Learning and Activity after Irradiation of the Young Mouse Brain Analyzed in Adulthood Using Unbiased Monitoring in a Home Cage Environment Niklas Karlsson, a,1 Marie Kalm, a,1 Marie K. L. Nilsson, b Carina Mallard, b Thomas Bjo ¨ rk-Eriksson c and Klas Blomgren a,d,2 a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, SE 405 30, Sweden; b Institute of Neuroscience and Physiology, University of Gothenburg, SE 405 30, Sweden; c Department of Oncology, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden; and d Department of Pediatric Oncology, The Queen Silvia Children’s Hospital, SE 416 85 Gothenburg, Sweden Karlsson, N., Kalm, M., Nilsson, M. K. L., Mallard, C., Bjo ¨rk-Eriksson, T. and Blomgren, K. Learning and Activity after Irradiation of the Young Mouse Brain Analyzed in Adulthood Using Unbiased Monitoring in a Home Cage Environment. Radiat. Res. 175, 336–346 (2011). Cranial radiotherapy during the treatment of pediatric malignancies may cause adverse late effects. It is important to find methods to assess the functional effects of ionizing radiation in animal models and to evaluate the possible ameliorating effects of preventive or reparative treatment strategies. We investigated the long-term effects of a single 8-Gy radiation dose to the brains of 14-day-old mice. Activity and learning were evaluated in adulthood using open field and trace fear conditioning (TFC). These established methods were compared with the novel IntelliCage platform, which enables unbiased analysis of both activity and learning over time in a home cage environment. Neither activity nor learning was changed after irradiation, as judged by the open field and TFC analyses. The IntelliCage, however, revealed both altered activity and learning impairment after irradiation. Place learning and reversal learning were both impaired in the IntelliCage 3 months after irradiation. These results indicate that activity and learning should be assessed using multiple methods and that unbiased analysis over time in a home cage environment may offer advantages in the detection of subtle radiation-induced effects on the young brain. g 2011 by Radiation Research Society INTRODUCTION Brain tumors constitute approximately one-third of all childhood neoplasms, and survival rates after treatment of primary or metastatic tumors located within or close to the central nervous system (CNS) have increased over the last decades (1). Despite improved techniques in neuro- surgery and advances in chemotherapy, radiation therapy remains an essential treatment modality for malignant brain tumors as well as for CNS involvement of leukemia and lymphoma. However, radiation therapy is also one of the major causes of long-term complications seen in survivors of pediatric brain tumors. Intellectual and memory impairments as well as perturbed growth and puberty are some of the late effects seen after radiation therapy (2–6). These impairments have been shown to be more severe in children younger than 3 years of age at the time of radiation therapy (7–9). Radiation-induced damage to the brain involves apop- tosis and loss of cells in the surrounding healthy brain tissue and has been reported in the immature, juvenile and adult rat brain (10–15). A number of studies have investigated the molecular mechanisms of injury to healthy tissue, aiming to develop novel strategies to protect the brain after irradiation. Behavioral changes after irradia- tion to the brain have previously been studied using, e.g., the Morris water maze and open field (16, 17). To our knowledge, there are no studies where irradiated animals have been studied in their home cage environment, with minimal handling and disturbance, over longer periods. It is reasonable to assume that testing in a social context over time would reveal more subtle changes not apparent when animals are tested individually. The IntelliCage platform was designed to minimize interaction between the experimenter and the animals and is therefore an interesting tool for the assessment of functional outcome in any brain injury paradigm. The aim of this study was to investigate the long-term effects of a single dose of radiation to the young brain by using two established methods, one for motor activity (open field) and one for learning (trace fear conditioning), and then compare these results with those obtained using the IntelliCage system. MATERIALS AND METHODS Animals C57BL/6 male mice were used (Charles River Laboratories, Sulzfeld, Germany). The animals were kept on a 12-h light cycle. 1 These authors contributed equally. 2 Address for correspondence: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Box 432, SE 405 30 Gothenburg, Sweden; e-mail: klas.blomgren@neuro.gu.se. RADIATION RESEARCH 175, 336–346 (2011) 0033-7587/11 $15.00 g 2011 by Radiation Research Society. All rights of reproduction in any form reserved. DOI: 10.1667/RR2231.1 336