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: 10012940
• 负责人: ZHIYI ZUO
• 金额: $ 33.51万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012940
• 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; 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.

美国每年有数百万儿童接受麻醉和手术。最近的研究 表明麻醉和手术可能会导致发育中的大脑的认知障碍。这 这一发现引起了极大的关注。能够识别可能有发育不良风险的儿童 并为那些有选择性的儿童提供干预，有必要有 手术所致认知功能障碍的生物标志物。我们的初步研究表明，手术对 出生后第7天(P7)大鼠的学习和记忆能力受损。手术也减少了神经胶质细胞系- 脑组织和尿液中的衍生神经营养因子。脑室注射GDNF 减轻手术引起的学习和记忆障碍。脑室注射安慰剂 抗GDNF抗体对正常大鼠的学习记忆能力有损害作用。因为神经炎是一种 成人手术后认知功能障碍的早期神经病理过程、神经发生和 树突状分枝对学习和记忆很重要，GDNF抑制神经炎症 并促进神经发生和树突的树枝形成，我们假设手术减少了GDNF， 这会加重神经炎症，减少神经发生和树突树枝形成，从而 导致学习和记忆障碍，尿液中GDNF减少是 麻醉和手术导致的学习和记忆障碍。在这个项目中，我们将确定 是否：1)麻醉和手术减少幼年大鼠的生长因子，包括GDNF；2)减少 尿液中GDNF的存在预示着手术后学习和记忆的损害；以及3)GDNF的减少 导致神经炎症加重，神经发生和树突发育受损 大脑。P7大鼠在七氟醚麻醉下行右颈动脉探查或剖腹手术 麻醉。学习和记忆将通过巴恩斯迷宫和恐惧条件反射进行评估。大脑会 用于生化检查和脑细胞发生及树突状细胞测定 树木化。尿液中的GDNF水平将被量化。接收器工作特性(ROC)曲线将 用于评估尿GDNF水平作为手术诱导的生物标志物的价值 学习和记忆障碍。这些研究将确定手术诱导的可能生物标记物。 新生大鼠学习记忆障碍的研究。他们还将揭示GDNF对 神经炎症与发育期脑组织结构的长期变化。