Early life environmental enrichment yields resilience to selected behavioural and brain responses to 5-fluorouracil in mice

Abstract

Chemotherapy remains the primary treatment modality for multiple cancer types, but the cytotoxicity of chemotherapeutic drugs often leads to persistent psychological disturbances that undermine daily function. Minimizing such unwanted effects is challenging in the rehabilitation/prehabilitation of cancer survivors, hence the impetus to identify modifiable external factors capable of improving the recovery process. The importance of social stimulation has been demonstrated in a mouse model showing that grouped housing lowered the likelihood of developing mood disturbance following exposure to chemotherapeutic drugs compared with isolated housing. Social impoverishment thus constitutes a risk factor, and social enrichment may be protective. However, the potential benefits of conventional environmental enrichment that entails extensive sensory and physical stimulation have remained untested in mice. Using C57BL/6 mice, we investigated this research gap by introducing environmental enrichment from an early age (at weaning) to maximize its resilience potential and delaying exposure to the common chemotherapeutic drug, 5-fluorouracil (5-FU), until adulthood (10 weeks old), which comprised six cycles of injections at 40 mg/kg/day × 5 days per fortnight. Our results showed that enriched housing nullified the elevation in anxiety behaviour and proliferation of hippocampal microglial cells caused by chronic 5-FU exposure. Enriched housing also lowered hippocampal IL-17 expression, effectively buffered against the stimulated release of IL-17 by 5-FU. These data extended the potential benefits of social engagement and an active lifestyle in easing the burdens of chemotherapy. Notwithstanding, the negative impacts of 5-FU on hippocampal neurogenesis and musculoskeletal properties were only notable in the enriched mice, suggesting that while environmental enrichment can buffer against certain psychological side effects, the enhanced adaptive plasticity may also increase the susceptibility to specific antineoplastic effects of chemotherapy.