基于脑网络研究脑内长期乙醛蓄积诱发脑损伤的多层次表征

Long-term excessive accumulation of acetaldehyde should cause disorder of brain function. It is one of the important factors leading to neuropsychiatric disorders, and gives serious harm and heavy burden for community and family. It is important to study the neural injury induced by long-term excess of acetaldehyde accumulation based on the brain network. However, the technology of whole brain resting state analysis of rodents is not yet mature, and there are few studies on neural injury caused by excess acetaldehyde accumulation with multi-level analysis approaches based on brain network. At first, applicants would establish a new set of tool for analysis of the whole brain resting state network for rodents. The project used alcohol preferring rats to establish the long-term acetaldehyde accumulation animal models ('aldehyde reaction' model - intervention of disulfiram and long-term over-drinking model - 30% alcohol training). The animal behavior method was used to evaluate the impact of acetaldehyde accumulation on the cognitive behavior; and the whole brain rest state analysis was used to study the change of the functional network, and systemically screening the key brain regions associated with neural injury. Then the structural input and output networks of the key brain regions were mapped using various neurotropic virus circuitry tracing tools. With the combination of the technologies of proteomics and microdialysis, the effects of long-term excessive alcohol on neural injury were multi-levelly characterized. Based on the brain network, this project gradually revealed the effects of long-term excessive acetaldehyde accumulation on the neural injury, it should provide a scientific evidences for prevention and treatment of neuropsychiatric diseases caused by alcohol abuse and alcohol addiction.

脑内长期过量乙醛蓄积会引起脑功能网络紊乱，是导致神经精神疾病的重要因素之一，给社会和家庭带来严重危害和沉重负担。基于脑网络水平研究长期过量乙醛蓄积诱发神经损伤具有重要意义。由于啮齿类动物全脑静息态技术尚不成熟，基于脑网络多层次分析过量乙醛蓄积导致的神经损伤研究较少。申请者先建立一套普适性用于啮齿类动物全脑静息态网络数据分析的新工具。以酒精偏好大鼠为对象建立长期乙醛蓄积动物模型（“醛反应”模型—戒酒硫干预和长期过量饮酒模型—30%酒精培训），利用动物行为研究其对认知行为的影响；全脑静息态技术研究全脑功能网络变化，确定与神经损伤相关的关键靶点；嗜神经病毒环路标记技术确定该靶点的输入输出网络，有机整合蛋白质组学和微透析技术对长期过量饮酒诱发神经损伤进行多层次表征。该项目基于脑网络逐步揭示长期过量乙醛蓄积诱发神经损伤，为酗酒和酒精成瘾导致神经精神类疾病的预防和治疗提供可借鉴的科学依据。

长期过量饮酒或酒精成瘾会诱发大脑内过量乙醛蓄积，进而引起脑功能网络紊乱，是导致神经精神疾病的重要因素之一，给社会和家庭带来严重危害和沉重负担。因此，基于脑网络水平研究长期过量饮酒或酒精成瘾诱发脑损伤具有重要意义。然而由于啮齿类动物全脑静息态技术尚不成熟，基于脑网络水平多层次分析过量乙醛蓄积导致的神经损伤研究较少。因此，本项目首先建立一系列普适性用于啮齿类动物全脑静息态网络数据分析的新工具，用于新型清醒动物模型大脑静息态网络和功能网络的分析，并拓展应用于酒精成瘾诱发脑损伤，麻醉机制与睡眠剥夺诱发脑损伤及其相关机制的探索；另外，项目优化了现有的代谢动力学策略，成功应用于研究脑出血诱发脑功能紊乱及脊髓损伤诱发脑紊乱的研究。最终项目基于上述建立的脑网络研究新技术和改善的代谢动力学研究新方案（技术优于微透析，可解析神经递质的变化速率），整合动物行为和代谢组学技术系统研究青少年大鼠长期过量饮酒诱发的脑损伤、酒精成瘾大鼠在成瘾过程中大脑功能网络的变化以及D-青霉胺暴露研究长期过量乙醛暴露对大鼠脑结构和功能的影响。该项目基于脑网络技术整合多种长期过量饮酒动物模型逐步揭示过量饮酒诱发的脑损伤，为酗酒和酒精成瘾导致神经精神类疾病的预防和治疗提供可借鉴的科学依据。