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。这使得能够对整个大脑对神经元电路的激活或抑制的动态反应进行细胞类型的特定映射。此外，功能正电子发射断层扫描(FPET)通过持续的[18F]FDG输注，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递过程中的能量消耗图，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。黑质致密部的多巴胺能神经元投射到背侧纹状体，在运动行为中起重要作用。因此，它的活动和与其他大脑区域的连通性一直受到几项人类功能磁共振研究的影响，这些研究中的大胆反应通常被解释为多巴胺释放的变化。为了能够研究运动相关障碍患者早期神经递质释放的突触功能障碍，必须了解SNC的放电模式是否以及如何影响整个大脑网络的动力学，以便准确地解释神经成像数据。在这里，我们的目标是使用同步的PET/fMRI结合纤维光度法来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。通过利用重组腺相关病毒(AAV)载体过表达光敏离子通道ChR2，通过光基因激活黑质纹状体神经元，可以实现受控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，探测从低频率刺激到高频刺激的一系列诱发的多巴胺幅度。我们将进一步进行纤维光度测量，以高时间分辨率量化背侧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。由于除了多巴胺以外的其他神经化学物质在光遗传SNC刺激后在背侧纹状体中释放，我们将在我们的方法中加入GABA传感器和多巴胺传感器。最后，我们将结合这三种模式，提供一个独特的组合，以了解大脑网络动态如何依赖于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.