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皮质神经元回路中的信息流仍然知之甚少。通过笼化化合物的双光子光释放，可以实现活神经元中受体的局部激活。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，尽管它们对研究多巴胺能调节的功能非常有用。我们拟利用新合成的双光子激光释放的笼化化合物RuBi-Dopa，高精度地光激活多巴胺受体，绘制前额叶锥体神经元棘中多巴胺功能反应的分布，研究其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皮质多神经元放电的时间模式，

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.