Decipher the functional phenotypes of the transgenic Parkinson disease mouse model using simultaneous optogenetic fMRI and MRS with calcium and dopamine dynamic signal recordings

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We propose to establish a micro carbon fiber electrode (CFE)-based dopamine recording platform with concurrent optogenetic fMRI and needle-like micro RF probe-based MRS (MR spectroscopy) brain imaging. Carbon fiber composites represent promising biomedical material for MRI-guided intervention given their low density, high strength, similar magnetic susceptibility to that of water, and related lower electrical conductivity than metal. However, it remains challenging to acquire the dopamine signal through the CFE with fMRI due to the eddy current induced in carbon fiber with the fluctuating magnetic gradients. The eddy current could lead to artifacts for both fMRI and electrochemical signal acquisition. Here, we will design an interleaved MR sequence to sample the BOLD and MRS signal during the optogenetically driven dopamine release so as to compensate the potential artifacts contributing to both MRI and CFE recording. The goal of this proposal is to merge the multi-modal fMRI and novel MR spectroscopy (MRS) methods with the CFE-based dopamine recording to reveal the dopamine modulation of neural circuit specific brain activity at the systems level. We will first implement the MRI-guided robotic arms (MgRA) to precisely target the functional nuclei, e.g. substantia nigra (SN), or ventral tegmental area (VTA), mediating dopamine release in the brain. This technical establishment allows us to real time track the fiber optic insertion trajectory inside the brain so that the optogenetic deep brain stimulation (ODBS) could be delivered with high region specificity in rodent brains. Secondly, the simultaneous fMRI with fiber optic calcium recordings can be used to directly characterize the neural-circuit specific functional patterns at both the scale of whole brain structure, as well as at the striatal or prefrontal cortical regions projected from VTA or SN. Thirdly, the needle-like micro RF probe allows us to directly measure the metabolite contents, which could be concurrently acquired with fiber optic calcium recording and CFE-based dopamine release signal, in the targeted focal regions. This methodological development will allow the multi-dimensional brain function study, which links specific neurotransmitters (or multiple metabolite components) to the neuronal circuit specific modulation of the brain function in the systems level. This innovative combination of multiple techniques bring significant advantage to further understand the abnormal brain functional phenotypes of Parkinson disease (PD) mouse model with DJ-1 knockout, of which the loss-of-function mutations in PARK7 (DJ-1, protecting oxidative stress) is one most common cause of autosomal recessive PD in patients.