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 (Kd) of 1 μM, whereas Kds 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.
Highlights
Monoamines such as dopamine, norepinephrine, and serotonin belong to a group of signaling molecules in the brain collectively known as neuromodulators
With appropriate in vivo firing behavior of striatal dopamine neurons, we show that optimally selected sensor kinetics and imaging frame rates can capture behavior-relevant dynamics of phasic firing in the dorsal striatum, with the necessary temporal resolution and signal-to-noise ratio to distinguish individual dopamine transient events elicited by release and reuptake
Our work quantifies the spatial and temporal nature of this chemical signal by using the dorsal striatum as a model system, and provides the requisite imaging and nanosensor kinetic parameters necessary to record chemical signaling in real time in vivo
Summary
Monoamines such as dopamine, norepinephrine, and serotonin belong to a group of signaling molecules in the brain collectively known as neuromodulators. Small clusters of dopamine neuron cell bodies located in the substantia nigra pars compacta (SNc) make extensive connections with the medium spiny neurons (MSN) of the dorsal striatum, forming the nigrostriatal pathway.[2] This pathway is responsible for controlling fine motor movements and its dysfunction underlies the pathology of Parkinson’s Disease.[3] Dopaminergic cell bodies in the ventral tegmental area project into the nucleus accumbens and the prefrontal cortex, forming the mesolimbic and mesocortical pathways, respectively.[2] These systems play significant roles in cognitive control of behavior and reward processing, and their dysfunction underpins the pathology of depression, addiction, schizophrenia and attention deficit hyperactivity disorder (ADHD), among others.[4, 5 6 7, 8] In all of these systems, neuromodulation, as opposed to neurotransmission, is the primary mode of influence This diffusion-mediated transport of dopamine in the ECS is known as volume transmission.[9]
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