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

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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.