Optical Tools to Study Neuropeptide Signaling

 描述（由申请人提供）：神经肽是调节大脑中细胞、突触和神经回路生理学的神经调节剂。例如，阿片类神经肽与疼痛和镇痛有关，并且在成瘾、抑郁和焦虑以及包括帕金森氏病在内的许多其他神经系统疾病中观察到阿片类神经肽水平的改变。显然，神经肽在调节行为和认知方面发挥着重要作用，但神经肽信号传导的许多方面尚不清楚。与谷氨酸和 GABA 等经典的快速突触递质不同，神经肽既可以在突触内释放，也可以在突触外释放。神经肽还可以从它们释放的地方扩散到很远的地方。在远处的位点，神经肽可以通过激活高亲和力的 G 蛋白偶联受体，在低浓度下继续发挥信号作用。因此，神经肽在比突触传递更广泛的空间和时间尺度上参与信号传导，并且这些时空特征使得精确研究神经肽信号如何在整个大脑中传播变得困难。这一实验障碍在我们对如何调节负责行为和认知的神经回路的知识中留下了重要的空白。因此，为了克服这一关键障碍并使神经肽能够在健康和患病脑组织中直接研究，本提案的目标是开发新的基因编码光学工具来（1）记录和（2）调节神经肽信号传导。

 DESCRIPTION (provided by applicant): Neuropeptides are neuromodulators that regulate the physiology of cells, synapses, and neural circuits in the brain. For example, opioid neuropeptides are involved in pain and analgesia, and altered opioid neuropeptide levels have been observed in addiction, depression and anxiety, as well as a number of other neurological disorders including Parkinson's disease. Clearly, neuropeptides play a significant role in modulating behavior and cognition, but many aspects of neuropeptide signaling are not well understood. Unlike classical fast synaptic transmitters such as glutamate and GABA, neuropeptides can be released both at the synapse and outside the synapse. Neuropeptides can also diffuse significant distances from where they were released. At distant sites, neuropeptides can continue to function as signals at low concentrations by activating high affinity G-protein coupled receptors. Thus, neuropeptides engage in signaling over much broader spatial and temporal scales than synaptic transmission, and these spatiotemporal characteristics have made it difficult to precisely study how neuropeptide signals propagate throughout the brain. This experimental barrier has left important gaps in our knowledge of how the neural circuits that are responsible for behavior and cognition are modulated. Therefore, in order to overcome this critical barrier and enable neuropeptides to be directly studied in healthy and diseased brain tissue, it is the goal of this proposal is to develop new genetically-encoded optical tools to (1) record and (2) modulate neuropeptide signaling.