Abstract
Although an effective treatment for pediatric brain tumors, cranial radiation therapy (CRT) damages surrounding healthy tissue, thereby disrupting brain development. Animal models of pediatric CRT have primarily relied on visual tasks to assess cognitive impairment. Moreover, there has been a lack of sex comparisons as most research on the cognitive effects of pediatric CRT does not include females. Therefore, we utilized olfaction, an ethologically relevant sensory modality, to assess cognitive impairment in an animal model of CRT that included both male and female mice. Specifically, we used the novel odor recognition (NOdorR) task with social odors to test recognition memory, a cognitive parameter that has been associated with olfactory neurogenesis, a form of cellular plasticity damaged by CRT. In addition to odor recognition memory, olfactory ability or discrimination of non-social and social odors were assessed both acutely and 3 months after CRT. Magnetic resonance imaging (MRI) and histology were performed after behavioral testing to assess long-term damage by CRT. Long-term but not acute radiation-induced impairment in odor recognition memory was observed, consistent with delayed onset of cognitive impairment in human patients. Males showed greater exploration of social odors than females, but general exploration was not affected by irradiation. However, irradiated males had impaired odor recognition memory in adulthood, compared to non-irradiated males (or simply male controls). Female olfactory recognition memory, in contrast, was dependent on estrus stage. CRT damage was demonstrated by (1) histological evaluation of olfactory neurogenesis, which suggested a reduction in CRT versus control, and (2) imaging analyses which showed that the majority of brain regions were reduced in volume by CRT. Specifically, two regions involved in social odor processing (amygdala and piriform cortex) were damaged by cranial irradiation in males but not females, paralleling olfactory recognition findings.
Highlights
Cranial radiation therapy is a successful treatment for cancer of the central nervous system,the second leading type of cancer in children (American Cancer Society, 2012)
In the last two decades, pre-clinical or animal models of cranial radiation therapy (CRT) have largely focused on measuring cognitive changes associated with impairment in hippocampal cell proliferation and neurogenesis (Raber et al, 2004; Rola et al, 2004; WongGoodrich et al, 2010; Roughton et al, 2012), a cellular impairment that persists after CRT (Rodgers et al, 2016)
The goal of this study was to determine whether CRT during development induces olfactory memory impairment in male and female mice
Summary
Cranial radiation therapy is a successful treatment for cancer of the central nervous system,the second leading type of cancer in children (American Cancer Society, 2012). Because we (Rodgers et al, 2016) and others (Raber et al, 2004; Rola et al, 2004) have found reduced hippocampal neurogenesis months after cranial irradiation, DCX was used in this study to demonstrate a similar late effect in a neurogenic region (SVZ to RMS) associated with the NOdorR task (Gil-Perotin et al, 2011). There are only a few reported sex differences in behavioral outcomes after CRT which have generally indicated greater cognitive impairment in female rodents (Yazlovitskaya et al, 2006; Roughton et al, 2012) though this is influenced by dose of radiation (Villasana et al, 2010). Histological assessment was performed to evaluate neurogenesis impairment along the RMS, an impairment associated with NOdorR (Gil-Perotin et al, 2011)
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