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

我们建议建立一个基于微碳纤维电极(CFE)的多巴胺记录平台，同时进行光遗传功能磁共振成像和基于针状微RF探头的MRS(磁共振波谱)脑成像。碳纤维复合材料具有密度低、强度高、磁化率与水相似、导电性低于金属等优点，是一种很有前途的核磁共振引导介入生物医学材料。然而，由于磁场梯度波动的碳纤维中产生的涡流，利用功能磁共振成像通过CFE获取多巴胺信号仍然具有挑战性。涡流可能会导致功能磁共振成像和电化学信号采集的伪影。在这里，我们将设计一个交错的MR序列，在光遗传驱动的多巴胺释放过程中对BOLD和MRS信号进行采样，以补偿可能对MRI和CFE记录造成影响的伪影。该方案的目标是将多模式功能磁共振成像和新颖的磁共振波谱(MRS)方法与基于CFE的多巴胺记录相结合，以在系统水平上揭示多巴胺对神经回路特异性脑活动的调制。我们将首先实施MRI引导的机械臂(MGRA)，以精确定位功能核团，例如黑质(SN)或腹侧被盖区(VTA)，介导大脑中的多巴胺释放。这一技术设施使我们能够实时跟踪光纤在脑内的插入轨迹，以便在啮齿类动物的大脑中进行高区域特异性的光遗传脑深部刺激(ODBS)。其次，结合光纤钙离子记录的同时功能磁共振成像可以在整个大脑结构以及从VTA或SN投射的纹状体或前额叶皮质区域直接表征神经回路特定的功能模式。第三，针状微型射频探头使我们可以直接测量目标焦点区域的代谢物含量，这些代谢物可以与光纤钙记录和基于CFE的多巴胺释放信号同时获得。这一方法的发展将使多维脑功能研究成为可能，它将特定的神经递质(或多种代谢物成分)与系统水平上大脑功能的神经元回路特定调制联系起来。这种多种技术的创新组合为进一步了解DJ-1基因敲除的帕金森病(PD)小鼠模型的脑功能异常表型带来了显著的优势，其中Park7功能缺失突变(DJ-1，保护氧化应激)是常染色体隐性遗传性PD患者最常见的原因之一。

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.