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、产前免疫激活和剖腹产)是后来出现神经精神疾病的公认危险因素。这些疾病的特点是多巴胺能功能亢进，包括精神分裂症、自闭症、注意缺陷多动障碍(ADHD)、抽动症(TS)和强迫症(OCD)。然而，宫内并发症很难量化，目前还没有生物标记物来鉴定因宫内并发症而导致神经精神障碍易感性增加的个体。为了建立重要的新的生物标志物，我们将结合无创性的体内纵向1H磁共振成像(MRI)和磁共振波谱(MRS)、体外1H核磁共振波谱、免疫组织化学和围产期控制性窒息后出生大鼠的行为研究。采用纵向研究方法，在出生后1周、4周和8周对单个受试者的纹状体、海马体和前额叶皮质进行磁共振波谱分析。结果将根据与宫内并发症相关的出生后神经和行为变化进行分析，包括多巴胺(DA)途径中的主要代谢物酪氨酸羟基酶(TH)，以及与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，我们将进行相关的体内MRS和体外核磁共振研究。将进行药物操作来改变神经代谢物，并对两种技术产生的光谱进行比较。这些综合性研究将通过提供重要的、必要的验证和将非侵入性MRS应用于涉及宫内并发症的小动物成像研究而开辟新的天地。这些结果将为导致神经精神障碍出现的发育途径的重要新研究奠定坚实的基础，并对识别导致早期诊断和干预策略的非侵入性生物标志物至关重要。这项提案涉及具有重要儿科和神经精神病学影响的全球儿童健康和福利重大问题。我们的长期目标是确定宫内事件与神经发育障碍出现之间的联系机制。在这一综合应用中提出的实验结合了成像、分子、神经化学、生理和行为方法，将为识别神经精神功能障碍的生物标记物奠定重要基础，并有助于为产前诊断和干预、产后护理和制定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.