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

Area of Science:

• Neuroscience
• Developmental Biology
• Oncology

Background:

• Cranial radiation therapy (CRT) is vital for pediatric brain tumors but causes cognitive deficits by damaging healthy brain tissue.
• Existing animal models often use visual tasks and lack sex comparisons, overlooking potential sex-specific effects of CRT.
• Olfaction, a crucial sensory modality, and its associated cognitive functions, like recognition memory, are understudied in the context of pediatric CRT.

Purpose of the Study:

• To investigate the long-term cognitive effects of CRT using an olfactory-based task in a preclinical model.
• To compare the impact of CRT on cognitive function between male and female mice.
• To assess the structural brain damage and olfactory neurogenesis following CRT.

Main Methods:

• Utilized the novel odor recognition (NOdorR) task with social odors to assess recognition memory in male and female mice post-CRT.
• Assessed olfactory abilities and discrimination of social/non-social odors acutely and 3 months after CRT.
• Conducted magnetic resonance imaging (MRI) and histology to evaluate long-term structural damage and olfactory neurogenesis.

Main Results:

• Long-term impairment in odor recognition memory was observed, but not acutely, suggesting a delayed onset of cognitive deficits.
• Irradiated adult males showed significantly impaired odor recognition memory compared to controls, while females' memory was estrus stage-dependent.
• Histology revealed reduced olfactory neurogenesis, and MRI showed decreased brain volumes, with specific damage to social odor processing regions (amygdala, piriform cortex) in males.

Conclusions:

• Olfactory recognition memory is a sensitive measure for detecting long-term cognitive impairment after CRT, with delayed onset.
• Significant sex differences exist in CRT-induced cognitive deficits, with males exhibiting greater vulnerability in social odor recognition memory.
• CRT causes widespread brain volume reduction and neurogenesis damage, impacting specific social processing regions, particularly in males.