Optical imaging of dopamine kinetics in prefrontal cortex of normal and schizophrenia model mice

正常和精神分裂症模型小鼠前额皮质多巴胺动力学的光学成像

• 批准号: 9195373
• 负责人: Samuel Clark
• 金额: $ 4.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195373
• 关键词: 22q11.2; Acute; Address; Affect; Amphetamines; Anhedonia; Antipsychotic Agents; Area; Attention; Axon; Brain; Catecholamines; Cephalic; Collaborations; Defect; Delusions; Dopamine; Etiology; Exhibits; Future; Generations; Genes; Hallucinations; Human; Image; Imaging Techniques; Implant; Interneurons; Intrinsic factor; Kinetics; Link; Measurement; Measures; Medial; Membrane; Mental disorders; Methods; Modeling; Mus; Nature; Neurobehavioral Manifestations; Neurons; Neurotransmitters; Norepinephrine; Pathology; Patients; Pharmaceutical Preparations; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Primates; Resolution; Role; Sampling; Schizophrenia; Short-Term Memory; Slice; Speech; Structure; Symptoms; Synapses; Techniques; Testing; Therapeutic; Thinking; Time; Training; Vesicle; Wild Type Mouse; behavior test; cognitive function; dopamine transporter; effective therapy; executive function; fluorescence imaging; in vivo; insight; median forebrain bundle; mouse model; neurotransmission; noradrenaline transporter; novel; optical imaging; presynaptic; research study; response; social; tool; vesicular monoamine transporter

PROJECT SUMMARY Schizophrenia is a debilitating lifelong psychiatric disorder with a worldwide prevalence of 1%. It is characterized by positive symptoms (delusions, hallucinations, disorganized thinking), negative symptoms (flattened affect, anhedonia, paucity of speech) and cognitive symptoms (defects in executive function, attention, and working memory (WM)). While the positive symptoms can be effectively managed with antipsychotic drugs, there are no treatments for the negative and cognitive symptoms. Recent PET imaging of schizophrenic patients has confirmed that there is a cortical dopamine (DA) deficit following a challenge with the DA releasing drug amphetamine (AMPH). This deficit in cortical DA has long been thought to play a critical role in the pathology of the negative and cognitive symptoms of schizophrenia, including the deficit in WM. Due to a lack of tools with which to study neurotransmission with single synapse resolution in vivo, the nature of this deficit has yet to be determined. In order to study DA neurotransmission in vivo with single synapse resolution, we have optimized a novel tool for in vivo multiphoton imaging of mice. Fluorescent false neurotransmitters (FFNs) are fluorescent substrates for the DA transporter (DAT), the norepinephrine transporter (NET), and the vesicular monoamine transporter (VMAT), that are taken up into the presynaptic boutons of axons where they are subsequently loaded into presynaptic vesicles. FFNs have previously been used in acute brain slice experiments to allow determination of the kinetics of synaptic release, however, their use in vivo is an unpublished application. We have used FFNs to image catecholamine neurotransmission in the cortex in vivo. For this project, we will utilize multiphoton imaging in vivo of FFNs and GCaMP6f, to record DA release from presynaptic mesocortical terminals in the medial prefrontal cortex of WT and schizophrenia model mice both during AMPH induced electrically evoked, and spontaneous release and during a task of WM. This proposal implements a novel method to examine DA release in vivo in WT and two mouse models of schizophrenia to provide the first measurement of in vivo kinetics of DA during both AMPH induced release and a task of WM. Elucidating the mechanism underlying DA deficits in schizophrenia mouse models may provide key translational information for the changes that occur in schizophrenic patients and may reveal new targets to aid future therapeutic strategies.

项目摘要 精神分裂症是一种使人衰弱的终身精神病，全球患病率为1％。它的特征是 通过积极症状（妄想，幻觉，混乱的思维），负面症状（扁平的影响， Anhedonia，言语稀少）和认知症状（执行功能，注意力和工作缺陷 内存（WM））。虽然可以用抗精神病药有效地管理阳性症状 负面和认知症状的治疗方法。 精神分裂症患者的最新宠物成像已经证实存在皮质多巴胺（DA）赤字 在DA释放药物苯丙胺（AMPH）的挑战之后。皮质DA的这种赤字长期以来一直是 被认为在精神分裂症的负面和认知症状的病理学中起着至关重要的作用，包括 Wm的赤字。由于缺乏研究神经传递的工具，并在 体内，这种赤字的本质尚未确定。 为了通过单个突触分辨率在体内研究DA神经传递，我们优化了一种新型工具 用于小鼠的体内多光子成像。荧光假神经递质（FFN）是荧光底物 对于DA转运蛋白（DAT），去甲肾上腺素转运蛋白（NET）和囊泡单胺转运蛋白 （VMAT），将其置于轴突的突触前胸子中，然后将其加载到 突触前囊泡。 FFN先前已用于急性脑切片实验以允许测定 但是，在突触释放的动力学中，它们在体内的使用是未发表的应用。我们使用了FFN 在体内图像Catecholamine神经传递。对于这个项目，我们将使用多霍顿 在FFN和GCAMP6F的体内成像，以记录从突触前中皮层终端中释放的成像 在AMPH诱导的电诱发的WT和精神分裂症模型的WT和精神分裂症模型的内侧前额叶皮层， 和自发释放以及WM任务。 该提案实现了一种新的方法，可以检查WT中的DA释放和两个小鼠模型 精神分裂症可在AMPH诱导的释放和 WM的任务。阐明精神分裂症小鼠模型中DA缺陷的机制可能会提供 精神分裂症患者发生的变化的关键翻译信息，可能会揭示新的目标 协助未来的治疗策略。