Novel caged Dopamine compounds

描述（由申请人提供）：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疾病的重要病理生理学基础。 然而，多巴胺受体如何调节单个神经元和前额叶皮层神经元回路中的信息流仍然知之甚少。 活神经元中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，谷氨酸的双光子释放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，光释放多巴胺的光化学工具很少，即使它们对研究多巴胺能调节的功能非常有用。 我们建议使用一种新合成的笼状化合物，RuBi-Dopa，它可以用双光子激光光释放，以高精度光学激活多巴胺受体，并绘制功能性多巴胺反应在前额叶锥体神经元脊髓中的分布，研究它们的激活如何改变多巴胺能传递。 最后，我们将测试多巴胺如何影响前额皮质多神经元放电的时间模式， 通过释放RuBi-Dopa，同时在清醒的制剂中进行体内双光子钙成像。 这项工作将扩大生物释放的化学工具箱，包括新的高质量的笼状多巴胺化合物，可以用双光子激光释放。 这些新化合物将使多巴胺能传递对选择性亚细胞区室的功能影响的详细研究成为可能，这可能对我们理解多巴胺如何改变正常和患病的脑功能产生重大影响。 这些化合物中的一些可能用于开发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棘的功能影响。 由于棘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.