Imaging Neuronal Activation: Comparison of Hemodynamic, Metabolic, and Molecular Responses Using Simultaneous fPET/fMRI

01.08.2023 bis 31.07.2026

Optogenetic functional magnetic resonance imaging (ofMRI) combines a precise neuronal stimulation technique with fMRI as an indirect readout of neuronal activation. This enables a cell-type specific mapping of the whole brain dynamic response to the activation or inhibition of neuronal circuits. In addition, functional positron emission tomography (fPET) detects metabolic changes with good temporal resolution on a single subject level via a continuous [18F]FDG infusion. Both methods map energy expenditure during pre- and postsynaptic neuronal signaling, which leads to an increased demand for oxygen and glucose from the vascular system. The neurotransmitter dopamine plays an essential role in many neurological diseases and has been shown to have vasomodulatory properties. Dopaminergic neurons of the substantia nigra pars compacta (SNc) project to the dorsal striatum and play a central role in motor behavior. Thus, its activity and connectivity with other brain regions have been subject to several human fMRI studies, and BOLD responses in these studies are often interpreted as a change in dopamine release. To enable the study of early synaptic dysfunctions of neurotransmitter release in motor-related disorers, it is imperative to understand if and how SNc firing pattern influence whole brain network dynamics to interpret neuroimaging data accurately. Here, we aim to use simultaneous PET/fMRI in combination with fiber photometry to better understand the association between neuronal activation, metabolic demand, and dopamine concentrations. Controlled and selective neuronal activation will be achieved by optogenetic activation of nigrostriatal neurons using recombinant adeno-associated viral (AAV) vectors for the overexpression of the light-sensitive ion channel ChR2. To isolate the influence of dopamine and dopamine receptors on the hemodynamic response, we will use graded optogenetic stimulations that will probe a range of evoked dopamine amplitudes ranging from low to high-frequency stimulations. We will further perform fiber photometry measurements to quantify dopamine release in the dorsal striatum with a high temporal resolution to measure the local dopamine response during different stimulation paradigms. Since neurochemicals other than dopamine are released in the dorsal striatum following optogenetic SNc stimulation, we will include a GABA sensor into our approach in combination with a dopamine sensor. Finally, we will combine the three modalities offering a unique combination to understand how brain network dynamics depend on SNc firing patterns.