title: Effects of early chemotherapeutic treatment on learning in adolescent mice: implications for cognitive impairment and remediation in childhood cancer survivors.
abstract: OBJECTIVE
  Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40% to 70% of survivors experience neurocognitive impairment. The present study used a preclinical mouse model to investigate the effects of early exposure to common ALL chemotherapeutics methotrexate (MTX) and cytarabine (Ara-C) on learning and memory.
  
  
  METHODS
  Preweanling mouse pups were treated on postnatal day (PND) 14, 15, and 16 with saline, MTX, Ara-C, or a combination of MTX and Ara-C. Nineteen days after treatment (PND 35), behavioral tasks measuring different aspects of learning and memory were administered.
  
  
  RESULTS
  Significant impairment in acquisition and retention over both short (1 hour) and long (24 hours) intervals, as measured by autoshaping and novel object recognition tasks, was found following treatment with MTX and Ara-C. Similarly, a novel conditional discrimination task revealed impairment in acquisition for chemotherapy-treated mice. No significant group differences were found following the extensive training component of this task, with impairment following the rapid training component occurring only for the highest MTX and Ara-C combination group.
  
  
  CONCLUSIONS
  Findings are consistent with those from clinical studies suggesting that childhood cancer survivors are slower at learning new information and primarily exhibit deficits in memory years after successful completion of chemotherapy. The occurrence of mild deficits on a novel conditional discrimination task suggests that chemotherapy-induced cognitive impairment may be ameliorated through extensive training or practice.
authors.affiliation: Neuroscience Program, Temple University, Philadelphia, Pennsylvania, USA. emily.bisen-hersh@vanderbilt.edu
authors.forename: Emily B
authors.initials: EB
authors.lastname: Bisen-Hersh
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hineline
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Walker
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D060825:Cognitive Dysfunction / Q000139:chemically induced*; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000188:drug therapy; D011247:Pregnancy; D017741:Survivors
chemical_list: D003561:Cytarabine; D008727:Methotrexate