Optical platform to image neuronal and vascular effects of cocaine in awake rodents

用于成像可卡因对清醒啮齿动物神经元和血管影响的光学平台

• 批准号: 9197743
• 负责人: Congwu Du
• 金额: $ 19.51万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197743
• 关键词: Acute; Address; Angiography; Animal Model; Animals; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Brain imaging; Cells; Cerebrovascular Circulation; Chronic; Cocaine; Cocaine Dependence; Corpus striatum structure; DRD2 gene; Defect; Detection; Development; Dopamine; Dopamine D2 Receptor; Doppler tomography; Drug Addiction; Fluorescence; Foundations; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Grant; Image; Imaging Device; Imaging Techniques; Intoxication; Investigation; Ischemia; Maps; Measurement; Medial; Mediating; Mus; Neurobiology; Neurons; Neurotransmitters; Optical Coherence Tomography; Optics; Pathology; Pathway interactions; Penetration; Pharmaceutical Preparations; Physiological; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Process; Research; Resolution; Rest; Rewards; Rodent; Role; Signal Transduction; Solid; Techniques; Technology; Testing; Time; Toxic effect; Transgenic Mice; Trees; Viral; addiction; awake; capillary; cell type; cerebrovascular; cocaine exposure; fluorescence imaging; gamma-Aminobutyric Acid; hemodynamics; imaging platform; in vivo; innovation; insight; multimodality; neuroimaging; neuronal circuitry; neurotoxicity; neurovascular; neurovascular coupling; novel; optical imaging; response; spatiotemporal; temporal measurement; tool; vasoconstriction

The medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction. The mechanism underlying mPFC dysfunction in cocaine abusers are not well understood and could reflect disruption of cerebral blood flow (cocaine’s vascular effects) and/or disruption of dopaminergic modulation of the prefrontal cortex (cocaine’s neuronal effects). However, current neuroimaging tools cannot readily separate vascular from neuronal effects nor distinguish between cell specific (e.g., D1r vs D2r neuronal) responses to cocaine. This application, "Optical platform to image neuronal and vascular effects of cocaine in awake rodents", proposes to develop an innovative and integrated optical imaging platform to address these challenges and demonstrate its value in addiction research. Specifically, we propose to develop a unique optical platform that enables simultaneous (1) fluorescence imaging of D1r/D2r-specific neuronal Ca2+ dynamics (marker of neuronal activity) taking advantage of cre transgenic mice and viral delivery of optically encoded Ca2+ indicator (GCaMP6f) to identify specific neuronal populations, and (2) 3D ultrahigh-resolution optical coherence Doppler tomography (1.3m ODT) of micro cerebral blood flow (CBF) in deep layers of the mPFC (>1.4mm). We will demonstrate the value of this integrated approach to assess the vascular and neuronal responses in mPFC of awake animals to acute and chronic cocaine. Our recent optical tool advances and their use for studying the effects of cocaine in cerebrovascular networks and in neuronal function separately for D1r- and D2r- expressing neurons have laid a solid foundation for the proposed study of cocaine-induced mPFC dysfunction. Successful development of the proposed novel fluorescence-ODT platform will not only provide new insights into cocaine-induced mechanism underlying mPFC dysfunction but also will be of value for studying neurovascular interactions and their disruption in animal models of various brain disorders.

内侧前额叶皮质(MPFC)在可卡因成瘾中起关键作用。其背后的机制 可卡因滥用者的mPFC功能障碍尚不清楚，可能反映了脑部血液的紊乱 前额叶皮质多巴胺能调节的流动(可卡因的血管效应)和/或干扰 (可卡因的神经效应)。然而，目前的神经成像工具不能很容易地将血管与 神经元效应也不区分细胞特异性(例如，D1R和D2R神经元)对可卡因的反应。 这项名为“光学平台成像可卡因对清醒啮齿动物的神经和血管效应的应用”， 建议开发创新的集成光学成像平台来应对这些挑战 并论证了其在成瘾研究中的价值。具体地说，我们建议开发一种独特的光学 能够同时(1)荧光成像D1R/D2R特异性神经元钙离子动力学的平台 (神经元活性的标志)利用cre转基因小鼠和光学编码的病毒传递 钙离子指示剂(GCaMP6f)用于识别特定的神经元群体，以及(2)3D超高分辨率光学 相干多谱勒断层成像(1.3mODT)测量大脑中动脉深部微血流量 MPFC(&gt；1.4 mm)。我们将展示这种综合方法的价值，评估血管和 清醒动物mPFC对急、慢性可卡因的神经元反应。 我们光学仪器的最新进展及其在研究可卡因对脑血管影响方面的应用 网络和神经元功能分别为D1R和D2R表达的神经元奠定了坚实的基础 为可卡因引起的mPFC功能障碍的拟议研究奠定基础。成功地开发了 提出的新型荧光寡核苷酸平台不仅将为研究可卡因诱导的 MPFC功能障碍的机制，但对研究神经血管相互作用也有价值 以及它们在各种大脑疾病的动物模型中的破坏。