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An improved understanding of dopamine signaling patterns in the brain's reward processing systems will lead to mechanistic descriptions of reward-related behavior, and also to the discovery of new biomarkers and therapeutic intervention points for treatment of addiction. Here we propose to use a unique new molecular-level functional brain imaging technique to characterize dopamine signaling evoked by some of the most widely studied and broadly significant stimuli in addiction research. The technique uses magnetic resonance imaging (MRI) in conjunction with contrast agents that bind and report dopamine concentrations, reversibly, as a function of time. In Specific Aim 1, we will use this "molecular fMRI" technique to map the structure and dynamics of dopamine release patterns in the striatum, a key target of dopamine signaling related to reward and addiction. We will measure dopamine release in response to an important addictive drug, amphetamine, as well as to reward-related brain stimulation.
We will also push the spatial coverage and resolution of the imaging itself in order to characterize details of the dopamine response, such as specificity to anatomically and neurochemically defined striatal subregions, and we will for the first time conduct dopamine MRI studies in awake animals. Data will be obtained at a spatial resolution of 100-200 µm and over temporal scales ranging from seconds to minutes, sufficient for resolving both phasic and longer-lasting dopamine changes. In Specific Aim 2, we will establish a quantitative, spatially-resolved correspondence between molecular fMRI readings and conventional hemodynamic fMRI signals, which broadly reflect neuronal population activi- ty. These experiments will provide an empirical description of the relationship between BOLD signal and dopamine release, and also facilitate circuit level description of dopaminergic function at a neural population level across the striatum and beyond. In Specific Aim 3, we propose to develop an alternative MRI sensor that will detect dopamine concentrations of 0.1-1 µM, 10-100 times better than our current sensors, and in the range of levels evoked by naturalistic rewarding stimuli. The improved sensors will be formed from na- noscale arrays of magnetic particles that change configuration in the presence of target ligands, bringing about MRI contrast changes. In additional to enabling sensitive dopamine detection, the new design will in the future be generalizable to other neural targets.