Selective cognitive changes in a multidrug mouse model of chemotherapy-induced adverse effects

Chemotherapy has substantially improved cancer survival but is associated with adverse effects such as chemotherapy-induced cognitive impairment (CICI) and peripheral neuropathy (CIPN). Clinically relevant and reliable animal models of chemotherapy-induced neurotoxicity remain limited. We therefore investigated the behavioral and acute neurobiological effects of a clinically inspired multidrug chemotherapy regimen in female C57BL/6J mice. Following four weeks of treatment, thermoception was assessed using the tail flick test, while spatial learning, memory, and reversal learning were evaluated in the Morris water maze. Chemotherapy exposure produced marked and persistent reductions in body weight but did not significantly affect spatial acquisition or spatial memory. Selective treatment-related alterations were observed during early reversal learning, whereas group differences were no longer evident from the second reversal day onward. No statistically detectable treatment-related alterations in tail flick latency were observed. Exploratory immunohistochemical analyses of IBA1, MBP, and SHANK3 measures likewise revealed no significant group differences immediately after treatment. Together, these findings indicate that chemotherapy exposure did not produce a generalized spatial learning or memory deficit but was associated with selective alterations in cognitive flexibility during early adaptation to a relocated platform. The present model may therefore be useful for investigating subtle and temporally specific behavioral consequences of multidrug chemotherapy exposure.