Optical Tools to Study Neuropeptide Signaling

 描述（由申请人提供）：神经肽是调节脑中细胞、突触和神经回路的生理学的神经调质。例如，阿片类神经肽参与疼痛和镇痛，并且在成瘾、抑郁和焦虑以及包括帕金森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中起着重要作用，但神经肽信号传导的许多方面还没有得到很好的理解。与经典的快速突触递质如谷氨酸和GABA不同，神经肽可以在突触和突触外释放。神经肽也可以从它们被释放的地方扩散到很远的地方。在远处，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，神经肽参与比突触传递更广泛的空间和时间尺度的信号传递，这些时空特征使得难以精确研究神经肽信号如何在整个大脑中传播。这一实验障碍在我们对负责行为和认知的神经回路是如何调节的知识中留下了重要的空白。因此，为了克服这一关键障碍，并使神经肽能够直接在健康和患病的脑组织中进行研究，本提案的目标是开发新的遗传编码光学工具，以（1）记录和（2）调节神经肽信号。

 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.