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.

项目概要 精神分裂症是一种使人终生衰弱的精神疾病，全球患病率为 1%。它的特点是 阳性症状（妄想、幻觉、思维混乱）、阴性症状（情绪低落、 快感缺失、言语缺乏）和认知症状（执行功能、注意力和工作方面的缺陷） 内存（WM））。虽然抗精神病药物可以有效控制阳性症状，但目前还没有 消极症状和认知症状的治疗。 最近精神分裂症患者的 PET 成像证实存在皮质多巴胺 (DA) 缺陷 受到 DA 释放药物安非他明 (AMPH) 的挑战后。皮质 DA 的这种缺陷长期以来一直存在 人们认为在精神分裂症的阴性和认知症状的病理学中发挥着关键作用，包括 WM 的赤字。由于缺乏研究单突触分辨率神经传递的工具 vivo，这种缺陷的性质尚未确定。 为了以单突触分辨率研究体内 DA 神经传递，我们优化了一种新工具 用于小鼠体内多光子成像。荧光假神经递质 (FFN) 是荧光底物 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），被吸收到轴突的突触前纽扣中，随后被加载到 突触前小泡。 FFN 之前曾用于急性脑切片实验，以进行确定 然而，它们在体内的应用尚未发表。我们已经使用了 FFN 对体内皮质中的儿茶酚胺神经传递进行成像。对于这个项目，我们将利用多光子 FFN 和 GCaMP6f 的体内成像，记录突触前中皮层末梢的 DA 释放 AMPH 诱导电诱发期间 WT 和精神分裂症模型小鼠的内侧前额皮质， 以及自发释放和 WM 任务期间。 该提案实施了一种新方法来检查 WT 和两种小鼠模型体内 DA 释放 精神分裂症提供了 DA 在 AMPH 诱导释放和释放过程中体内动力学的首次测量 WM 的一项任务。阐明精神分裂症小鼠模型中 DA 缺陷的机制可能提供 精神分裂症患者发生的变化的关键转化信息可能会揭示新的目标 帮助未来的治疗策略。