Novel caged Dopamine compounds

描述(申请人提供)：新型笼状多巴胺化合物。多巴胺受体的异常调节被认为是精神分裂症、双相情感障碍和抑郁症等精神障碍的重要病理生理机制。然而，多巴胺受体如何调节单个神经元和前额叶皮质神经元回路中的信息流仍然知之甚少。活神经元上受体的局部激活可以通过笼状化合物的双光子光释放来实现。事实上，谷氨酸的双光子去功能化已经彻底改变了目前对哺乳动物神经元兴奋性传递和整合的理解。不幸的是，尽管光化学工具对研究多巴胺能调节功能非常有用，但用于光释放多巴胺的工具还很少。我们建议使用一种新合成的笼状化合物Rubi-多巴，它可以用双光子激光光释放，高精度地光学激活多巴胺受体，并绘制前额锥体神经元脊髓中功能性多巴胺反应的分布图，研究它们的激活如何改变谷氨酸能传递。最后，我们将测试多巴胺如何影响前额叶皮质多神经元放电的时间模式， 通过在清醒的制剂中进行体内双光子钙成像的同时取消Rubi-多巴。这项拟议的工作将扩大生物包埋的化学工具箱，包括可以用双光子激光进行光释放的新型高质量笼状多巴胺化合物。这些新化合物将使详细研究多巴胺能传递对选择性亚细胞隔室的功能影响，这可能对我们理解多巴胺如何改变正常和疾病的大脑功能产生重大影响。其中一些化合物有可能被用来开发治疗精神疾病的光学疗法。最后，我们的数据将首次揭示多巴胺能输入对树突的功能影响。由于脊椎介导了大多数兴奋性连接，这些结果也可能改变我们对兴奋性输入是如何整合的理解。

DESCRIPTION (provided by applicant): Novel caged dopamine compounds. The abnormal regulation of dopamine receptors has been postulated as a prominent pathophysiology of several mental disorders, such as schizophrenia, bipolar disorder and depression. However, how dopamine receptors modulate information flow in individual neurons and neuronal circuits in prefrontal cortex is still poorly understood. Local activation of receptors in living neurons cn be achieved by two-photon photorelease of caged compounds. Indeed, two-photon uncaging of glutamate has revolutionized current understanding of excitatory transmission and integration in mammalian neurons. Unfortunately, opto-chemical tools to photorelease dopamine are scant, even though they would be extremely useful to study the function of dopaminergic modulation. We propose to use a newly synthesized caged compound, RuBi-Dopa, which can be photoreleased with two-photon lasers, to optically activate dopamine receptors with high precision and map the distribution of functional dopamine responses in spines from prefrontal pyramidal neurons, studying how their activation alters glutamatergic transmission. Finally, we will test how dopamine affects the temporal patterns of multi-neuronal firing in prefrontal cortex, by uncaging RuBi-Dopa while performing two-photon calcium imaging in vivo in awake preparations. The proposed work will expand the chemical toolbox of biological uncaging to include novel high-quality caged dopamine compounds that can be photo- released with two-photon lasers. These new compounds will enable the detailed investigation of the functional effects of dopaminergic transmission on selective subcellular compartments, something likely to have a major impact on our understanding of how dopamine alters normal and diseased brain function. It is possible that some of these compounds could be used to develop optical therapies for mental disease. Finally, our data will reveal, for the first time, the functional efect of dopaminergic inputs onto dendritic spines. Since spines mediate most excitatory connections, these results could also alter our understanding of how excitatory inputs are integrated.