Aging dependent changes in the normal brain tissue response to irradiation: New translational models of whole and focal brain irradiation

Radiation therapy is integral in the management of brain-associated cancers and is increasingly being utilized for the treatment of many functional neurological disorders. The therapeutic benefits are often accompanied by late-delayed cognitive side effects that are attributed to toxicity in healthy brain tissue. Cranial irradiation induces a dynamic neurobiological response that includes changes in neurogenesis and inflammation that are hypothesized to be functionally relevant. Important characteristics of the patient population, however, have not been modeled in the laboratory. The majority of adult patients receiving radiation therapy and developing side effects are middle-aged and older, but experimental studies have only used very young and young-adult animals. The experiments conducted for this dissertation are the first to assess the cellular response to whole brain irradiation in rodents at ages that model the adult patients treated in the clinic. Importantly, the radiation-induced chronic decrease in hippocampal neurogenesis that has been associated with late-delayed cognitive impairment in younger rodents did not occur in middle-age or older rats. Basal levels of inflammation and the radiation-induced inflammatory response measured by the density and percentage of activated microglia increased with age. A greater inflammatory response may mediate the more severe cognitive impairments seen in older patients. Additionally, a new animal model has been developed for basic scientific and translational studies of the responses of the brain to focal irradiated as used in stereotactic radiosurgery. Hippocampal irradiation in a young-adult rat with a single, 10 Gy maximum, dose in one hemisphere decreased neurogenesis and increased activated microglia in the irradiated hippocampus. Levels in the contralateral hippocampus were not different than age-matched shams. Focal irradiation of middle-aged rodents increased the density of activated microglia in both the targeted and contralateral hippocampus. The work in this thesis proves that age is an important modifier of the neurobiological response to low dose brain irradiation and that the microglial response is exacerbated in older rodents. Concomitantly, two new translational models have been developed that better approximate the clinical population treated with ionizing radiation that will aid future studies of radiation-induced brain injury and test the efficacy of interventional treatments for the clinic.