title: A mouse model replicating hippocampal sparing cranial irradiation in humans: A tool for identifying new strategies to limit neurocognitive decline.
abstract: Cancer patients undergoing cranial irradiation are at risk of developing neurocognitive impairments. Recent evidence suggests that radiation-induced injury to the hippocampi could play an important role in this cognitive decline. As a tool for studying the mechanisms of hippocampal-dependent cognitive decline, we developed a mouse model replicating the results of the recent clinical RTOG 0933 study of hippocampal sparing whole-brain irradiation. We irradiated 16-week-old female C57BL/6J mice to a single dose of 10 Gy using either whole-brain irradiation (WBRT) or hippocampal sparing irradiation (HSI). These animals, as well as sham-irradiated controls, were subjected to behavioral/cognitive assessments distinguishing between hippocampal-dependent and hippocampal-independent functions. Irradiation was well tolerated by all animals and only limited cell death of proliferating cells was found within the generative zones. Animals exposed to WBRT showed significant deficits compared to sham-irradiated controls in the hippocampal-dependent behavioral task. In contrast, HSI mice did not perform significantly different from sham-irradiated mice (control group) and performed significantly better when compared to WBRT mice. This is consistent with the results from the RTOG 0933 clinical trial, and as such this animal model could prove a helpful tool for exploring new strategies for mitigating cognitive decline in cancer patients receiving cranial irradiation.
authors.affiliation: Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY 10461, USA.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Tomé
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Şölen
authors.initials: Ş
authors.lastname: Gökhan
authors.affiliation: Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY 10461, USA.
authors.forename: N Patrik
authors.initials: NP
authors.lastname: Brodin
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gulinello
authors.affiliation: Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY 10461, USA.
authors.forename: John
authors.initials: J
authors.lastname: Heard
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Mehler
authors.affiliation: Institute for Onco-Physics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY 10461, USA.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D016371:Cranial Irradiation / Q000009:adverse effects / Q000379:methods; D005260:Female; D006624:Hippocampus; D006801:Humans; D051379:Mice; D023421:Models, Animal; D058953:Neural Stem Cells / Q000378:metabolism / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects; D059351:Organ Sparing Treatments; D011829:Radiation Dosage; D065852:Spatial Memory / Q000528:radiation effects; D013997:Time Factors