Effects of Muscular Overexpression of PGC-1alpha on Hippocampal Neurogenesis

Abstract

Effects of Muscular Overexpression of PGC-1alpha on Hippocampal Neurogenesis Jonas Bergqvist, Master Thesis in Medicine 2017, Department of Neuroscience & Physiology, Gothenburg University, Sahlgrenska Academy, Gothenburg, Sweden Radiation therapy is an important treatment modality for tumors in the central nervous system. However, ionizing radiation (IR) gives rise to long-term cognitive deficits in patients, such as intellectual and memory impairments and this is believed to be partly due to irradiation-damage on adult neurogenesis, birth of new neurons, in the dentate gyrus of the hippocampus in the brain. Studies on rodents have shown that voluntary running can restore adult hippocampal neurogenesis after IR. Further, one study have reported a potential link between exercise and adult neurogenesis through a PGC-1a/FNDC5 pathway. Here, we examine if expression of the muscle exercise gene PGC-1a contributes to beneficial effects on recovery after cranial IR in mouse using a transgenic mouse model that constitutively overexpress PGC-1a in skeletal muscle. Male animals were subjected to whole brain IR (4 Gy) at 4 months age. Animals were given daily intraperitoneal injections of BrdU (50 mg/kg) from day 3 to 8 post IR. For voluntary exercise, female animals were single housed in cages with free access to running wheels. After 5 days of acclimatization, half of the running wheels were unlocked and animals were given daily intraperitoneal injections of BrdU (50 mg/kg) for 3 consecutive days. Animals were euthanized 4 weeks after IR, or unlocking of running wheels, for immunohistochemical analysis. We did not find any changes in baseline or exercise-induced levels of neurogenesis, or difference in baseline or irradiation-reduced levels of neurogenesis. In summary, we conclude that forced muscular expression of PGC-1a does not have a beneficial effect on hippocampal neurogenesis after IR in mice. This suggests that overexpression of PGC-1a in skeletal muscle is by itself not sufficient to mimic exercise-induced recovery after IR.