Ultra-Resolution Imaging of Brain Circuitry and its Development in Mental Health

描述（由申请人提供）：四分之一的美国成年人在给定的一年中经历过心理健康障碍。大约有240万美国人患有精神分裂症。越来越多的证据表明，精神分裂症可能起源于早期神经发育，涉及异常的神经元回路。然而，精神分裂症最早要到成年早期才能被诊断出来，那时神经发育的最快阶段已经完成。缺乏早期风险评估严重限制了我们对疾病发展轨迹的了解，从而阻碍了在症状出现之前进行更有效的干预。该项目将开发一种新的非侵入性MRI技术，该技术将提供必要的灵敏度和分辨率（10微米），以检测与神经元回路相关的潜在发育异常。我们的初步研究表明，与最先进的MRI技术相比，其灵敏度和分辨率显著提高。我们将进一步发展这项新技术，并确定其提高灵敏度的分子基础。我们将在精神分裂症的转基因小鼠模型上测试该技术，并研究其在症状发生前检测神经元回路异常的能力。特别是，我们将确定新的图像对比度和髓鞘形成和突触与皮质纹状体和皮质海马连接异常之间的关系。这项研究的基本原理是，拟议的多学科成像遗传学研究将有助于我们更好地了解疾病的遗传和发育组成部分，在行为症状出现之前检测电路异常，并最终指导治疗策略。

DESCRIPTION (provided by applicant): One in four adult Americans experiences a mental health disorder in a given year. About 2.4 million Americans live with schizophrenia. There are considerable and growing evidences suggesting schizophrenia may originate from early neurodevelopment involving abnormal neuronal circuits. However, schizophrenia still cannot be diagnosed until young adulthood at the earliest when the most rapid phase of neurodevelopment has already completed. The lack of earlier risk assessment has severely limited our understanding of the developmental trajectory of the disease thus preventing more effective intervention before symptom onset. This project will develop a novel non-invasive MRI technique that will provide the necessary sensitivity and resolution (10 micron) to detect potential developmental abnormalities associated with neuronal circuits. Our preliminary studies have demonstrated a markedly improved sensitivity and resolution compared to state-of- the-art MRI techniques. We will further develop this novel technique and determine its molecular basis of the improved sensitivity. We will test the technique on transgenic mouse models of schizophrenia and investigate its ability to detect abnormalities in neuronal circuits before symptoms occur. In particular, we will determine the relationship between the new image contrast and abnormalities of myelination and synapses associated with corticostriatal and corticohippocampal connectivity. The rationale of the research is that the proposed multidisciplinary imaging-genetics study would help us to better understand the genetic and developmental components of the disease, to detect circuit abnormalities before behavioral symptoms, and to eventually guide treatment strategies.