The chemotherapeutic agent paclitaxel selectively impairs learning while sparing source memory and spatial memory

Abstract

Chemotherapeutic agents are widely used to treat patients with systemic cancer. The efficacy of these therapies is undermined by their adverse side-effect profiles such as cognitive deficits that have a negative impact on the quality of life of cancer survivors. Cognitive side effects occur across a variety of domains, including memory, executive function, and processing speed. Such impairments are exacerbated under cognitive challenges and a subgroup of patients experience long-term impairments. Episodic memory in rats can be examined using a source memory task. In the current study, rats received paclitaxel, a taxane-derived chemotherapeutic agent, and learning and memory functioning was examined using the source memory task. Treatment with paclitaxel did not impair spatial and episodic memory, and paclitaxel treated rats were not more susceptible to cognitive challenges. Under conditions in which memory was not impaired, paclitaxel treatment impaired learning of new rules, documenting a decreased sensitivity to changes in experimental contingencies. These findings provide new information on the nature of cancer chemotherapy-induced cognitive impairments, particularly regarding the incongruent vulnerability of episodic memory and new learning following treatment with paclitaxel.

Animal models of episodic memory

“…Rats revisited the replenishment location at a higher rate than the nonreplenishment location while avoiding revisits to chow locations ( Figure 3B). These data are consistent with the hypothesis that rats remember the source of encoded information (Crystal & Alford, 2014;Crystal & Smith, 2014;Smith, Slivicki, et al, 2017;Smith et al, 2016). Moreover, source memory is quite long-lasting ( Figure 3C), surviving retention-interval challenges of at least 1 week (Crystal & Alford, 2014;Crystal & Smith, 2014).…”

“…We developed an animal model of source memory (Crystal & Alford, 2014;Crystal, Alford, Zhou, & Hohmann, 2013;Crystal & Smith, 2014;Smith, Dalecki, & Crystal, 2017;Smith, Slivicki, Hohmann, & Crystal, 2017;Smith et al, 2016;reviewed in Crystal, 2016a; see Basile & Hampton, 2017, for an example of source memory in rhesus monkeys). Source memory is memory for the origin of episodic memories (Janowsky, Shimamura, & Squire, 1989;Johnson, Hashtroudi, & Lindsay, 1993;Mitchell & Johnson, 2009).…”

The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory

“…Rats are able to remember what, where, and how they encountered distinct flavors using source memory (Crystal, 2016; Crystal and Alford, 2014; Crystal et al, 2013). Treatment with paclitaxel did not impair episodic memory in a source memory task, even after a long retention interval, or the development of proactive interference (Smith, Slivicki, Hohmann, and Crystal, 2017). However, paclitaxel-treated rats showed deficits in their sensitivity to changes in experimental contingencies, as assessed by reversing the source memory rule (Smith et al, 2017), a finding consistent with chemotherapy-induced reductions in cognitive flexibility.…”

“…Notably, rule learning is a feature embedded in the source memory task used by Smith and colleagues (Smith et al, 2017). Because the source information rule reversal represented both new learning and reversal learning, it is still an open question as to whether chemotherapy impaired new learning, reversal learning, or both.…”

“…However, it is not known if chemotherapy treatment differentially affects new learning and/or reversal learning. The current work presents the opportunity to validate and expand on whether paclitaxel treatments spare episodic memory and impairs learning (Smith et al, 2017). …”