Brain-wide analysis of input/output relationships in reward system function

About This Grant

The brain’s reward system comprises a set of interconnected regions that jointly direct goal-oriented behavior and underlie numerous pathologies. In order to understand how this system promotes behavioral outcomes, it is essential to characterize how neural information propagates among multiple brain structures and cell populations in the reward network, and how this leads ultimately to actions. Here we propose to use cutting-edge functional magnetic resonance imaging (fMRI) techniques to study integrated input/output relationships between brain re- gions involved in reward-related tasks. The centerpiece of our approach is a novel genetically encoded sensor for fMRI, called NOSTIC, that permits noninvasive functional imaging of discrete neural circuit components at a population level; the NOSTIC probe can be applied using a retrogradely transported virus to enable selective functional imaging of afferent input to any targeted region of the brain. We will use NOSTIC-based circuit-specific fMRI, in combination with complementary anatomical and physiological measurements, to dissect the propaga- tion of neural information during rewarding stimulation, reward-based classical conditioning, and closed-loop rewarding self-stimulation. Experimental data will be used to construct network-based models of reward system function and address fundamental hypotheses about information flow between brain regions, the origin of reward prediction signals, the basis of reward-induced plasticity, and the relationship between individual behavior and defined neural circuit components. Our agenda consists of three aims: In Aim 1 we will use the NOSTIC tech- nology to examine how functional inputs from across the brain converge on three key structures, the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC), during rewarding stimulation in rats. Results will define for the first time the broad topographies of information flow among multiple brain regions during rewarding stimulation, dissecting inputs from functionally and neurochemically distinct brain regions and testing the hypothesis that these inputs combine in approximately linear fashion to produce regional activity. In Aim 2, we will apply NOSTIC to examine circuit-level bases of brain-wide plasticity during paradigmatic classical conditioning paradigms, addressing key questions about the origins of reward prediction error signals in the brain at a comprehensive spatial scale. These studies will be performed in complementary awake rat and mouse preparations implemented in two laboratories, serving to disseminate NOSTIC technology as well as apply it. Then in Aim 3, we will introduce a cell type-specific application of NOSTIC that enables separate excitatory and inhibitory contributions to reward circuit dynamics to be measured and interpreted in the experimental paradigms of Aims 1 and 2. Collectively, these experiments will provide a first-of-their-kind spatially comprehensive dissec- tion of neural circuit mechanisms involved in diverse reward-related brain functions.