Episodic-like memory in mice: simultaneous assessment of object, place and temporal order memory

Episodic memory refers to the conscious recollection of a unique past experience in terms of "what" happened and "where" and "when" it happened. Since deficits in episodic memory are found in a number of neuropsychiatric diseases, such as Alzheimer's disease, for which several pharmacological, lesion and genetic animal models are available, there is a need for animal models of episodic-like memory, which can be used to devise appropriate treatments. However, even when the problem of conscious recollection in animals is factored out, episodic memory has been difficult to demonstrate in nonhuman mammals because it has not yet been possible to demonstrate an integrated memory for "what",-"where"-and-"when". We designed a three-trial "what",-"where"-and-"when" object exploration task in which different versions of the novelty preference paradigm were combined to subsume (a) object recognition memory, (b) the memory for locations in which objects were explored and (c) the temporal order memory for objects presented at distinct time points. Our results suggest that mice are able to (a) recognize previously explored objects, (b) remember the location in which particular objects were previously encountered and (c) discriminate the relative recency in which different objects were presented. We suggest that our protocol providing the simultaneous assessment of object memory for "what",-"where"-and-"when" in mice might be useful in the search for the neural substrates of episodic memory, the screening for promnestic drugs and the behavioral phenotyping of genetic models of neuropsychiatric diseases affecting episodic memory.     

Domain‐specific contributions of biological sex and sex hormones to what,where and when components of episodic‐like memory in adult rats

Episodic memory involves the integration and recall of discrete events that include information about what happened, where it happened and when it occurred. Episodic memory function is critical to daily life, and its dysfunction is both a first identifiable indicator and an enduring core feature of cognitive decline in ageing and in neuropsychiatric disorders including Alzheimer's disease and schizophrenia. Available evidence from human studies suggests that biological sex and sex hormones modulate episodic memory function in health and disease. However, knowledge of how this occurs is constrained by the limited availability and underutilization of validated animal models in investigating hormone impacts on episodic‐like memory function. Here, adult female, adult male and gonadally manipulated adult male rats were tested on the what–where–when episodic‐like memory task to determine whether rats model human sex differences in episodic memory and how the hormonal milieu impacts episodic‐like memory processes in this species. These studies revealed salient ways in which rats model human sex differences in episodic memory, including a male advantage in spatial episodic memory performance. They also identified domain‐specific roles for oestrogens and androgens in modulating what, where and when discriminations in male rats that were unlike those engaged in corresponding novel object recognition and novel object location tasks. These studies thus identify rats and the what–where–when task as suitable for investigating the neuroendocrine bases of episodic‐like memory, and provide new information about the unique contributions that sex and sex hormones make to this complex mnemonic process.     

Episodic memory,semantic memory,and amnesia

Episodic memory and semantic memory are two types of declarative memory. There have been two principal views about how this distinction might be reflected in the organization of memory functions in the brain. One view, that episodic memory and semantic memory are both dependent on the integrity of medial temporal lobe and midline diencephalic structures, predicts that amnesic patients with medial temporal lobe/diencephalic damage should be proportionately impaired in both episodic and semantic memory. An alternative view is that the capacity for semantic memory is spared, or partially spared, in amnesia relative to episodic memory ability. This article reviews two kinds of relevant data: 1) case studies where amnesia has occurred early in childhood, before much of an individual's semantic knowledge has been acquired, and 2) experimental studies with amnesic patients of fact and event learning, remembering and knowing, and remote memory. The data provide no compelling support for the view that episodic and semantic memory are affected differently in medial temporal lobe/diencephalic amnesia. However, episodic and semantic memory may be dissociable in those amnesic patients who additionally have severe frontal lobe damage. Hippocampus 1998;8:205–211. Published 1998 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Dissociating the past from the present in the activity of place cells

It has been proposed that declarative memories can be dependent on both an episodic and a semantic memory system. While the semantic system deals with factual information devoid of reference to its acquisition, the episodic system, characterized by mental time travel, deals with the unique past experience in which an event took place. Episodic memory is characteristically hippocampus-dependent. Place cells are recorded from the hippocampus of rodents and their firing reflects many of the key characteristics of episodic memory. For example, they encode information about "what" happens "where," as well as temporal information. However, when these features are expressed during an animal's behavior, the neuronal activity could merely be categorizing the present situation and could therefore reflect semantic memory rather than episodic memory. We propose that mental time travel is the key feature of episodic memory and that it should take a form, in the awake animal, similar to the replay of behavioral patterns of activity that has been observed in hippocampus during sleep. Using tasks designed to evoke episodic memory, one should be able to see memory reactivation of behaviorally relevant sequences of activity in the awake animal while recording from hippocampus and other cortical structures.     

Episodic memory, frontal functioning, and aging

Episodic memory is commonly defined as the kind of memory that renders possible conscious recollection of personal happenings and events from one's personal past. Although it is classically assumed that episodic memory is subserved by a distinct neurocognitive system including mediotemporal cortex and hippocampus, recent evidence also supports the idea of a close relationship between episodic memory and frontal cortex. This view assumes that the frontal cortex plays a critical supervisory role in empowering encoding and retrieval episodic memory operations. In recent years, this view had significantly influenced research in the field of normal memory aging. Indeed, different data have highlighted that age-related cognitive differences, most particularly age-related memory differences, might be explained by the decline of executive-frontal functioning that accompanies aging. In this article, we provide studies on aging and episodic memory that, in support of the executive hypothesis of aging episodic memory, have provided evidence that age-related differences in strategies implemented at encoding and retrieval in this type of memory are mediated by the executive functioning difficulties of older adults.     

Episodic memory in animals: Remembering which occasion

Episodic memory, the recollection of past events in one's life, has often been considered a memory specific to humans. Recent work in a variety of species has challenged this view, and has raised important questions about the nature of episodic memory itself. We present a review of the types of task proposed as episodic-like in animals and consider that these tasks require animals to demonstrate memory for specific occasions in the past. We propose that identifying episodic memory as the memory for what happened where on a specific occasion is a more encompassing definition than one that relies on information about when an event occurred. These episodic-like tasks in animals support the view that the hippocampal system is necessary for episodic memory, and that the neural substrates of episodic memory can be dissociated from those of other forms of declarative memory.     

Retrograde episodic memory and emotion: A perspective from patients with dissociative amnesia

With his recent definition of episodic memory Tulving [Tulving, E. (2005). Episodic memory and autonoesis: Uniquely human? In H. Terrace & J. Metcalfe (Eds.), The missing link in cognition: Evolution of self-knowing consciousness (pp. 3-56). New York: Oxford University Press] claims that this memory system is uniquely human and thereby distinguishes human beings from other, even highly developed, mammals. First we will define the term episodic memory as it is currently used in neuropsychological research by specifying the three underlying concepts of subjective time, autonoëtic consciousness, and the self. By doing so, we will strongly focus on retrograde episodic memory and its relation to emotion and self-referential processing. We support this relation with a discussion of autobiographical memory functions in psychiatric disorders such as dissociative amnesia. To illustrate the connection of emotion and retrograde episodic memory we shortly present neuropsychological data of two cases of dissociative amnesia. Both cases serve to point to the protective mechanism of a block of self-endangering memories from the episodic memory system, often described as the mnestic block syndrome. On the basis of these cases and supportive results from further cases we will conclude by pointing out similarities and differences of patients with organic and dissociative (psychogenic) amnesia.     

Dissociating memory traces and scenario construction in mental time travel

There has been a persistent debate about how to define episodic memory and whether it is a uniquely human capacity. On the one hand, many animal cognition studies employ content-based criteria, such as the what-where-when criterion, and argue that nonhuman animals possess episodic memory. On the other hand, many human cognition studies emphasize the subjective experience during retrieval as an essential property of episodic memory and the distinctly human foresight it purportedly enables. We propose that both perspectives may examine distinct but complementary aspects of episodic memory by drawing a conceptual distinction between episodic memory traces and mental time travel. Episodic memory traces are sequential mnemonic representations of particular, personally experienced episodes. Mental time travel draws on these traces, but requires other components to construct scenarios and embed them into larger narratives. Various nonhuman animals may store episodic memory traces, and yet it is possible that only humans are able to construct and reflect on narratives of their lives – and flexibly compare alternative scenarios of the remote future.     

A new frontier in spaced retrieval memory training for persons with Alzheimer's disease

The objective of this pilot study was to investigate how a memory training technique called "Spaced Retrieval" (SR) might be effectively applied in helping persons with Alzheimer's disease improve their recall of recent events. Capitalising on the interdependence among spared and impaired memory systems, it was hypothesised that SR training with support at encoding and retrieval would facilitate the retention and recall of meaningful recent events. Eight participants with a diagnosis of Alzheimer's disease or related disorder were recruited for this study. The study employed a quasi-experimental multiple baseline treatment design across participants, items, and behaviours. SR training was provided in three domains: Semantic, Prospective, and Episodic recent memory. The results show important training gains made by all participants across conditions at post-training follow-up. In the Episodic condition, participants were able to recall specific details about recent events following training. This study provides preliminary evidence that individuals with mild to severe cognitive impairment can learn and recall new episodic information through Spaced Retrieval training. If replicated, these findings would support the use of Spaced Retrieval as an intervention tool to help individuals maintain their functioning in the area of episodic recent memory.     

Looking for episodic memory in animals and young children: prospects for a new minimalism

Because animals and young children cannot be interrogated about their experiences it is difficult to conduct research into their episodic memories. The approach to this issue adopted by Clayton and Dickinson [Clayton, N. S., & Dickinson, A. (1998). Episodic-like memory during cache recovery by scrub jays. Nature, 395, 272-274] was to take a conceptually minimalist definition of episodic memory, in terms of integrating information about what was done where and when [Tulving, E. (1972). Episodic and semantic memory. In E. Tulving, & W. Donaldson (Eds.), Organisation of memory (pp. 381-403). New York: Academic Press], and to refer to such memories as ‘episodic-like’. Some claim, however, that because animals supposedly lack the conceptual abilities necessary for episodic recall one should properly call these memories ‘semantic’. We address this debate with a novel approach to episodic memory, which is minimalist insofar as it focuses on the non-conceptual content of a re-experienced situation. It rests on Kantian assumptions about the necessary ‘perspectival’ features of any objective experience or re-experience. We show how adopting this perspectival approach can render an episodic interpretation of the animal data more plausible and can also reveal patterns in the mosaic of developmental evidence for episodic memory in humans.     

Bilateral hippocampal pathology impairs topographical and episodic memory but not visual pattern matching.

A virtual reality environment was used to test memory performance for simulated "real-world" spatial and episodic information in a 22-year-old male, Jon, who has selective bilateral hippocampal pathology caused by perinatal anoxia. He was allowed to explore a large-scale virtual reality town and was then tested on his memory for spatial layout and for episodes experienced. Topographical memory was tested by assessing his ability to navigate, recognize previously visited locations, and draw maps of the town. Episodic memory was assessed by testing the retrieval of simulated events which consisted of collecting objects from characters while following a route through the virtual town. Memory for the identity of objects, as well as for where they were collected, from whom, and in what order, was also tested. While the first task tapped simple recognition memory, the latter three tested memory for context. Jon was impaired on all topographical tasks and on his recall of the context-dependent questions. However, his recognition of objects from the virtual town, and of "topographical" scenes (as evaluated by standard neuropsychological tests), was not impaired. These findings are consistent with the view that the hippocampus is involved in navigation, recall of long term allocentric spatial information and context-dependent episodic memory, but not visual pattern matching.     

Episodic memory: Neuronal codes for what,where, and when

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent (“where”), sequence of events (“when”), and the content of the experience itself (“what”). Second, the code should arise instantly thereby being able to support memory formation of one‐shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory‐based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object‐coding and odor‐selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.     

Encoding processes during retrieval tasks

Episodic memory encoding is pervasive across many kinds of task and often arises as a secondary processing effect in tasks that do not require intentional memorization. To illustrate the pervasive nature of information processing that leads to episodic encoding, a form of incidental encoding was explored based on the "Testing" phenomenon: The incidental-encoding task was an episodic memory retrieval task. Behavioral data showed that performing a memory retrieval task was as effective as intentional instructions at promoting episodic encoding. During fMRI imaging, subjects viewed old and new words and indicated whether they remembered them. Relevant to encoding, the fate of the new words was examined using a second, surprise test of recognition after the imaging session. fMRI analysis of those new words that were later remembered revealed greater activity in left frontal regions than those that were later forgotten - the same pattern of results as previously observed for traditional incidental and intentional episodic encoding tasks. This finding may offer a partial explanation for why repeated testing improves memory performance. Furthermore, the observation of correlates of episodic memory encoding during retrieval tasks challenges some interpretations that arise from direct comparisons between "encoding tasks" and "retrieval tasks" in imaging data. Encoding processes and their neural correlates may arise in many tasks, even those nominally labeled as retrieval tasks by the experimenter.     

Autobiographical and episodic memory--one and the same? Evidence from prefrontal activation in neuroimaging studies

Laboratory investigations of episodic memory often require participants to encode and later retrieve lists of items (words, pictures, or faces). The underlying assumption is that recollection of items from the list is analogous to recollection of events from one's past, i.e. autobiographical re-experiencing. Functional neuroimaging studies of episodic memory have provided extensive evidence suggesting that regions of the prefrontal cortex (PFC) play a role in episodic memory retrieval. A review of PFC activations reported in imaging studies of autobiographical memory and matched sub-sets of list-learning episodic memory studies reveals patterns of similarity but also substantial differences. Episodic memory studies often report activations in the right mid-dorsolateral PFC, but such activations are absent in autobiographical memory studies. Additionally, activations in the ventromedial PFC, primarily on the left, are almost invariably found in autobiographical memory studies, but rarely occur in studies of episodic memory. It is suggested that these two regions mediate different modes of post-retrieval monitoring and verification. Autobiographical memory relies on quick intuitive 'feeling of rightness' to monitor the veracity and cohesiveness of retrieved memories in relation to an activated self-schema. Episodic memory for lists requires more conscious elaborate monitoring to avoid omissions, commissions and repetitions. The present analysis suggests that care and caution should be exercised in extrapolating from the way we recollect 'events' from a list learned in the laboratory to the way we recollect events from our lives.     

Memory function in normal aging

Basic findings obtained on memory functions in normal aging are presented and discussed with respect to five separate but interacting memory systems. These systems are: episodic memory, semantic memory, short-term memory, perceptual representation system and procedural memory. All available evidence from cross-sectional research shows that there is a linear, decreasing memory performance as a function of age for episodic memory. Longitudinal studies suggest, however, that this age deficit may be an overestimation, by showing a relatively stable performance level up to middle age, followed by a sharp decline. Studies on semantic memory, short-term memory, perceptual representation system, and procedural memory show a relatively constant performance level across the adult life span, although some tasks used to assess short-term memory and procedural memory have revealed an age deficit. Disregarding the mixed results for these latter two memory systems, it can be concluded that episodic memory is unique in showing an age deficit. Episodic memory is also unique in the sense that it is the only memory system showing gender differences in performance throughout the adult life span with a significantly higher performance for women.     

Which memory system is impaired first in Alzheimer's disease?

Diagnosis of Alzheimer's disease (AD) in its earliest stages becomes increasingly important as disease modifying agents are being developed. In this area of research, many clinical and neuroimaging studies focus on markers of hippocampal dysfunction. However, during the "transentorhinal stage" of AD, neurofibrillary tangles (NFT), related to tau protein pathology, develop in the anterior subhippocampal (perirhinal/entorhinal) cortex before the hippocampus. NFT are tightly correlated with clinical symptoms. Therefore, an accurate understanding of the behavioral correlate of transentorhinal dysfunction could critically contribute to the early diagnosis of the disease. Recent findings from studies in animals and human brain-damaged patients suggest that the anterior subhippocampal region, functionally integrated into an anterior mesiotemporal network, is involved in object based context-free memory. In this article, we evaluate the hypothesis according to which tau deposition in the anterior subhippocampal region during the earliest stages of the most common form of AD, with predominant MTL dysfunction, will lead to dysfunction of neural networks implicated in context-free memory. We challenge the view that impaired episodic memory is the hallmark of early AD. Instead, a model that integrates the localization and temporal sequence of NFT within the mesial temporal lobe (MTL) is proposed. Paralleling the development of NFT in anterior subhippocampal areas, impaired context-free, object-based, memory could be the first detectable sign in AD. In a subsequent, "hippocampal" stage, context-rich, episodic and spatial memory, becomes altered as well. The question as to the "episodic" nature of "episodic memory tasks" is also addressed.     

Positron emission tomography correlations in and beyond medial temporal lobes

This article discusses the potential usefulness of brain/ behavior correlational analyses in functional neuroimaging studies of memory, and how such analyses can illuminate the role of medial temporal lobes (MTL) and the hippocampus in episodic and declarative memory processes such as encoding and retrieval. Reanalysis of the results of four previously reported positron emission tomography (PET) studies yielded evidence of both positive and negative between-subjects correlations between recognition-memory accuracy and regional blood flow. The sites of these correlations were in MTL regions as well as in other cortical and subcortical areas, including frontal lobes (Brodmann areas 6, 9, 10, 11, and 47), temporal lobes (BAs 21, 22, and 38), insula, fusiform gyrus, and cuneus/precuneus. These findings were discussed with respect to issues such as localization of the correlation sites, the distinction between brain sites revealed by brain/cognition correlational analyses ("how" sites) and those yielded by cognitive subtraction methods ("what" sites), the tendency of the "how" sites in MTL to occur in the left hemisphere, the tendency of other "how" sites to occur in one or the other hemisphere, rather than bilaterally, and the meaning and "reality" of both brain/behavior correlations and task-related activations. Because of the known incidence of false-positives, all neuroimaging data, including those involving the localization of "what" and "how" memory sites in MTL and other brain regions, need to be interpreted cautiously, and findings of individual studies should not be overinterpreted.     

Predictive, interactive multiple memory systems

Most lesion studies in animals, and neuropsychological and functional neuroimaging studies in humans, have focused on finding dissociations between the functions of different brain regions, for example in relation to different types of memory. While some of these dissociations can be questioned, particularly in the case of neuroimaging data, we start by assuming a "modal model" in which at least three different memory systems are distinguished: an episodic system (which stores associations between items and spatial/temporal contexts, and which is supported primarily by the hippocampus); a semantic system (which extracts combinations of perceptual features that define items, and which is supported primarily by anterior temporal cortex); and modality-specific perceptual systems (which represent the sensory features extracted from a stimulus, and which are supported by higher sensory cortices). In most situations however, behavior is determined by interactions between these systems. These interactions reflect the flow of information in both "forward" and "backward" directions between memory systems, where backward connections transmit predictions about the current item/features based on the current context/item. Importantly, it is the resulting "prediction error"--the difference between these predictions and the forward transmission of sensory evidence--that drives memory encoding and retrieval. We describe how this "predictive interactive multiple memory systems" (PIMMS) framework can be applied to human neuroimaging data acquired during encoding or retrieval phases of the recognition memory paradigm. Our novel emphasis is thus on associations rather than dissociations between activity measured in key brain regions; in particular, we propose that measuring the functional coupling between brain regions will help understand how these memory systems interact to guide behavior.     

Functional Neuroimaging and Episodic Memory: A Perspective

One area of research that has significantly benefited from the recent development of functional neuroimaging techniques is the study of memory. In this review we explore what has been learned about the neural basis of normal memory function using these techniques. We focus on episodic memory, which is characterized by the ability to consciously recollect memories for facts or events. We highlight three neuroanatomical regions that have been linked to episodic memory: The hippocampal complex, the prefrontal cortex and the amygdala. For each of these regions, we discuss the behavioral methods of assessment and specific episodic memory processes, particularly encoding and retrieval. Finally, we briefly comment on the potential clinical applications for this research and other memory systems.     

Functional neuroimaging and episodic memory: a perspective

One area of research that has significantly benefited from the recent development of functional neuroimaging techniques is the study of memory. In this review we explore what has been learned about the neural basis of normal memory function using these techniques. We focus on episodic memory, which is characterized by the ability to consciously recollect memories for facts or events. We highlight three neuroanatomical regions that have been linked to episodic memory: The hippocampal complex, the prefrontal cortex and the amygdala. For each of these regions, we discuss the behavioral methods of assessment and specific episodic memory processes, particularly encoding and retrieval. Finally, we briefly comment on the potential clinical applications for this research and other memory systems.