Glial cell line-derived neurotropic factor and postoperative cognitive impairment in young rats

胶质细胞源性神经营养因子与幼年大鼠术后认知障碍

• 批准号: 10246802
• 负责人: ZHIYI ZUO
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246802
• 关键词: Affect; Amantadine; Anesthesia procedures; Anti-Inflammatory Agents; Antibodies; Antiviral Agents; Attenuated; Biochemical; Biological Markers; Brain; Cell Line; Cells; Child; Development; Finding by Cause; General Anesthesia; Goals; Growth Factor; Harvest; Hippocampus (Brain); Impaired cognition; Impairment; Infant; Injections; Intervention; Laparotomy; Learning; Memory; Memory impairment; Mus; Neonatal; Neuroglia; Operative Surgical Procedures; Pathologic Processes; Patients; Postoperative Period; Predictive Value; Process; Property; ROC Curve; Rattus; Research; Risk; Structure; Time; Urine; Youth; adult neurogenesis; behavioral impairment; brain cell; conditioned fear; environmental enrichment for laboratory animals; neonatal mice; neurogenesis; neuroinflammation; neurotropic; postnatal; response; sevoflurane; young adult

Millions of children each year undergo anesthesia and surgery in the U.S.A. Recent studies suggest that anesthesia and surgery can cause cognitive impairment in the developing brain. This finding causes significant concern. To be able to identify children that may be at risk for developing cognitive dysfunction and to provide intervention to those selective children, it is necessary to have biomarkers for surgery-induced cognitive dysfunction. Our preliminary study showed that surgery on postnatal day 7 (P7) rats impaired their learning and memory. Surgery also decreased glial cell line- derived neurotropic factor (GDNF) in the brain and urine. Intracerebroventricular injection of GDNF attenuated surgery-induced learning and memory impairment. Intracerebroventricular injection of an anti-GDNF antibody impaired the learning and memory of control rats. Since neuroinflammation is an early neuropathological process for surgery-induced cognitive dysfunction in adults, neurogenesis and dendritic arborization are important for learning and memory, and GDNF inhibits neuroinflammation and enhances neurogenesis and dendritic arborization, we hypothesize that surgery reduces GDNF, which then heightens neuroinflammation and decreases neurogenesis and dendritic arborization, to induce learning and memory impairment and that reduction of GDNF in the urine is a biomarker for anesthesia and surgery-induced learning and memory impairment. In this project, we will determine whether: 1) anesthesia and surgery reduce growth factors including GDNF in young rats; 2) decrease of GDNF in the urine predicts learning and memory impairment after surgery; and 3) GDNF decrease leads to heightened neuroinflammation and impairment of neurogenesis and dendritic development in the brain. P7 rats will be subjected to right carotid arterial exploration or laparotomy under sevoflurane anesthesia. Learning and memory will be evaluated by Barnes maze and fear conditioning. Brains will be harvested for biochemical examination and determination of brain cell genesis and dendritic arborization. Urine GDNF levels will be quantified. Receiver operating characteristic (ROC) curves will be constructed to assess the value of using urine GDNF levels as a biomarker for surgery-induced learning and memory impairment. These studies will identify possible biomarkers for surgery-induced learning and memory impairment in the neonatal rats. They will also reveal the effects of GDNF on neuroinflammation and the long-term brain structural changes in developing brain after surgery.

在美国，每年数百万儿童接受麻醉和手术。最近的研究 表明麻醉和手术会导致发育中的大脑认知障碍。这 发现引起了重大关注。能够识别可能有发展风险的孩子 认知功能障碍并为那些有选择性的孩子提供干预，有必要拥有 手术引起的认知功能障碍的生物标志物。我们的初步研究表明 产后第7天（P7）大鼠损害了他们的学习和记忆。手术还降低了神经胶质细胞系 大脑和尿液中衍生的神经性因子（GDNF）。室内注射GDNF 减弱手术引起的学习和记忆力障碍。脑室内注射 抗GDNF抗体会损害控制大鼠的学习和记忆。由于神经炎症是 针对成人，神经发生和 树突状树皮化对于学习和记忆很重要，而GDNF抑制神经炎症 并增强了神经发生和树突状树皮化，我们假设手术降低了GDNF， 然后增强神经炎症并降低神经发生和树突状树皮化，至 诱导学习和记忆力障碍，以及尿液中GDNF的减少是一种生物标志物 麻醉和手术引起的学习和记忆力障碍。在这个项目中，我们将确定 是否：1）麻醉和手术降低生长因子，包括年轻大鼠的GDNF； 2）减少 尿液中的GDNF预测手术后的学习和记忆力障碍； 3）GDNF减少 导致神经炎症的增强以及神经发生和树突状发育的损害 大脑。 P7大鼠将在Sevoflurane下进行右颈动脉勘探或剖腹手术 麻醉。学习和记忆将通过巴恩斯迷宫和恐惧调节来评估。大脑会 收获以进行生化检查和测定脑细胞的发生和树突状 树木化。尿液GDNF水平将被量化。接收器操作特征（ROC）曲线将 构造以评估使用尿液GDNF水平作为手术诱导的生物标志物的价值 学习和记忆力障碍。这些研究将确定手术引起的生物标志物 新生大鼠的学习和记忆力障碍。他们还将揭示GDNF对 神经炎症和手术后大脑发育的长期大脑结构变化。