Cancer chemotherapy impairs contextual but not cue-specific fear memory

Abstract

This study examined the effects of a standard breast cancer chemotherapeutic protocol on learning and memory in rats. Ovariectomized rats were treated once a week for 3 weeks with a combination of cyclophosphamide and doxorubicin prior to training in a classical fear conditioning task. Training took place 1 week after the final treatment. During the training session, an auditory stimulus (a tone) was paired with a mild foot-shock. The resulting conditioned fear to the tone (cue-specific fear) and to the training environment (contextual fear) was measured in subsequent test sessions. Chemotherapy did not affect the acquisition of the conditioned response (freezing) during the training session or the expression of fear during the tone test session. In contrast, rats treated with cyclophosphamide and doxorubicin exhibited decreased freezing during the context test session, suggestive of a specific deficit in hippocampal-related learning and memory. Together, these data indicate that administration of cyclophosphamide and doxorubicin may have toxic effects on the hippocampus and results in specific learning deficits shortly after treatment has ended. KeywordsCyclophosphamide; Doxorubicin; Chemotherapy; Learning; Rat A growing body of evidence indicates that cancer chemotherapy results in cognitive changes during treatment, immediately post-treatment, and up to 10 years following therapy [2,4,15,21,25,32]. The cognitive deficits that are experienced are diverse and vary in severity; however, problems with memory function and executive processes are the most

Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity

“…The results obtained here indicate that 5FU/OX chemotherapy affects different domains of memory: object recognition, spatial and complex contextual memories, potentially in a timedependent fashion. These results are consistent with those previously reported from our own laboratory (Fardell et al 2010) and others (Li et al 2008;MacLeod et al 2007;Seigers et al 2009). In contrast, learning in rodents may be unaffected affected by chemotherapy.…”

“…Each chamber had Plexiglas front and side walls, aluminium ceiling and end walls and stainless steel rod flooring. Similar to MacLeod et al (2007), rats received a single conditioning trial and were placed in the chambers for 2 min prior to three tone-shock pairings. A 1,500-Hz tone was presented for 10 s, followed immediately by a 1-s 0.6-mA shock through the flooring (scrambled, Med Associates, VT, USA).…”

Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

“…Thus, the dosing schedule and dose used in the present study may have more closely modeled what is used in the clinic for patients with breast cancer. Consistent with this interpretation, a recent study following the same dosing schedule as used in the present study reported a selective deficit in contextual fear conditioning in rats treated with combined cyclophosphamide and doxorubicin (40). Differences in cognitive outcomes between studies highlight the need for additional studies that compare the effects of single and combined chemotherapy agents while controlling dosing schedules and posttreatment assessment times.…”

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

“…For example, after three weekly injections of a combination of 37.5 mg/kg methotrexate and 75 mg/kg 5-fluorouracil, mice tested in variations of the Morris water maze exhibited deficits in spatial memory, nonmatching-to-sample learning, and delayed-non-matching-to-sample learning, while there were no changes noted in cued memory or discrimination learning (Winocur et al 2006). Similarly, rats treated with three weekly treatments of a combination of cyclophosphamide and doxorubicin showed impairments in contextual but not cue-specific fear responses (Macleod et al 2007). In the present study, three doses of methotrexate were combined with three doses of 5-fluorouracil for a total of nine different acute dose combinations.…”