PROJECT SUMMARY Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is widely used as a non-invasive technique to study brain function. It operates based on the premise that cerebral blood flow renews the supply of energetic substrates to brain regions with increased neuronal activity in a process known as neurovascular coupling. Accumulating results from our group and others indicate that conventional neurovascular coupling may not apply to the striatum and is likely that atypical vasoactive neurotransmission has been playing a largely unaccounted role in this brain area. The striatum is a critical hub for cognition, motivation, reward, and sensorimotor function, and understanding its aberrant hemodynamic activity will provide crucial context to these fields of research. We have developed two central hypotheses: that positive BOLD in the striatum is mediated through dopamine release but not local neuronal activity, and that negative BOLD in the striatum is induced by local neuronal activation and mediated through their downstream vasoconstrictive neurotransmission. We will use 3 neural modulation approaches, including optogenetics, chemogenetics, and pharmacology, together with 4 recording technologies, including fMRI, electrophysiology, fast-scan cyclic voltammetry, and optical fiber-photometry to manipulate and acquire the changes in BOLD, dopamine release, and neuronal activity in the striatum. We expect our results to provide novel insights into BOLD mechanisms, and lay the foundation for accurate fMRI data interpretation in subcortical brain areas that do not obey the traditional neurovascular coupling rules. 1

PROJECT NARRATIVE Our understanding of human brain function has been heavily influenced by functional magnetic resonance imaging (fMRI) – a technique that measures neuronal activity indirectly through blood oxygenation changes. Accumulating data indicates that our interpretation of fMRI data could have been wrong, or even opposed to the actual neuronal processes in a brain area called striatum. The striatum is involved in cognition, motivation, reward, sensorimotor function, and several neurological and neuropsychiatric disorders such as addiction, obsessive-compulsive disorder, schizophrenia, Parkinson’s disease, and major depression. We plan to use cutting-edge neuroscience tools including optogenetics, chemogenetics, pharmacology, fast-scan cyclic voltammetry, electrophysiology, dual-spectral fiber-photometry and fMRI to uncover the mechanism by which fMRI signal is formed in the striatum. 1