Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

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.

Short and Long-Term Changes in Social Odor Recognition and Plasma Cytokine Levels Following Oxygen (16O) Ion Radiation Exposure

“…Cell proliferation in the SVZ in rodents has been linked to performance on olfactory-based learning and memory tests [26,27,28] and is negatively affected by radiation exposure [28,29]. The Radiation Dose X Time Following Radiation Exposure ANOVA revealed a significant main-effect of Time Following Radiation Exposure (F(1,17) = 5.9, p = 0.032, effect size: ω 2 = 0.207).…”

“…Further, this pattern of dose- and time-dependent social recognition deficits appears to be different in female subjects, indicating a possible sex difference following radiation exposure that needs to be further examined [8,26,38,39]. For example, female mice do not develop radiation-induced social recognition deficits following the multi-ion GCR-like exposure described above [30].…”

Dose-dependent atrophy of the amygdala after radiotherapy

“…In that study, children who received whole-brain RT (WBRT) with chemotherapy had smaller amygdala volumes than those treated with chemotherapy alone, but amygdala volumes were similar in controls (patients with ALL who had not yet started treatment) and children who received chemotherapy. Pre-clinical data also implicate radiotherapy to the amygdala in changes to olfactory memory processing: a study using a mouse model of pediatric radiotherapy revealed significant reductions in diffusion tensor imaging of amygdala volume three months post-WBRT 42 . Cognitively, irradiated male mice had impaired odor-recognition memory in adulthood, compared to nonirradiated males.…”

Neuroimmunology of the female brain across the lifespan: Plasticity to psychopathology

“…However, very few cancer modelling studies have assessed the role of estrogen in these neurobehavioral results through ovariectomy, hormone replacement, or estrogen modulator treatments. One relevant study demonstrates that long-term olfactory recognition memory impairments in mice receiving cranial radiation therapy are dependent upon estrous stage (Perez et al, 2018). Cancer anorexia is also hypothesized to be influenced by sex-related hormones (Varma et al, 2001).…”