Abstract
Ascending dopaminergic projections from neurons located in the Ventral Tegmental Area (VTA) are key to the etiology, dysfunction, and control of motivation, learning, and addiction. Due to the evolutionary conservation of this nucleus and the extensive use of mice as disease models, establishing an assay for VTA dopaminergic signaling in the mouse brain is crucial for the translational investigation of motivational control as well as of neuronal function phenotypes for diseases and interventions. In this article we use optogenetic stimulation directed at VTA dopaminergic neurons in combination with functional Magnetic Resonance Imaging (fMRI), a method widely used in human deep brain imaging. We present a comprehensive assay producing the first whole-brain opto-fMRI map of dopaminergic activation in the mouse, and show that VTA dopaminergic system function is consistent with its structural VTA projections, diverging only in a few key aspects. While the activation map predominantly highlights target areas according to their relative projection densities (e.g., strong activation of the nucleus accumbens and low activation of the hippocampus), it also includes areas for which a structural connection is not well established (such as the dorsomedial striatum). We further detail the variability of the assay with regard to multiple experimental parameters, including stimulation protocol and implant position, and provide evidence-based recommendations for assay reuse, publishing both reference results and a reference analysis workflow implementation.
Highlights
The dopaminergic system consists of a strongly localized, and widely projecting set of neurons with cell bodies clustered in the midbrain into two lateralized nucleus pairs, the Substantia Nigra pars compacta (SNc) and the Ventral Tegmental Area (VTA, Fig. 1a)
In this article we demonstrate the suitability of opto-functional Magnetic Resonance Imaging (fMRI) for investigating a neurotransmitter system that exhibits node-like function in coordinating brain activity
We present the first wholebrain map of VTA dopaminergic signalling in the mouse in a standard space aligned with stereotactic coordinates [46]
Summary
The dopaminergic system consists of a strongly localized, and widely projecting set of neurons with cell bodies clustered in the midbrain into two lateralized nucleus pairs, the Substantia Nigra pars compacta (SNc) and the Ventral Tegmental Area (VTA, Fig. 1a). In order to target dopaminergic cells, they need to be sensitized to an otherwise inert stimulus in a transcriptiondependent manner This can be achieved via optogenetics, which is based on light-stimulation of cells expressing light-sensitive proteins such as channelrhodopsin [14]. A reference neurophenotype of stimulus-evoked dopaminergic function (represented as a brain-wide voxelwise map) should be published in standard space to facilitate co-registered data integration, operative targeting, and comparative evaluation of pathology or treatment-induced effects. These goals presuppose the production of experimental data, and the development of a transparent, reliable, and publicly accessible analysis workflow, which leverages preexisting standards for mouse-brain data processing [20] and extends them to the statistical analysis
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