Subcellular Mapping and Post-Synaptic Impacts of Striatal Dopamine Release During Behavior

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PROJECT SUMMARY/ABSTRACT The basal ganglia are a group of deep brain nuclei that play a central role in motivating, selecting, and learning actions. The largest of these nuclei, the striatum, serves as the principal input, receiving widespread convergent excitatory innervation from cortex and thalamus, as well as dopamine (DA) inputs from the midbrain. DA has been shown to be integral for numerous cognitive functions, including reward response, motivation, motor control, learning, and memory, and DA system abnormalities have been associated with a number of neurological and psychiatric illnesses, such as addiction, depression, schizophrenia, obsessive- compulsive disorder, and Parkinson's disease. Previous research has shown that dopamine neurons serving different functions project to broadly different targets within the striatum. However, little is known about the subcellular spatial organization of DA inputs onto single neurons, and whether there is also evidence for functional segregation at this level. Furthermore, it remains unknown as to how these inputs directly impact post-synaptic cell firing as a function of the spatial distribution of inputs along dendrites. This proposal seeks to 1) develop methodological advances by which dopamine release onto the dendrites of single striatal neurons can be investigated in real-time with subcellular resolution using 2-photon microscopy, 2) map functionally-relevant dopamine release onto striatal dendrites during spontaneous locomotion, unexpected reward, and expected reward, and 3) examine the relationship between dopamine input and the probability of postsynaptic neuronal firing output via simultaneous 2-photon microscopic imaging of dopamine and calcium signaling. The Brain Initiative, in its Brain 2025 Report, has stated among its priority areas “Maps at multiple scales: Generate circuit diagrams that vary in resolution from synapses to the whole brain”, “Identifying fundamental principles: Produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data analysis tools”, and “The brain in action… dynamic picture of the functioning brain”. We believe this proposal is very much in line with these stated priorities, by providing a deeper understanding of the in vivo spatial and functional mapping of dopaminergic striatal circuitry at the subcellular synaptic resolution, and further yielding novel insight into possible mechanisms by which behaviorally-relevant computations may be carried out in the brain at the cellular and subcellular level.