Dopaminergic regulation of dendritic spine function and plasticity in prefrontal cortex

项目总结/摘要 脊柱功能或发育的扰动会产生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重要组成部分， 精神分裂症虽然树突棘介导多巴胺能信号，但最近的证据表明， 在体外简化模型系统中调节树突棘可塑性。该项目的核心目标是确定 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 介导树突棘的出现、功能和修剪。在Aim-1中，我将使用全息成像， 树突棘对体内突触输入的功能反应。在AIM-2中，我将使用全息光遗传学 刺激多巴胺能神经元末梢和笼状多巴胺以研究树突棘的控制 通过多巴胺能信号传导的电压动力学。最后，在Aim-3中，我将使用谷氨酸盐和谷氨酸盐进行实验。 和多巴胺能信号转导，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的基因编码的电压指示剂针对树突棘（spASAP）。 为了测量棘的结构（形态差异）和功能（电压波动）反应， 将在小鼠前额叶皮层的前边缘区第5层执行这些目标，这是多巴胺能神经 神经元项目和牵连精神分裂症，以及一个表现出失调的脊柱数量， 形态分布，但没有显著的功能表征。我的研究计划将大大 扩大了解如何通过与电压波动相关的关键机制改变关系， 树突棘可塑性的多巴胺能调节，以及树突棘可塑性如何失调， 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.