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）是公认的晚期神经精神疾病出现的风险因素。这些障碍的特征在于多巴胺能功能亢进，并且包括精神分裂症、自闭症、注意力缺陷多动障碍（ADHD）、图雷特综合征（TS）和强迫症（OCD）。然而，子宫内并发症是难以量化的，目前还没有生物标志物来识别个体的发展神经精神障碍，由于子宫内并发症的脆弱性增加。为了建立重要的新的生物标志物，我们将结合联合收割机非侵入性纵向在体内1H磁共振成像（MRI）和磁共振波谱（MRS），在体外1H核磁共振（NMR）波谱，免疫组织化学和行为研究出生后大鼠暴露于控制围产期窒息。采用纵向研究方法，对单个受试者在出生后1、4、8周的纹状体、海马和前额叶皮层进行MRS分析。将分析与宫内并发症相关的预测出生后神经和行为变化相关的结果，包括酪氨酸羟化酶（TH），多巴胺（DA）通路中的主要代谢物，以及与高多巴胺能状态有关的认知，情感和社会行为。在横断面研究中，我们将进行相关的活体MRS和体外NMR研究.将进行药理学操作以改变神经代谢物，并比较两种技术的所得光谱。这些综合性研究将开辟新的领域，提供重要的，必要的验证和扩展的非侵入性MRS应用到小动物成像研究涉及宫内并发症。这些结果将为导致神经精神功能障碍出现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，这些生物标志物将导致早期诊断和干预策略的制定。该提案涉及全球范围内与儿童健康和福利的重要问题相关的问题，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和神经发育障碍的出现之间的联系机制。结合影像学、分子生物学、神经化学、生理学和行为学方法的综合应用中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，并有助于为产前诊断和干预、产后护理和建立发育计划指定翻译目标。

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.