Analysis of neural mechanisms involved in normal brain function and addiction-related perturbations to these functions could be dramatically accelerated using novel noninvasive measurement methods to report neural processing events mediated by multiple neurotransmitters with molecular specificity and across the entire brain. Recent work from our lab has shown that functional molecular neuroimaging can be performed using neurotransmitter-sensitive magnetic resonance imaging (MRI) contrast agents. However, current pro- tein-based sensors have only micromolar sensitivity, necessitating the use of strong stimuli and restricting our study to areas of the brain where neurotransmitter concentrations are unusually high. In addition, our current sensors are not readily adaptable to neurotransmitters beyond dopamine (DA) or serotonin, like glu- tamate and ?-aminobutyric acid (GABA), that mediate important processes relevant to motivation, reward, and addiction. Here we propose to develop a suite of nanoscale molecular MRI sensors, based on a novel, generalizable contrast mechanism, which will enable detection of the neurotransmitters dopamine, gluta- mate, GABA, and serotonin in vivo with nanomolar sensitivity. These highly-sensitive contrast agents will facilitate the measurement of mesoscale topological maps of neurotransmitter signaling throughout the brain. Such an approach will enable ?noninvasive neurochemical dissection? of addiction-related changes in neurotransmission, resulting in a more complete understanding of altered brain function in addiction which will ultimately guide the development of behaviorally-effective treatments. Our work on the project will ad- dress three Aims.
In Aim 1, we will establish a novel sensing mechanism based on paramagnetic nanoscale liposomes whose efficacy as contrast agents is regulated by binding to target neurotransmitters. We will pilot the design and explore design parameters in the context of dopamine sensors, where our earlier work establishes a precedent on which we plan to improve.
In Aim 2, we will extend the new liposome-based sensing mechanism to address the additional neurotransmitters glutamate, GABA, and serotonin.
In Aim 3, we will begin validating the new sensor design in vivo, focusing on the dopamine-sensitive nanoprobes and employing a stimulation and imaging paradigm we have used successfully in previous work. Completion of this work will open the way for detection of naturalistic signaling levels of four neurotransmitters and the mapping of their spatial relationships across large regions of the brain in experimental animals.
We will develop a novel molecular sensor platform for imaging the several of the most important neu- rotransmitters involved in addiction. The sensors are designed to be detected by noninvasive functional magnetic resonance imaging (fMRI), and will improve by more than ten-fold the sensitivity of earlier neuro- transmitter-sensitive MRI probes. The ability to map low levels of neurotransmitters with spatiotemporal dy- namics in the brain will shed light on how multiple neurochemical systems interact to implement mecha- nisms involved in addiction and reward-related learning.
| Ghosh, Souparno; Harvey, Peter; Simon, Jacob C et al. (2018) Probing the brain with molecular fMRI. Curr Opin Neurobiol 50:201-210 |
