Summary Vivid episodic memories in people have been characterized as the replay of unique events in sequential order [1–3]. Animal models of episodic memory have successfully documented episodic memory of a single event (e.g., [4–8]). However, a fundamental feature of episodic memory in people is that it involves multiple events, and notably, episodic-memory impairments in human diseases are not limited to a single event. Critically, it is not known whether animals remember many unique events using episodic memory. Here we show that rats remember many unique events and the contexts in which the events occurred using episodic memory. We used an olfactory memory assessment in which new (but not old) odors were rewarded using 32 items. Rats were presented with 16 odors in one context and the same odors in a second context. To attain high accuracy, the rats needed to remember item in context because each odor was rewarded as a new item in each context. The demands on item-in-context memory were varied by assessing memory with 2, 3, 5, or 15 unpredictable transitions between contexts, and item-in-context memory survived a 45-min retention-interval challenge. When the memory of item in context was put in conflict with non-episodic familiarity cues, rats relied on item in context using episodic memory. Our findings suggest that rats remember multiple unique events and the contexts in which these events occurred using episodic memory and support the view that rats may be used to model fundamental aspects of human cognition.

Vivid episodic memories in people have been characterized as the replay of multiple unique events in sequential order [1-3]. The hippocampus plays a critical role in episodic memories in both people and rodents [2, 4-6]. Although rats remember multiple unique episodes [7, 8], it is currently unknown if animals "replay" episodic memories. Therefore, we developed an animal model of episodic memory replay. Here, we show that rats can remember a trial-unique stream of multiple episodes and the order in which these events occurred by engaging hippocampal-dependent episodic memory replay. We document that rats rely on episodic memory replay to remember the order of events rather than relying on non-episodic memories. Replay of episodic memories survives a long retention-interval challenge and interference from the memory of other events, which documents that replay is part of long-term episodic memory. The chemogenetic activating drug clozapine N-oxide (CNO), but not vehicle, reversibly impairs episodic memory replay in rats previously injected bilaterally in the hippocampus with a recombinant viral vector containing an inhibitory designer receptor exclusively activated by a designer drug (DREADD; AAV8-hSyn-hM4Di-mCherry). By contrast, two non-episodic memory assessments are unaffected by CNO, showing selectivity of this hippocampal-dependent impairment. Our approach provides an animal model of episodic memory replay, a process by which the rat searches its representations in episodic memory in sequential order to find information. Our findings using rats suggest that the ability to replay a stream of episodic memories is quite old in the evolutionary timescale.

The search for symmetry in nonhuman subjects has been successful in recent studies in pigeons (e.g., Urcuioli, 2008). The key to these successes has been the use of successive discrimination procedures and combined training on identity, as well as arbitrary, baseline relations. The present study was an effort to extend the findings and theoretical analysis developed by Urcuioli and his colleagues to rats using olfactory rather than visual stimuli. Experiment 1 was a systematic replication of Urcuioli's (2008) demonstration of symmetry in pigeons. Rats were exposed to unreinforced symmetry probes following training with two arbitrary and four identity conditional discriminations. Response rates on symmetry probe trials were low and provided little evidence for emergent symmetry in any of the seven rats tested. In Experiment 2, a separate group of six rats was trained on four identity relations and was then exposed to probe trials with four novel odor stimuli. Response rates were high on identity probe trials, and low on nonmatching probe trials. The similar patterns of responding on baseline and probe trials that were shown by most rats provided a demonstration of generalized identity matching. These findings suggest that the development of stimulus control topographies in rats with olfactory stimuli may differ from those that emerge in pigeons with visual stimuli. Urcuioli's (2008) theory has been highly successful in predicting conditions necessary for stimulus class formation in pigeons, but may not be sufficient to fully understand determinants of emergent behaviors in other nonhuman species. Keywords symmetry; generalized identity; successive conditional discrimination; olfactometer; rats; nosepokeThe search for symmetry in nonhuman animals has been both active and controversial since the seminal paper by Sidman, Rauzin, Lazar, Cunningham, Tailby and Carrigan (1982). Sidman et al. showed emergent symmetry along with the other relations of stimulus equivalence in human children, but not in monkeys or baboons. Interest in the possible significance of this empirical difference between humans and nonhuman animals in the relations that may emerge following arbitrary or symbolic conditional discrimination training has led to numerous follow-up studies with many species and procedural variations Correspondence concerning this article should be addressed to Mark Galizio, Department of Psychology, University of North Carolina Wilmington, 601 S. College Rd., Wilmington NC, USA 28403. galizio@uncw.edu. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript that have yielded mixed results. While emergent identity and transitivity relations have been frequently observed across species, symmetry has been elusive at best (cf., Lionello-DeNolf, 2009;McIlvane, 2013;. Lionello-DeNolf's comprehensive review only found strong evidence for symmetry in two species: in sea lions after extensive training with multiple exemplars and class-specific reinforcers (Kastak & Schusterman, 2002;Schu...

Chemotherapy is widely used to treat patients with systemic cancer. The efficacy of cancer therapies is frequently undermined by adverse side effects that have a negative impact on the quality of life of cancer survivors. Cancer patients who receive chemotherapy often experience chemotherapy-induced cognitive impairment across a variety of domains including memory, learning, and attention. In the current study, the impact of paclitaxel, a taxane derived chemotherapeutic agent, on episodic memory, prior learning, new learning, and reversal learning were evaluated in rats. Neurogenesis was quantified post-treatment in the dentate gyrus of the same rats using immunostaining for 5-Bromo-2′-deoxyuridine (BrdU) and Ki67. Paclitaxel treatment selectively impaired reversal learning while sparing episodic memory, prior learning, and new learning. Furthermore, paclitaxel-treated rats showed decreases in markers of hippocampal cell proliferation, as measured by markers of cell proliferation assessed using immunostaining for Ki67 and BrdU. This work highlights the importance of using multiple measures of learning and memory to identify the pattern of impaired and spared aspects of chemotherapy-induced cognitive impairment.

The Odor Span Task is an incrementing non-matching-to-sample procedure that permits the study of behavior under the control of multiple stimuli. Rats are exposed to a series of odor stimuli and selection of new stimuli is reinforced. Successful performance thus requires remembering which stimuli have previously been presented during a given session. This procedure has been frequently used in neurobiological studies as a rodent model of working memory; however, only a few studies have examined the effects of drugs on performance in this task. The present experiments explored the behavioral pharmacology of a modified version of the Odor Span Task by determining the effects of stimulant drugs methylphenidate and methamphetamine, NMDA antagonist ketamine, and positive GABAA modulator flunitrazepam. All four drugs produced dose-dependent impairment of performances on the Odor Span Task, but for methylphenidate and methamphetamine, these occurred only at doses that had similar effects on performance of a simple odor discrimination. Generally, these disruptions were based on omission of responding at the effective doses. The effects of ketamine and flunitrazepam were more selective in some rats. That is, some rats tested under flunitrazepam and ketamine showed decreases in accuracy on the Odor Span Task at doses that did not affect simple discrimination performance. These selective effects indicate disruption of within-session stimulus control. Overall, these findings support the potential of the Odor Span Task as a baseline for the behavioral pharmacological analysis of remembering.