model is developed from f i rst-principles and simulates release,dif f usion, and reuptake of dopamine in a 3D simulation volume of striatal tissue. We f i nd that in vivo imaging ofneuromodulation requires simultaneous optimization of dopamine nanosensor reversibility and sensitivity: dopamine imaging inthe striatum or nucleus accumbens requires nanosensors with an optimal dopamine dissociation constant (K d ) of 1 μM, whereasK d s above 10 μM are required for dopamine imaging in the prefrontal cortex. Furthermore, as a result of the probabilistic natureof dopamine terminal activity in the striatum, our model reveals that imaging frame rates of 20 Hz are optimal for recordingtemporally resolved dopamine release events. Our work provides a modeling platform to probe how complex neuromodulatoryprocesses can be studied with f l uorescent nanosensors and enables direct evaluation of nanosensor chemistry and imaginghardware parameters. Our stochastic model is generic for evaluating f l uorescent neurotransmission probes, and is broadlyapplicable to the design of other neurotransmitter f l uorophores and their optimization for implementation in vivo.KEYWORDS: Fluorescent probes, neurochemical imaging, nanosensor kinetics, stochastic simulation, dopamine, striatum,neuromodulation■INTRODUCTIONDif f use volume transmission constitutes an important elementof neuronal signaling for certain neurotransmitters such asacetylcholine, dopamine, norepinephrine, and serotonin. Whileclassical neurotransmission is conf i ned to communicationbetween the pre- and postsynaptic neuron, and is mediatedby fast acting ligand-gated ion channels, neuromodulationemploys slower acting metabotropic receptors that exhibit ahigh level of extrasynaptic expression. 1 Thus, modulatoryneurotransmitter activity extends well beyond the synapse. As aconsequence, neuromodulators such as dopamine inf l uence apopulation of neurons beyond the synapse, enabling a singleneuron to modulate the activity of a larger network of neuronalcells. It is therefore of great interest to develop tools to observeand quantify the release, dif f usion, and reuptake of neuro-modulatory neurotransmitters such as dopamine, where theReceived: May 25, 2017Accepted: July 17, 2017Published: July 17, 2017Research Articlepubs.acs.org/chemneuro© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.7b00193ACS Chem. Neurosci. XXXX, XXX, XXX−XXX

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