A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice

Abstract

Purpose-Chemotherapeutic agents are known to produce persistent cognitive deficits in cancer patients. However, little progress has been made in developing animal models to explore underlying mechanisms and potential therapeutic interventions. We report an electrophysiological model of chemotherapy-induced cognitive deficits using a sensory gating paradigm, to correspond with performance in two behavioral tasks.Experimental Design-Mice received four weekly injections of methotrexate and 5-fluorouracil. Whole-brain event-related potentials (ERPs) were recorded throughout using a paired-click paradigm. Mice underwent contextual fear conditioning (CFC) and novel-object recognition testing (NOR).Results-Chemotherapy treated animals showed significantly impaired gating five weeks after drug treatments began, as measured by the ratio of P1-N1 between first and second auditory stimuli. There was no effect of drug on the amplitude of P1-N1 or latency of P1. The drug treated animals also showed significantly increased freezing during fear conditioning and increased exploration without memory impairment during novel object recognition.Conclusions-Chemotherapy causes decreased ability to gate incoming auditory stimuli, which may underlie associated cognitive impairments. These gating deficits were associated with a hyperactive response to fear conditioning and reduced adaptation to novel objects, suggesting an additional component of emotional dysregulation. However, amplitudes and latencies of ERP components were unaffected, as was NOR performance, highlighting the subtle nature of these deficits.

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

“…Similarly, patients receiving adjuvant chemotherapy (which includes 5FU in the regime) for cancer experience impairments in verbal and visual memory, processing speed, concentration and attention (de Ruiter et al 2011;Vardy and Tannock 2007). In contrast, Gandal et al (2008) failed to find impairments in NOR or fear conditioning in mice treated with combined 5FU and MTX, while inexplicably, Lee et al (2006) found transient improvements in spatial MWM and Stone maze performance in rats treated with 5FU alone, which then disappeared with later testing. However, these results may be explained by differences in experimental design.…”

“…However, these results may be explained by differences in experimental design. For example, Gandal et al (2008) employed a 24-h delay between NOR sample and test trials, while a maximum of 2 h separated the sample and test trials in the present experiment.…”

Animal Models of Psychosis: Current State and Future Directions

“…In contrast to behavior, one measures the exact same phenomenon across species and no interpretations of “meaning or intent” are required. Many studies have demonstrated that both mouse and human ERP components are similarly affected by certain pharmacological treatments and stimulus manipulations [61–63]. Thus, recording EEG and ERPs in preclinical studies provides the most translational model system for physiological deficits associated with psychosis.…”

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

“…In mice the P1, P2, P3, and N1 peaks are equivalent in stimulus and pharmacological response properties to human peaks P50, P200, P300, and N100, respectively, when using auditory ERPs, described by Connolly and collaborators (2004). In an effort to establish an electrophysiological model of chemotherapy-induced cognitive impairment, Gandal and colleagues (2008) studied the effect of chronic regimens of methotrexate or 5-fluorouracil in mice using an auditory ERP paradigm (Gandal et al 2008). Chemotherapy-treated mice showed a significant impairment in sensory gating as evidenced by an increased response ratio between P1 and N1 amplitudes following presentation of auditory stimuli.…”