Application of MR Spectroscopy Techniques to Animal Models of Obstetric Complicat

描述（由申请人提供）：宫内并发症（即围产期窒息、产前免疫激活和剖宫产）是后来出现神经精神疾病的公认危险因素。这些疾病以高多巴胺能功能为特征，包括精神分裂症、自闭症、注意缺陷多动障碍（ADHD）、妥瑞氏综合征（TS）和强迫症（OCD）。然而，宫内并发症很难量化，目前还没有生物标志物用于识别因宫内并发症而易患神经精神疾病的个体。为了建立重要的新生物标志物，我们将结合无创体内纵向1H磁共振成像（MRI）和磁共振光谱（MRS），体外1H核磁共振（NMR）光谱，免疫组织化学和产后大鼠暴露于控制围产期窒息后的行为研究。采用纵向方法，通过在出生后3个关键年龄（1、4和8周）应用MRS获取并分析单个受试者纹状体、海马和前额叶皮层的神经代谢谱。结果将分析与宫内并发症相关的预测产后神经和行为变化，包括酪氨酸羟化酶（TH），多巴胺（DA）途径的主要代谢物，以及与高多巴胺能状态相关的认知、情绪和社会行为。在横断面研究中，我们将进行相关的体内核磁共振和体外核磁共振研究。将进行药理学操作来改变神经代谢物，并将两种技术的结果光谱进行比较。这些综合研究将通过为涉及宫内并发症的小动物成像研究提供重要的、必要的验证和扩展非侵入性MRS应用，从而开辟新的领域。该结果将为神经精神功能障碍的发展途径的重要新研究奠定坚实的基础，并且对于识别非侵入性生物标志物至关重要，这将导致早期诊断和干预策略的发展。该提案涉及与儿童健康和福利的重要问题相关的全球问题，具有重要的儿科和神经精神影响。我们的长期目标是确定宫内事件与神经发育障碍出现的联系机制。结合影像学、分子、神经化学、生理和行为等多种方法提出的实验将为识别神经精神功能障碍的生物标志物奠定重要基础，并有助于确定产前诊断和干预、产后护理和建立发展计划的翻译目标。

DESCRIPTION (provided by applicant): Intrauterine complications (i.e, perinatal asphyxia, prenatal immune activation and cesarean delivery) are a recognized risk factor for the emergence of later neuropsychiatric disorders. These disorders are characterized by hyperdopaminergic function, and include schizophrenia, autism, Attention Deficit Hyperactivity Disorder (ADHD), Tourette's Syndrome (TS) and Obsessive Compulsive Disorder (OCD). However, intrauterine complications are difficult to quantify, and there presently exist no biomarkers for identification of individuals with increased vulnerability for developing neuropsychiatric disorders due to intrauterine complications. To establish important new biomarkers, we will combine non-invasive longitudinal in vivo 1H Magnetic Resonance Imaging (MRI) and MR Spectroscopy (MRS), in vitro 1H Nuclear Magnetic Resonance (NMR) Spectroscopy, immunohistochemistry and behavioral studies of postnatal rats following exposure to controlled perinatal asphyxia. Using a longitudinal approach, neurometabolic spectra will be acquired and analyzed in the striatum, hippocampus and prefrontal cortex of single subjects by applying MRS at three key postnatal ages (1,4 and 8 weeks). Results will be analyzed in relation to predicted postnatal neural and behavioral changes associated with intrauterine complications, including Tyrosine Hydroxylase (TH), a major metabolite in the dopamine (DA) pathway, and cognitive, emotional and social behaviors implicated in hyperdopaminergic states. In cross- sectional studies, we will perform correlative in vivo MRS and in vitro NMR studies. Pharmacological manipulations will be performed to alter neurometabolites, and the resulting spectra compared for the two technique. These integrative studies will break new ground by providing important, necessary validation and extension of non-invasive MRS applications to small animal imaging studies involving intrauterine complications. The results will establish a solid basis for important new studies of developmental pathways leading to the emergence of neuropsychiatric dysfunction, and are vital for identification of non-invasive biomarkers that will lead to early diagnosis and the development of intervention strategies. This proposal addresses issues that are globally relevant to vital problems of child health and welfare with important pediatric and neuropsychiatric implications. Our long-term goal is to identify the mechanisms linking intrauterine events and the emergence of neurodevelopmental disorders. The experiments proposed in this integrative application combining imaging, molecular, neurochemical, physiological and behavioral approaches will lay important groundwork for identification of biomarkers of neuropsychiatric dysfunction and help specify translational goals for prenatal diagnosis and intervention, postnatal care and the establishment of developmental programs.