Scientific Understanding of Consciousness
fMRI Imaging of Dopaminergic Signaling
Science 2 May 2014: Vol. 344 no. 6183 pp. 533-535
Molecular-Level Functional Magnetic Resonance Imaging of Dopaminergic Signaling
Taekwan Lee, Lili X. Cai, Victor S. Lelyveld, Aviad Hai, Alan Jasanoff
Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.
Department of Nuclear Science and Engineering, MIT, 77 Massachusetts Avenue, Room 16-561, Cambridge, MA 02139, USA.
We demonstrate a technique for mapping brain activity that combines molecular specificity and spatial coverage using a neurotransmitter sensor detectable by magnetic resonance imaging (MRI). This molecular functional MRI (fMRI) method yielded time-resolved volumetric measurements of dopamine release evoked by reward-related lateral hypothalamic brain stimulation of rats injected with the neurotransmitter sensor. Peak dopamine concentrations and release rates were observed in the anterior nucleus accumbens core. Substantial dopamine transients were also present in more caudal areas. Dopamine-release amplitudes correlated with the rostrocaudal stimulation coordinate, suggesting participation of hypothalamic circuitry in modulating dopamine responses. This work provides a foundation for development and application of quantitative molecular fMRI techniques targeted toward numerous components of neural physiology.
Despite development of magnetic resonance imaging (MRI) contrast agents sensitive to molecular aspects of brain function, neural activity mapping using such probes has not previously been demonstrated. Molecular imaging using contrast agents could provide a powerful method for determining topography and dynamics of neural activity components over brain volumes inaccessible to conventional electrophysiology or optical imaging. MRI-based molecular mapping would also substantially exceed the spatiotemporal resolution of positron emission tomography.
A prime target for molecular functional MRI (fMRI) is the ventral striatum, a brain region that integrates multiple neurochemically and anatomically defined neural populations involved in motivated behavior. Particular interest focuses on dopaminergic striatal afferents that project from the midbrain. These cells are phasically activated by rewards and reward-predictive cues and are targets of drugs that boost striatal dopamine concentrations. Although neuroarchitecture of dopaminergic systems and some regional differences in dopamine release have been studied, spatial aspects of signaling are generally less well understood. This complicates characterization of relationships among dopamine neuron firing, dopamine release, and broader neural activity.
Neurotransmitter-sensitive MRI contrast agents that we recently developed could be used for mapping dopamine signaling in living brains. These probes are engineered forms of BM3h, a paramagnetic heme protein that alters T1-weighted MRI signals. BM3h-based contrast agents can be injected intracranially to fill volumes of several cubic millimeters, comparable in size to the entire ventral striatum.
This work establishes a foundation for extension of molecular fMRI techniques along multiple trajectories. Relationships between dopamine signaling and other components of neural activity could be analyzed by combining our dopamine imaging method with conventional hemodynamic fMRI or additional molecular fMRI approaches. Higher-resolution imaging could be performed to characterize signaling at spatial scales below 100 μm. Sensitivity would be enhanced beyond concentrations of 2 to 5 μM dopamine achieved here by using better contrast agents or different imaging parameters, and improved probe delivery strategies could enable completely noninvasive experiments. These steps will facilitate application of molecular fMRI to numerous problems in neuroscience.
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