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.

项目摘要/摘要脊柱功能或发育的扰动会产生深刻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。虽然树突状棘突介导谷氨酸能信号传导，但最近的证据表明多巴胺调节体外还原模型系统中的树突状脊柱可塑性。该项目的核心目标是确定多巴胺对体内树突状脊柱可塑性的作用。我的主要假设是局部多巴胺能信号传导介导树突状刺的出现，功能和修剪。在AIM-1中，我将使用全息图像树突状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端和笼中多巴胺，以研究树突状脊柱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，我将使用两种谷氨酸进行实验以及多巴胺能信号传导，研究其在精神分裂症小鼠模型中的树突状脊柱动力学中的作用。我将使用针对树突状刺（SPASAP）的新型遗传编码的电压指示器，使用电压成像。为了测量刺的结构（形态学差异）和功能性（电压波动）响应，I 将在小鼠前额叶皮层的前比前区域的第5层执行这些目标，该区域的多巴胺能神经元项目并与精神分裂症有关，并且表现出脊柱数量失调的一个和形态分布但没有明显的功能表征。我提出的研究将大大扩展理解与电压波动的关系如何通过与树突状脊柱可塑性的多巴胺能调节，以及树突状脊柱可塑性的失调精神分裂症等疾病。