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A clinically relevant dose of cyclophosphamide chemotherapy impairs memory performance on the delayed spatial alternation task that is sustained over time as mice age

Janelsins, M.C.; Heckler, C.E.; Thompson, B.D.; Gross, R.A.; Opanashuk, L.A.; Cory-Slechta, D.A.

Neurotoxicology 56(24): 287-293

2016


ISSN/ISBN: 1438-3276
PMID: 27371409
DOI: 10.1007/bf03366735
Accession: 080299496

Cyclophosphamide chemotherapy is a mainstay of adjuvant breast cancer treatment. Unfortunately, this drug is associated with cognitive impairments in cancer patients that may accelerate cognitive aging. Memory is particularly affected in many patients. In order to better understand the precise cognitive impairments caused by this chemotherapy agent, we investigated a clinically relevant dose and administration paradigm on delayed spatial memory abilities in C57BL/6 mice. We utilized a delayed alternation paradigm similar to a delayed match to sample paradigm reported to be sensitive in human neurotoxicology research. A dose of 200mg/kg cyclophosphamide was administered intravenously (at weekly intervals) for 4 weeks to C57BL/6 mice starting at 6 ½ months of age. Memory was tested in mice using a reward-based delayed spatial alternation paradigm with delay values of 1.5, 3, 6.1, 12.4 and 25s presented randomly over 80 sessions (16 reinforcers per session), and testing began at the initiation of chemotherapy through 3 months. At the longest delay, i.e., that requiring the greatest memory, mice treated with chemotherapy exhibited a significant decline over time in percent correct which leveled off compared to controls that continued to improve slightly. Our clinically relevant model shows cyclophosphamide chemotherapy causes a slight decline in delayed spatial memories at the longest delay that is sustained over time as mice age.

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