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

光遗传功能磁共振成像（ofMRI）结合了精确的神经元刺激技术和fMRI作为神经元激活的间接读数。这使得整个大脑对神经元回路的激活或抑制的动态反应的细胞类型特异性映射成为可能。此外，功能性正电子发射断层扫描（fPET）通过连续[18F]输注FDG，在单个受试者水平上以良好的时间分辨率检测代谢变化。这两种方法都绘制了突触前和突触后神经元信号传导过程中的能量消耗，这导致血管系统对氧气和葡萄糖的需求增加。神经递质多巴胺在许多神经系统疾病中起着重要作用，并已被证明具有血管调节特性。黑质致密部（SNc）多巴胺能神经元投射到背纹状体，在运动行为中起核心作用。因此，它的活动和与其他大脑区域的连通性已经受到几项人类功能磁共振成像研究的影响，这些研究中的BOLD反应通常被解释为多巴胺释放的变化。为了研究运动相关疾病中神经递质释放的早期突触功能障碍，有必要了解SNc放电模式是否以及如何影响全脑网络动力学，以准确解释神经影像学数据。在这里，我们的目标是同时使用PET/fMRI与纤维光度法相结合，以更好地了解神经元激活、代谢需求和多巴胺浓度之间的关系。利用重组腺相关病毒（AAV）载体过表达光敏离子通道ChR2，对黑质纹状体神经元进行光遗传激活，可以实现控制和选择性的神经元激活。为了分离多巴胺和多巴胺受体对血流动力学反应的影响，我们将使用分级光遗传刺激，探测从低到高频刺激引起的多巴胺振幅范围。我们将进一步进行纤维光度测量，以高时间分辨率量化背纹状体中的多巴胺释放，以测量不同刺激模式下的局部多巴胺反应。由于在光遗传SNc刺激后，背纹状体中会释放多巴胺以外的神经化学物质，因此我们将在我们的方法中结合GABA传感器和多巴胺传感器。最后，我们将结合三种模式，提供一种独特的组合，以了解大脑网络动力学如何依赖于SNc放电模式。

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.