Effects of Early Chemotherapeutic Treatment on Learning in Adolescent Mice: Implications for Cognitive Impairment and Remediation in Childhood Cancer Survivors

Abstract

Purpose Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40-70% 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. Experimental Design Pre-weanling 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 following treatment (PND 35), behavioral tasks measuring different aspects of learning and memory were administered. Results Significant impairment in acquisition and retention over both short (1h) and long (24h) intervals, as measured by autoshaping and novel object recognition tasks, were 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 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 treatment. 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.

A selective cannabinoid CB2 agonist attenuates damage and improves memory retention following stroke in mice

“…The operant responding task is an example of instrumental/reinforcement learning and involves frontal cortical and many subcortical brain regions, including the hippocampus, ventral tegmental area, nucleus accumbens, and amygdala (Cardinal, Parkinson et al 2002; Bisen-Hersh, Hineline et al 2013). These brain regions were not primary sites of damage induced by the stroke, as seen by their ability to take up the TTC staining.…”

“…All behavioral testing was done by an experimenter blinded to the treatment of the individual animals. The novel object recognition task was executed as described previously by our laboratory (Bisen-Hersh et al 2013). On the morning of day 6, mice were individually placed into the testing cage for a 20-min acclimation period and then returned to their home cage for 30 min.…”

Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model

“…The results showed that the mice that had received MTX alone or MTX in conjunction with AraC performed less well on behavioral tasks when compared to the non-treatment cohort. 20 Unfortunately, the study did not investigate physiological changes that could have confirmed the behavioral results, such as molecular assays. Assessment of neurophysiology could be beneficial in understanding mechanistic changes that lead to damage.…”

Single and combined effects of plant‐derived and synthetic cannabinoids on cognition and cannabinoid‐associated withdrawal signs in mice

“…Instrumental discrimination learning was assessed in mice using an appetitive‐motivated operant conditional discrimination procedure (Bisen‐Hersh et al, ) that used a tone/light compound stimulus and temporal duration. Following the habituation period, mice were separated into individual cages, weighed and food‐restricted for 24 h prior to the start of experimental testing.…”