Dopaminergic regulation of dendritic spine function and plasticity in prefrontal cortex

前额皮质树突棘功能和可塑性的多巴胺能调节

基本信息

批准号：
10613916
负责人：
Douglas R Miller
金额：
$ 6.95万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613916
关键词：
Accidents Affect Antipsychotic Agents Area Axon Basic Science Behavior Behavioral Biological Models Brain Chemosensitization Classification Clinical Research Dendrites Dendritic Spines Detection Development Disease Dopamine Dopamine D2 Receptor Electric Stimulation Elements Excitatory Synapse Exhibits Fluorescence Functional disorder Glutamates Goals Haloperidol Holography Image Impaired cognition Implant In Vitro Incubated Invaded Lasers Measures Mediating Mental Depression Mental disorders Methodology Methods Mission Monitor Morphology Mus National Institute of Mental Health Neocortex Nerve Degeneration Neurologic Neuromodulator Neurons Opsin Optical Methods Parents Pharmacology Physiologic pulse Play Prefrontal Cortex Prevention Property Recovery Regulation Role Schizophrenia Signal Transduction Structure Synapses Synaptic Potentials Testing Tube Ventral Tegmental Area Vertebral column cell motility density dopaminergic neuron experimental study extracellular flexibility glutamatergic signaling in vivo in vivo imaging millisecond mouse model neocortical nerve supply neural circuit neurotransmission novel optogenetics photomultiplier postsynaptic prevent receptor redshift response two-photon voltage

项目摘要

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.

项目概要/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的关键组成部分，例如精神分裂症。虽然树突棘介导谷氨酸信号传导，但最近的证据表明多巴胺在体外简化模型系统中调节树突棘可塑性。该项目的中心目标是确定多巴胺对体内树突棘可塑性的作用。我的主要假设是局部多巴胺能信号传导介导树突棘的出现、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态。最后，在 Aim-3 中，我将使用谷氨酸进行实验和多巴胺能信号传导，以研究它们在精神分裂症小鼠模型的树突棘动力学中的作用。我将使用电压成像和针对树突棘的新型基因编码电压指示器（spASAP）。为了测量脊柱的结构（形态差异）和功能（电压波动）反应，我将在小鼠前额皮质前边缘区域的第 5 层执行这些目标，该区域是多巴胺能区域神经元投射并与精神分裂症有关，以及表现出脊柱数量和神经失调的神经元形态分布但没有显着的功能表征。我提出的研究将极大地扩大对与电压波动的关系如何通过相关关键机制进行改变的理解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。