Dissect brain functional connectivity using hemogenetic fMRI

Hemogenetic fMRI is a new technique designed to translate molecular signaling events in the central nervous system into localized changes in BOLD fMRI signals, using genetically encoded reporter genes. The resulting MRI signals from reporter-expressing cells—referred to as artificial BOLD signals—can be distinguished from the brain’s intrinsic BOLD activity by administering a reporter-specific inhibitor. For the first-generation, calcium-sensitive hemogenetic fMRI reporters, we engineered nitric oxide synthases for targeting image contrast (NOSTIC) to convert intracellular calcium fluctuations into hemodynamic changes. Neuronal nitric oxide synthase (nNOS), in particular, is a calcium-activated enzyme that generates cell-permeable NO, thereby influencing local vascular dynamics. By utilizing advanced viral vector strategies to introduce these reporters, hemogenetic fMRI enables the investigation of circuit-specific brain activities that are difficult to capture using conventional BOLD-fMRI. In this presentation, I will detail the design of the NOSTIC reporter gene and demonstrate how it can be employed to analyze neural circuitry in rodent models. I will also discuss additional hemogenetic fMRI strategies that achieve cell-type specificity and target distinct molecular events, further expanding the utility of this innovative approach.