Translating Chemobrain: Executive Function Impairments in Rodent Models of Chemotherapy

Abstract

Chemotherapy-induced cognitive impairment (CICI), commonly termed "chemobrain," is a measurable and clinically significant consequence of cancer treatment. Executive function (EF), a set of higher-order cognitive abilities that guide goal-directed behaviour, is particularly vulnerable. Its disruption is strongly associated with reduced psychosocial functioning and quality of life. This thesis used preclinical rodent models to characterise the nature and mechanisms of chemotherapy-related EF impairments. Chapters 2 and 3 synthesised the existing literature. Meta-analyses in Chapter 2 demonstrated selective impairments in working memory, behavioural flexibility, and problem-solving, with inhibition and attention largely preserved. These effects were consistent across species, age, treatment regimens, and time points, with stronger working memory deficits following alkylating agents and antitumour antibiotics relative to mitotic inhibitors. Chapter 3 identified oxidative stress, mitochondrial dysfunction, white matter abnormalities, and impaired neuronal plasticity as key correlates of EF impairment, particularly for working memory. Chapters 4-6 presented new experimental findings. Oxaliplatin alone did not impair working memory or reversal learning but reduced recognition memory. Combined oxaliplatin/5-fluorouracil treatment impaired set-shifting and working memory while sparing reversal learning and recognition memory, consistent with prefrontal cortex vulnerability. Doxorubicin-treated rats showed preserved physical and cognitive effort-based decision-making but exhibited persistent high-effort responding under less optimal options, suggesting subtle disruptions in behavioural flexibility and working memory. Overall, the findings demonstrate selective, domain-specific EF deficits following chemotherapy, with working memory and behavioural flexibility emerging as key intervention targets.