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.

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.

We built upon previous work by Fujita et al. (2012, Animal Cognition, 15(6), 1055-1063) to create an experiment that investigated the presence of incidental memory for the spatial location of uneaten food in the domestic dog. Here, we dissociated potentially incidental spatial memory from the incidental memory for the characteristics of objects, in this case, food bowls. Eighteen household domestic dogs of various breeds and age were presented with four bowls. Each bowl contained either a novel object, treats the dog could consume, treats it could not consume, or it was left empty. Following a delay, the dogs returned to the laboratory and were presented with empty bowls in the same spatial orientation as the initial exposure and could move freely between bowls. This experiment required no previous training outside of basic obedience and so avoids the possibility that performance on the test was a conditioned response. We hypothesized that domestic dogs would be able to remember the location of uneaten food when presented with an unexpected memory test. We found that dogs in this study showed no evidence that they encoded spatial location in the absence of other cues that could be used to distinguish food bowls at specific locations. This suggests that dogs in previous experiments were more dependent on incidentally encoding the "what" and "in what" of this task than the "where," in the absence of features making each location distinct.

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