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


METHODS
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.
Medical Scientist Training Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
M J
MJ
Gandal
R S
RS
Ehrlichman
N D
ND
Rudnick
S J
SJ
Siegel
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D001307:Auditory Perception / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology*; D004569:Electroencephalography; D004594:Electrophysiology; D005071:Evoked Potentials / Q000502:physiology; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity; D008297:Male; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000523:psychology; D021641:Recognition, Psychology / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005472:Fluorouracil; D008727:Methotrexate