Genetically encoded anatomical probes for neuronal activity and plasticity

神经科学研究的一个主要挑战是确定负责各种神经系统过程（如感觉知觉、学习和记忆）的精确功能神经回路，以及强调病理条件（如慢性疼痛、抑郁、成瘾和癫痫）的异常回路。该领域以前的工作主要集中在设计分子传感器，使用光学方法检测瞬态电压变化或钙内流。然而，利用这些传感器来研究哺乳动物神经系统的体内复杂神经生理和病理生理过程的研究非常有限。此外，这些传感器不允许激活电路的解剖重建。在这个EUREKA应用中，我们建议开发新的遗传编码解剖探针，用于直接可视化神经元活动和可塑性。这些探针将用标记物（如荧光蛋白）标记激活的神经元和突触（以及那些最有可能经历可塑性的神经元和突触），以便于组织学检测和解剖追踪。这种非传统探针设计的主要原理是利用活性（强钙内流）诱导非翻译标记蛋白的翻译。活动诱导解剖探针的成功开发将极大地促进我们对神经系统功能和功能障碍的理解。

A major challenge in neuroscience research is to identify the precise functional neural circuits that are responsible for diverse nervous system processes such as sensory perception, learning and memory, as well as the aberrant circuits that underline the pathological conditions such as chronic pain, depression, addiction, and epilepsy. Previous work in this area has focused on designing molecular sensors that detect transient voltage change or calcium influx using optical methods. However, the use of these sensors for studying in vivo complex neural physiology, and pathophysiology processes of the mammalian nervous system have been extremely limited. Moreover, these sensors do not allow for anatomical re-construction of the activated circuits. In this EUREKA application, we propose to develop novel genetically encoded anatomical probes for visualizing neuronal activity and plasticity directly. These probes will label activated neurons and synapses (and those most likely undergo plasticity) with a marker (e.g. a fluorescent protein) for easy histological detection and anatomical tracing. The chief principle underlying this unconventional design of probes is to use activity (strong calcium influx) to induce the translation of an otherwise un-translated marker protein. Successful development of the activity-induced anatomical probes will greatly advance our understanding of the functions and dysfunctions of the nervous system.