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A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice
M J Gandal1, R S Ehrlichman, N D Rudnick
1Medical Scientist Training Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
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 5 weeks after drug treatments began, as measured by the ratio of the first positive peak in the ERP (P1) minus the first negative peak (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.
Insights
Chemotherapy impairs sensory gating, a key cognitive function, potentially explaining deficits in cancer patients. This study developed an electrophysiological model to investigate these chemotherapy-induced cognitive impairments.
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Chemotherapy can cause lasting cognitive problems in cancer patients.
- Developing reliable animal models for chemotherapy-induced cognitive deficits is crucial for research.
- Electrophysiological and behavioral approaches are needed to understand these deficits.
Purpose of the Study:
- To establish an electrophysiological model of chemotherapy-induced cognitive deficits.
- To investigate sensory gating deficits using a paired-click paradigm.
- To correlate electrophysiological findings with behavioral task performance.
Main Methods:
- Mice received weekly injections of methotrexate and 5-fluorouracil.
- Whole-brain event-related potentials (ERPs) were recorded using a paired-click paradigm.
- Mice underwent contextual fear conditioning (CFC) and novel-object recognition (NOR) tests.
Main Results:
- Chemotherapy-treated mice exhibited significantly impaired sensory gating 5 weeks post-treatment.
- No significant effects were observed on the amplitude or latency of specific ERP components (P1-N1).
- Drug-treated animals showed increased freezing in CFC and altered exploration in NOR, suggesting emotional dysregulation.
Conclusions:
- Chemotherapy-induced sensory gating deficits may contribute to cognitive impairments.
- These deficits are linked to hyperactivity in fear responses and reduced adaptation.
- Subtle cognitive deficits, like unaffected NOR performance and ERP components, highlight the complexity of chemotherapy's effects.
