Towards an Integrated Understanding of Neurotransmitter Dysfunction in Schizophrenia: a Multimodal MRI Study

全面了解精神分裂症神经递质功能障碍：多模态 MRI 研究

基本信息

批准号：
10462595
负责人：
Jodi Jay Weinstein
金额：
$ 22.76万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-09 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462595
关键词：
Age Anatomy Animal Model Anterior Antipsychotic Agents Attention Back Base of the Brain Biological Blood Brain Cerebrum Clinical Corpus striatum structure Data Development Disease Dopamine Ensure Environment Equilibrium Ethnic Origin Fostering Functional disorder Funding Glutamates Glutamine Goals Hippocampus (Brain)Human Hyperactivity Imaging Techniques Individual Interneuron function Interneurons Lead Link Literature Longevity Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Medical Methodology Methods Methylazoxymethanol Acetate Midbrain structure Modeling Molecular Multimodal Imaging Neurobiology Neurons Neuropsychology Neurosciences Neurotransmitters Output Participant Parvalbumins Pathology Patients Pharmaceutical Preparations Physicians Physiologic pulse Positron-Emission Tomography Prevention Protocols documentation Proxy Psychotic Disorders Research Research Personnel Research Training Resources Rodent Rodent Model Schizophrenia Scientist Severities Signal Transduction Socioeconomic Status Substantia nigra structure Symptoms System Testing Tobacco use Training Training Programs United States National Institutes of Health Ventral Striatum clinical high risk for psychosis contrast enhanced dopamine system dopaminergic neuron drug development gamma-Aminobutyric Acid imaging modality imaging study in vivo in vivo imaging indexing individual patient innovation magnetic field multimodality neural circuit neurochemistry neuroimaging neuromelanin new therapeutic target novel pre-clinical prenatal recruit relating to nervous system responsible research conduct sex therapeutic evaluation

项目摘要

PROJECT SUMMARY / ABSTRACT Schizophrenia is among the most severe and burdensome medical conditions worldwide, yet the brain alterations that lead to the symptoms of schizophrenia remain unknown. This K23 application presents a research and training program that will support the applicant on a path towards becoming an NIH-‐funded independent investigator focused on understanding the neurobiology of schizophrenia and related psychotic disorders. The activities in this application build on the candidate’s prior training and are set in a resource-‐rich environment that will foster her development of expertise in 1) application of MRS and advanced MRI neuroimaging methodologies; 2) physician-‐scientist approaches to studying pathophysiology in patients with schizophrenia; 3) neurocircuitry and systems neuroscience perspectives on hippocampus pathology in psychotic disorders; and 4) responsible conduct of research. The overarching goal of the research to be carried out in this application is to take findings from animal models of schizophrenia, which were motivated by original research in patients with the disorder, back to the clinical setting in order to determine whether the brain circuit alterations observed in the animal models are observable in human patients. Specifically, findings in the prenatal methylazoxymethanol acetate (MAM) rodent model, which was developed to model the alterations in dopamine function seen in patients with schizophrenia, suggest hyperactivity of the ventral (anterior) hippocampus may increase its glutamatergic output to the ventral striatum and lead, via ventral pallidal and other GABAergic projections to the ventral midbrain, to disinhibited firing of dopamine neurons. In addition, a convergence of several post mortem and in vivo imaging findings in patients suggests that abnormal GABAergic activity in the hippocampus may further compound hippocampal glutamatergic overdrive. This project will directly test the relationships among these neurochemical alterations in individual medication-‐free patients with schizophrenia using sophisticated magnetic resonance imaging methods. If this non-‐invasive, multimodal imaging paradigm provides evidence to relate hippocampal GABA and glutamate abnormalities to dopamine system dysfunction in patients with schizophrenia, it would have important implications for our understanding of the brain bases of schizophrenia, and would generate a novel multimodal imaging paradigm for testing new molecular, anatomical, and circuit-‐modulating targets for treatment of this devastating illness.

项目摘要/摘要精神分裂症是全球最严重，最繁重的医疗状况之一，但大脑的改变导致精神分裂症的症状仍然未知。该K23应用程序提出了研究和培训计划在路径方向上支持该应用程序的计划成为NIH资金资助的独立研究者了解精神分裂症和相关精神病的神经生物学。此应用程序中的活动建立在候选人之前的培训的基础上，并设置在资源 - 丰富的环境中，这将促进她的发展 1）MRS和高级MRI神经影像学方法的专业知识； 2）医师 - 科学家的方法研究精神分裂症患者的病理生理学； 3）神经通路和系统神经科学观点心理疾病中的海马病理学； 4）负责任的研究。总体目标在此应用中要进行的研究是从精神分裂症的动物模型中获取的结果，由对该疾病患者的原始研究的动机，回到临床环境，以确定是否是否在动物模型中观察到的脑回路改变在人类患者中可以观察到。具体而言，在产前甲基二甲醇乙酸盐（MAM）啮齿动物模型，该模型的开发是为了模拟改变的改变在精神分裂症患者中观察到的多巴胺功能表明腹侧（前）海马的活跃性可能通过腹侧苍白球和其他Gabaergic投影将其谷氨酸能输出提高到腹侧纹状体和铅腹中间脑，以抑制多巴胺神经元的发射。另外，几个验尸的收敛性和患者的体内成像发现表明海马中的GABA能活性异常可能会进一步复合海马谷氨酸能超速驾驶。该项目将直接测试这些关系单个药物的神经化学改变 - 使用社会化磁性的无精神分裂症患者共振成像方法。如果这种无创的多模式成像范式为相关海马提供了证据精神分裂症患者的多巴胺系统功能障碍的GABA和谷氨酸异常对我们对精神分裂症大脑碱基的理解的重要意义，并会产生一种新颖用于测试新分子，解剖和电路的多模式成像范式 - 调节靶标这种毁灭性的疾病。