Dopaminergic regulation of dendritic spine function and plasticity in prefrontal cortex

项目摘要/摘要 脊柱功能或发育的紊乱会导致严重的行为和认知功能障碍 仍然是神经发育和神经退行性突触病变的关键组成部分，如 精神分裂症。虽然树突棘介导谷氨酸能信号，但最近的证据表明，多巴胺 在体外简化的模型系统中调节树突棘的可塑性。该项目的中心目标是确定 多巴胺在体内树突棘可塑性中的作用。我的主要假设是局部多巴胺能信号 调节树突棘的出现、功能和修剪。在AIM-1中，我将使用全息成像 在体树突棘对突触输入的功能反应。在AIM-2中，我将使用全息光遗传 刺激多巴胺能神经元终末和笼养多巴胺研究树突棘的控制 通过多巴胺能信号的电压动态。最后，在AIM-3中，我将使用两种谷氨酸进行实验 和多巴胺能信号，以研究它们在精神分裂症小鼠模型树突棘动力学中的作用。我 将使用电压成像与一种新型的针对树突的遗传编码电压指示器(SpASAP)。 为了测量脊椎的结构(形态差异)和功能(电压波动)反应，即 将在小鼠前额叶皮质的第5层前额叶皮质实现这些目的，这是一个多巴胺能 神经元投射并牵涉到精神分裂症，以及一种表现出脊柱数量和 形态分布，但没有明显的功能特征。我提出的研究将极大地 扩展对电压波动的关系如何由与以下相关的关键机制改变的理解 多巴胺能对树突棘可塑性的调节，以及树突棘可塑性如何在 精神分裂症等疾病。

Project Summary/Abstract Perturbation of spine function or development produces profound behavioral and cognitive dysfunction and remains a critical component to neurodevelopmental and neurodegenerative synaptopathies such as schizophrenia. While dendritic spines mediate glutamatergic signaling, recent evidence suggests that dopamine modulates dendritic spine plasticity in in vitro reduced model systems. The central goal of this project is to identify the role of dopamine on dendritic spine plasticity in vivo. My main hypothesis is that local dopaminergic signaling mediates the emergence, function, and pruning of dendritic spines. In Aim-1 I will use holographic imaging of functional responses of dendritic spines to synaptic inputs in vivo. In Aim-2, I will use holographic optogenetic stimulation of dopaminergic neuron terminals and caged dopamine to investigate the control of dendritic spine voltage dynamics via dopaminergic signaling. Finally, in Aim-3 I will perform experiments using both glutamate and dopaminergic signaling to study their roles in dendritic spine dynamics in mouse models of schizophrenia. I will use voltage imaging with a novel genetically encoded voltage indicator targeted to dendritic spines (spASAP). To measure the structural (morphological differences) and functional (voltage fluctuation) responses of spines, I will perform these aims in layer 5 of prelimbic area of mouse prefrontal cortex, an area where dopaminergic neurons project and implicated in schizophrenia, as well one that exhibits dysregulation of spine number and morphology distribution but without significant functional characterization. My proposed studies will greatly expand the understanding how relationships to voltage fluctuations are altered by key mechanisms related to dopaminergic modulation of dendritic spine plasticity, and how dendritic spine plasticity are dysregulated in diseases such as schizophrenia.