The Effects of Chemotherapy on Cognitive Function in a Mouse Model: A Prospective Study

Abstract

Purpose: Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short-and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model.Experimental Design: Normal mice received three weekly injections of a combination of methotrexate þ 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing.Results: The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment.Conclusions: Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting.

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits

“…Taken together, these findings suggest that agonists of nAChRs may be therapeutic to those suffering from 'chemo-brain. ' Many aspects of cognitive function can be assessed in animals using well established behavioral procedures, and studies have demonstrated the presence of cognitive deficits in animals following exposure to chemotherapeutic agents using several behavioral tasks [74][75][76]. Animals exposed to chemotherapeutic agents exhibit deficits in tests of attention and working memory, recognition memory, associative learning and memory and spatial memory [77], in agreement with clinical observations of 'chemo-brain.'…”

“…Tasks involving serial search sequences such as the radial arm maze or requiring the use of information from an immediately preceding trial such as the nonmatching to sample or delayed non-matching to sample task are frequently used to assess working memory function. During training in the submerged radial arm maze, rats receiving a single exposure to the chemotherapeutic agent carmustine exhibit an increased number of errors when compared to controls, indicative of impaired working memory [93], and exposure to the chemotherapeutic combination methotrexate and 5-fluorouracil has been shown to impair performance on non-matching to sample and delayed non-matching to sample tasks [66, 76,94].…”

Challenges in research on the neural basis of „chemobrain”

“…Exposure to chemotherapeutic agents was associated with decreased performance on different types of learning tasks utilizing hippocampal and frontal network functions [17][18][19][20].…”

The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory

“…To date, measures of chemotherapy-induced cognitive deficits in rodents have predominantly focused on hippocampal and frontal dependent functions including spatial navigation (Morris Water maze), novelty recognition (novel location recognition), associative learning and memory (non-match to sample and delayed non-match to sample). Chemotherapy impaired spatial memory, conditional associative learning, and discrimination learning (some of which were chronically observed (Winocur, Henkelman, Wojtowicz, Zhang, Binns, and Tannock, 2012)), and it suppressed hippocampal neurogenesis (Winocur et al, 2015). …”