Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space

Abstract

Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise from individual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS. Our model is developed from first-principles and simulates release, diffusion, and reuptake of dopamine in a 3D simulation volume of striatal tissue. We find that in vivo imaging of neuromodulation requires simultaneous optimization of dopamine nanosensor reversibility and sensitivity: dopamine imaging in the striatum or nucleus accumbens requires nanosensors with an optimal dopamine dissociation constant (K) of 1 μM, whereas Ks above 10 μM are required for dopamine imaging in the prefrontal cortex. Furthermore, as a result of the probabilistic nature of dopamine terminal activity in the striatum, our model reveals that imaging frame rates of 20 Hz are optimal for recording temporally resolved dopamine release events. Our work provides a modeling platform to probe how complex neuromodulatory processes can be studied with fluorescent nanosensors and enables direct evaluation of nanosensor chemistry and imaging hardware parameters. Our stochastic model is generic for evaluating fluorescent neurotransmission probes, and is broadly applicable to the design of other neurotransmitter fluorophores and their optimization for implementation in vivo.

Ultralarge Modulation of Single Wall Carbon Nanotube Fluorescence Mediated by Neuromodulators Adsorbed on Arrays of Oligonucleotide Rings

“…Prior work has shown the fluorescence intensity of (GT)15-SWNT increases by 60% (∆F/F = 0.6) upon exposure to 100 μM of DA, which translates to ∆F/F = 0.3 at peak physiological dopamine concentrations that follow burst neuronal firing events (~1 µM). 21,28,29 Motivated by the goal of producing an in vivo compatible neuromodulator nanosensor for a broader dynamic range of physiological relevance, we synthesized a (GT)N based ssDNA-SWNT library for N = 4, 6,7,8,12,15,19,22,26, and 30 with a previously described protocol. 30 Near infrared fluorescence and absorption spectroscopy confirm that all sequences from N = 4 to N = 30 produced stable DNA-SWNT suspensions, as evidenced by sharply defined spectral line shapes corresponding to known SWNT electronic transitions ( Figure S1).…”

“…26 The spatiotemporal sensitivity required for in vivo utilityin particular for fast processes such as chemical neurotransmission in the brainmust account not just for analyte concentration levels, but also for the spatial spread of the signal (micrometers) as well as its temporal duration (milliseconds). 27,28 An ideal probe therefore must satisfy several requirements, including high sensitivity, molecular selectivity, and optimal binding kinetics among others. The versatility and ease with which SWNTs can be functionalized by a wide range of polymers provides a great opportunity for a rational design of synthetic optical probes capable of detecting biomolecules in their native environment.…”

Dual Near‐Infrared Two‐Photon Microscopy for Deep‐Tissue Dopamine Nanosensor Imaging

“…Given our experimental conditions, we would expect an imaging resolution of approximately the beam waist, 4.8 µm, to produce an image using pixel dwell times on the order of milliseconds. Micrometer length and millisecond time frames are in‐line with the requisite imaging parameters necessary to capture relevant processes in brain neurotransmission …”

Advances in nanomaterials for brain microscopy

“…Dopamine reuptake in brain slices was also demonstrated both in artificial cerebral spinal fluid, and also in brain slices exposed to antidepressant drug nomifensine, with high spatiotemporal resolution. These results, combined with recent analytical modeling of SWNT nanosensors for dopamine sensing [98, 99], provide promising steps towards utilizing these nanosensors for ex vivo and in vivo studies investigating neurochemistry in the living brain.…”