Abstract
Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored.
Highlights
Close to 1.6 million new cases of cancer [1] and 64,530 primary brain tumors are expected to be diagnosed in the United States in 2011 [2]
Since our results indicated that hypoxia can reverse learning deficits induced by whole brain radiation therapy (WBRT), we assessed whether the hypoxiainduced learning improvements are maintained after animals are returned to normal ambient oxygen levels (Figure 6A)
Our results indicate that WBRT induces an early, transient decline in contextual learning and memory, impairments in working memory, and a progressive deterioration of spatial learning in mice
Summary
Close to 1.6 million new cases of cancer [1] and 64,530 primary brain tumors are expected to be diagnosed in the United States in 2011 [2]. The most common form of treatment for metastatic or primary tumors located in brain regions that are difficult to surgically remove continues to be whole brain radiation therapy (WBRT) [3]. This treatment regimen is effective in eliminating tumors, damage to normal brain tissue is inevitable. The specific etiology for the deficits in learning and memory have not been established, previous studies suggest that decreased neurogenesis [9], increases in inflammatory cytokines [10], degradation of extracellular matrix [11] and/or alterations in synaptic morphology [8] may contribute to impaired CNS function. Much research remains to be performed, these studies, and others, suggest that WBRT affects multiple pathways and cell types within the CNS leading to a decline in learning and memory
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