Episodic Memory in Humans and Rodents

Perhaps you’ve had the experience of mentally traveling back in time to an event after it is brought up in a conversation, such as a wedding day or a funeral. With a single verbal cue, all sorts of memories can flood in. Memories of the emotions, the weather, the food, the guests, are all expressible in a single condensed narrative.

Storytelling is a foundational aspect of being human and is one of the major behavioral and cognitive characteristics that differentiates us from other animals. This act relies on our ability to encode, store, and retrieve episodic memories. Colorful and alive, these memories are drawn upon when we talk about events in our lives that are rich in sensory and emotional detail.

Episodic memory is a type of declarative memory, that is, explicit memory, that is consciously accessible and verbally recallable. This memory system was first proposed by psychologist Endel Tulving in 1972, who defined it as a memory system that “receives and stores information about temporally dated episodes or events, and temporal-spatial relations among these events”^.[1]

The concept grew out of semantic memory, the other side of the declarative memory coin. Semantic memory concerns general facts such as historical events, mathematical formulas, and similar information that is not localized to an experienced place and time. Semantic information develops from accumulated and abstracted episodic memories.

In contrast, episodic memory is concerned with the happenings of things in particular places at particular times. By encoding the “when”, “where”, and “what” of events in a given spatiotemporal context, episodic memory allows us the unique ability to reconstruct and re-experience past events. This includes the multimodal sensory information that was present when the memory was initially stored.^[2]

Dual-Process Theory of Episodic Memory

Episodic memory is typically understood in terms of two independent processes:

• Recollection: Recollection is the process that elicits the retrieval of this multisensory spatial and temporal information pertaining to a given event.^[2] This is knowledge of an object or event in relation to its context, such as when or where it happened.
• Familiarity: Familiarity is a unidimensional signal that permits simple judgments of past occurrences.^[2] This involves a basic awareness of an object and its features.

This is known as the dual-process theory of episodic memory. In this framework, recollection involves remembering, while familiarity involves knowing, thereby granting the rememberer a sense of oldness.

Neuroimaging evidence supports that these processes are subserved by distinct neural systems. The hippocampal formation is selectively activated for recollection or associative memories, whereas the entorhinal and perirhinal cortex are involved in familiarity-based and item-based non-associative memories.^[2]

What Makes Episodic Memory Unique?

Compared to other memory systems, episodic memory is unique in that:^[3]

• It is the most vulnerable to neuronal dysfunction from a variety of disorders, syndromes, and conditions
• Subject to rapid forgetting with increasing time and age
• It is multidimensional, integrating “where”, “what”, and “when” components of experience
• In humans, involves autonoetic awareness, or the ability to be aware of one’s self as an entity in time
• Emerges at approximately 3 or 4 years of age in humans
• It is dependent on language for the most accurate episodic recollection

We can report that we remember an event with the help of language, but non-verbal animals are unable to express their subjective state, which has made episodic memory difficult to assess in non-human animals.

For this reason, the existence of episodic memory in non-human animals is debated, but there is evidence that they may bear an implicit form of episodic memory, inferable from behavior. Later, we will discuss some tasks that have been adapted to assess episodic-like memory in rodents.

Episodic memory is subserved by a widely distributed network of cortical and subcortical brain regions. One of the major hubs of this network are the medial temporal lobe structures, including the hippocampus and the surrounding parahippocampal cortical areas. These interacting regions have been known for decades to be fundamental for the acquisition and retrieval of episodic memories. Additionally, the organization of these pathways are largely conserved across mammalian species from rodents to primates.^[2]

Let’s take a deeper look at the main regions in the hippocampal formation supporting episodic memory. After that, we will also discuss the contributions to episodic memory from the prefrontal cortex and a few limbic regions.

The Parahippocampal Regions

Before funneling into the hippocampus, information is processed within the parahippocampal regions. The parahippocampal regions receive inputs from the cortical association areas, wherein complex processing and integration of sensory information occurs. This interconnected set of medial temporal lobe structures surround the hippocampus and includes the:

• perirhinal cortex
• parahippocampal cortex (known as the postrhinal cortex in rodents)
• entorhinal cortex.

Perirhinal Cortex

The perirhinal cortex is densely connected with all sensory regions and plays an important role in transferring information to and from the hippocampus. It is thought to be important for the “what” quality of episodic memory, including individual object recognition and familiarity of non-associative, item-based memory. For instance, in studies surveying the effects of perirhinal cortex damage, researchers have found that this area is critical to memory for individual stimuli within the context of delayed nonmatch-to-sample tasks in both rats and monkeys.^[4]

Parahippocampal Cortex

The parahippocampal cortex receives inputs from areas that process multisensory spatial information. This region has a functional role in many aspects of cognition, but in terms of episodic memory, it is thought to be important in processing contextual associations (the memory of associations between items), thereby binding a given memory item within a particular context.^[5]

Entorhinal Cortex

The entorhinal cortex is the main relay center between the hippocampus and the neocortex. It receives input from limbic and cortical association areas and sends hippocampal output back out to cortical regions. The entorhinal cortex is thought to encode sensory cues and associations between those cues. While the medial entorhinal cortex supports the processing of spatial components of episodic memory, entorhinal neurons in the lateral region can acquire selectivity to nonspatial features of experience as well, such as the temporal flow of experience.^[6]

The Hippocampus

In this section, we will discuss how the hippocampus interacts to support episodic memory at two different levels of analysis: the cellular level and network-level.

Network-level Contributions to Episodic Memory

The hippocampus is central to episodic memory because of its functional role in combining information from multiple cortical streams. In turn, this supports our ability to encode and retrieve episodic memories that are rich in sensory detail.

One theory, called the contextual binding theory, suggests the hippocampus binds relevant contextual information encoded in the parahippocampal cortex with object information encoded in the perirhinal cortex to form a coherent episodic representation. Hippocampal lesions in rats and humans disrupt the ability to combine the “what”, “when”, and “where” qualities of each experience, a requirement to compose a retrieved memory.

One of the most influential models of the hippocampus is known as the hippocampal indexing theory. According to this model, the hippocampus acts as an index, storing the different patterns of neocortical activity associated with our memories. When a particular cue is present, a hippocampal representation is activated, which reinstates the original pattern of activity in the cortex, resulting in a re-experiencing of the event.^[7]

Research is split on whether or not episodic memories always rely on the hippocampus. Some believe hippocampus stores episodic memories for a short time until the memories are consolidated to the neocortex.

The Cellular Basis of Hippocampal-dependent Episodic Memory

The hippocampus mediates episodic memory processes by coding for both spatial and temporal dimensions of an experience. The hippocampus generates cognitive maps through place cell firing patterns, also known as place fields.

Place cells are pyramidal neurons that spatially code the environment by firing when the animal is in a particular location. Recent evidence suggests place fields are highly sensitive to context, so the hippocampus may create unique contextual representations via these place fields. This function is a necessary prerequisite for episodic memory, which by definition includes spatial and temporal context.^[8]

The temporal organization of episodic memory is coded by hippocampal time cells. These cells have been studied in rats and monkeys, and have been found to fire when the animal is at a particular moment in a temporally-structured experience. Generally speaking, time cells are active in tasks that involve remembering sequences of events, and so code for temporal flow. This may be remembering a left turn in a maze environment for a rat, or, in humans, recalling a specific movie clip scene.^[9] 

Prefrontal Cortex

Initially, it was thought that frontal damage impaired episodic memory retrieval by its effects on attention, organization, and motivation. But, recent studies have shown that frontal systems are important for:^[10]

• memory retrieval strategies,
• tagging contextual or temporal information in memory,
• delayed response,
• associative learning,
• temporally ordering memories.

The prefrontal cortex plays an important executive “choosing” role in episodic memory by monitoring, managing, and selecting memories. Without the prefrontal cortex intact, we would be unable to effectively use controlled processes such as searching and monitoring during memory retrieval or store information in an organized manner.^[10]

Prefrontal cortex damage causes selective deficits in recollection. This is seen experimentally by the high rate of false-positive responses to items not seen in the current study phase of the task but experienced in preceding study lists. Additionally, individuals with prefrontal cortex damage are able to learn new information, but do so in a disordered fashion.^[10]

Neocortical areas outside the frontal region, such as the temporal and parietal regions, contribute to declarative memory through various aspects of cognitive and perceptual processing, depending on the sensory modality in question. Generally speaking, these areas are thought to act as the permanent storehouse of episodic memories.

Amygdala

A key brain region of the limbic system, the amygdala, is important for processing motivation and emotions such as fear. Emotion increases the chance that an event will be remembered later and more vividly. Emotions are thought to selectively impact episodic memory recollection rather than familiarity, which is supported by the perirhinal cortex.

Neuroimaging and electrophysiological studies show that the amygdala modulates the encoding and storage of hippocampal-dependent memories.^[11] In particular, the amygdala may support the binding of memory items to emotion, rather than context (such as in the hippocampus). Ultimately,  this item-emotion binding helps to support quick episodic memory recollection with relatively slow forgetting. The relationship is bidirectional as well, the hippocampal formation can modulate amygdala activity when emotional stimuli are encountered.^[11]

Mammillary Bodies

The mammillary bodies are part of the limbic system and consists of two groups of nuclei known as the lateral and medial mammillary bodies. They receive afferent connections from the hippocampus, and send efferent projections to the thalamus. Being part of the limbic system, the mammillary bodies are implicated in emotional as well as memory processes.

The mammillary bodies are important for recollective memories. These limbic nuclei are  commonly damaged in both Korsakoff’s syndrome and Alzhemer’s disease. In humans, lesioned mammillary bodies induce temporal order judgement deficits and anterograde amnesia.

By contrast, in rodents, mammillary body damage induces deficits in the contextual fear conditioning paradigm. As a limbic region, its contribution to emotional arousal suggests it may be important for spontaneous retrieval processes used in episodic memory tasks wherein information may be bound to specific emotional cues.^[12]

Episodic memory in humans is measured in a number of different tasks that rely on recall, recognition, or a combination of both. We will also discuss virtual reality tasks, a more recent development that more accurately captures the real-life intricacies of episodic memory.

Recall Tasks

Recall tasks for episodic memory assessment come in three main flavors: free, cued, and serial. In the section below, we will take a look at these tasks.

Free Recall Task

Free recall tasks are the most common in human episodic memory literature and are often part of neuropsychological evaluations. In free recall tasks, subjects remember items on a list based on internally-generated cues, which they can recall in any order.

According to one longitudinal study, free recall episodic memory tests can significantly predict dementia 10 years prior to a clinical diagnosis.^[13]

Indeed, they have been found to improve the validity of diagnoses of mild cognitive impairment by decreasing the rate of false positives in the prediction of medial temporal lobe atrophy.^[14]

Cued Recall Task

In cued recall tasks, memory retrieval occurs in response to specific external cues that trigger retrieval. In this way, the cue facilitates retrieval because it is related to the to-be-remembered object.^[15]

For example, participants may be given word pairs to study. The experimenter then cues the participant with one word from the pair, who then must recall the other word that makes up the pair.

Cued recall is used in many neuropsychological tests, such as the California Verbal Learning Test. It is used to identify memory deficits in disorders such as mild cognitive impairment (MCI) and Alzheimer’s disease.^[15]

Serial Recall Task

Serial recall refers to the retrieval of events in a specified order, whether that be chronological events in episodic memory or the recall of words, letters or digits presented in a list. Serial sequences in short-term memory are stored as discrete items, but in long-term memory, they are stored as a whole.

Serial recall is commonly found in neuropsychological evaluations. The participant may be asked to recall a series of list items forward or backward, either immediately after presentation or after a short delay.^[16]

In general, serial recall ability decreases as the length of the list or sequence increases. Similar to free recall, participants show better recall of items earlier in the sequence and later in the sequence, dubbed the primacy and recency effect, respectively. Serial recall tasks are sensitive to the memory-impairing effects caused by disorders such as Alzheimer’s disease, concussive injuries, and temporal lobe epilepsy.^[16]

Verbal Learning Tests

Episodic memory assessment is usually conducted in a clinical setting by requesting the subject to remember a verbally presented story or a list of words. Between memory encoding and retrieval (i.e. before the learning and testing periods), the participant is given a distracting task or “interference list.” This is done so that they can’t mentally rehearse the learned material.

One example of a verbal learning test is the Picture Sequence Memory Test (PSMT). In this test, the participant is presented with a series of pictured objects and activities in a given order on a screen while the content of the pictures is simultaneously described verbally.^[17]

The participant is requested to reproduce the shown sequence over several learning trials. The difficulty of this task can be manipulated by decreasing the level of connectivity between picture sequences, so that the items are not meaningfully related in any obvious way.^[17]

Generally speaking, these tasks do not measure the spatial or temporal context of the learning event, so these factors have to be measured directly.

Self-report Tests

Self-report or interviews are generally given in a clinical setting as a questionnaire for important life events. These tests are effective ways to assess the nature of episodic cognition and its neural substrates, since these tasks tap into the “mental time travel” required for episodic recollection.

During the autobiographical interview, the participant may be asked to give a detailed report on three personal time periods, such as childhood, early adult life, and recent events. In general, the fewer the episodic details remembered for a given time period, the stronger the deficits in episodic memory functioning. Performance may be scored by the frequency of episodic details given, categorically grouped by event, time, place, perception, thought, and emotion.^[18]

The major drawback of using self-report tests is that they may be measuring semantic memory rather than episodic. Since meaningful life events in one’s personal history are commonly recollected and rehearsed many times over the years, the more these events become factual and semantic.

Nonetheless, self-report tests are sensitive to the early stages of neurodegenerative disorders. Self-reported personal events tend to be less specific, less vivid, and overgeneralized in these patient populations compared to healthy persons.^[18]

Virtual Reality Tests

Neuropsychological tests often weakly correlate with the multifaceted nature of episodic memory. However, virtual reality is an optimal paradigm to investigate episodic memory that better offers an immersive and realistic way to capture “real life” complex episodic memory performance.

In these tasks, subjects are immersed in digital scenarios that are representative of everyday life situations such as being in a living room, kitchen, or grocery store. Then, the researcher can implement simple tasks to evaluate the nature of episodic memory with precise control over the stimuli shown.^[19]

For instance, in 2001, Burgess and colleagues used a VR-based episodic memory task alongside neuroimaging. Participants were immersed in a virtual town and asked to follow a route where they received 16 objects from two people in two unique locations. With concurrent functional MRI recording, the memory of the objects, places, and people were then tested.^[20]

Plancher and colleagues benchmarked virtual-reality episodic memory tasks against neuropsychological assessments and found the virtual tests better correlated with daily self-reported memory complaints. VR testing was also better at characterizing the subjects in the study as either healthy, mild cognitively impaired, or suffering from Alzheimer’s disease.^[21]

Ultimately, such a set-up tests the participant’s ability to encode, store, and retrieve episodic memories within an interactive environment that contains life-like spatial and temporal dimensions. Assessments like this can allow researchers to craft specific spatiotemporal contexts for to-be-remembered episodes and allows them to more accurately delineate the complex nature of episodic memory.

In rodents, episodic memory has been difficult to measure in lab environments, since recollecting accurately is dependent on language. However, because episodic memory is broadly defined in terms of the “what”, “where”, and “when” of experiences, tasks have been developed that allows animals to demonstrate “episodic-like” memory. These tasks do not require evidence of conscious verbal recollection or a sense of self in subjective time, criteria from Tulving’s 1972 definition of episodic memory as mentioned previously.

What-where-when Tasks

In a what-where-when paradigm, the animal is assessed for memory of an object (what), its location (where), and the occasion (when). Taken together, these components define a unique experience and form a single, integrated representation that is used to flexibly guide goal-oriented behavior. Compared to what-where or what-when paradigms, what-where-when tasks have the most strict behavioral criteria, so it is the best suited for determining episodic-like behavior in non-human animals.^[22]

To demonstrate successful memory for all three components, the rats must show increased exploration for unfamiliar objects over familiar objects (novel-object recognition) as well as enhanced exploration for displaced objects over non-displaced objects (object-place recognition). In addition, the rats must show memory for temporal order as indicated by the increased exploration of objects presented before the test phase.^[23]

What-where-when tasks strongly depend on hippocampal integrity and are dissociable from tasks that solely assess familiarity of objects or their locations.^[22]

What-where-which Tasks

Rodents have been found to have poor memory for the temporal aspects of an episode, and so a related behavioral assay substitutes the “when” component with “which context”. In this way, the temporal information defined by “when” is represented instead by the contextual information in which the event occurs, or the occasion-setter “which”. Therefore, instead of remembering the temporal order of an event, rodents within this task instead have to remember the particular occasion of the event as being defined by the broader context in the environment (including the colors, objects, etc.), without the use of familiarity-based retrieval strategies.^[24]

One task that assesses memory for what-where-which occasion in rodents is the E-Maze. The E-Maze is like the Open Field maze but it’s shaped like an E, with three arms of equal dimensions attached to an alleyway in a perpendicular manner. The task allows the experimenter to manipulate the context (floor and wall coverings), objects, and their locations. It takes advantage of the rodent’s tendency to explore novel environments, seen as novel object-location-context combinations.^[25]

Performance can be measured by recording parameters such as the time it took for the rodent to find the non-habituated object, the number of turns towards the habituated or non-habituated object (which are out of sight from the starting point), and exploration time.^[25]

This maze has the advantage of not requiring food or water deprivation, nor extensive rule learning (which may induce semantic memories rather than episodic). While the maze is sensitive to diseases affecting memory, it requires many trials to draw any conclusions, which may be a drawback.^[25]

Contextual and Serial Discrimination Task

The Contextual and Serial Discrimination (CSD) task is used for assessing episodic-like memory as it relates to context and associations.

In the CSD task, the animals search for food rewards in a 4 hole-board apparatus under two different contexts. This task consists of two different phases: the acquisition and retrieval phase. In the acquisition phase, animals learn two contextual discriminations separated by a delay lasting for a few minutes, depending on the protocol. Each context is distinguishable by the color, texture, and location of the baited hole. Only one of the four holes is baited, but in different positions depending on which context the animal is placed in.^[26]

In the test phase, the mice are exposed to one of the two contexts which they experienced during the acquisition phase. Then, performance and episodic memory of the context are subsequently measured.

Memory performance is assessed via the rate of exploration by the animal into the different holes. Specifically, contextual memory performance is measured by the number of correct responses, defined as the number of entries into the hole baited on the same floor-context as seen in the acquisition phase.^[26]

The CSD task simultaneously measures memory for flexible information (using contextual and temporal cues) in addition to processing of allocentric spatial information. While mice show the same performance for either context in short time intervals separating the acquisition and testing phase, long delays (~24 hours) create a performance differential. That is to say, mice more accurately retrieve the first context than the second, suggesting internal cues play a fundamental role in long-term memory performance within this task. Aged mice and mice with hippocampal lesions show impairments in remembering the first context, but demonstrate spared memory of the second (more recent) context.^[26]

Serial Odor Task

The serial odor task is an unsupervised learning task that tests the ability of the experimental rodents to encode the identity of olfactory cues embedded within a sequence. In this paradigm, mice are first habituated to three pairs of identical odors in a serial order. Following exposure to the series and after a few minute delay, the test phase is conducted to assess odor discrimination ability.^[27]

In the test phase, the mice are presented with a new pair of smells, containing one of the previous odors alongside a novel odor. Odor exploration is scored by the time spent exploring the novel odor compared to the familiar odor. Healthy mice explore the novel odor more than the familiar odor, indicating successful recollection of the already-presented odor. Serial odor learning is dependent on the bilateral function of the lateral perforant pathway, projecting from the entorhinal cortex to the dentate gyrus.^[27]

Contextual Fear Conditioning Procedure

The contextual fear conditioning task is a one-trial conditioning procedure to test episodic-like memory. In this task, mice or rats start in a novel conditioning cage, in which they hear an auditory tone alongside an aversive, unconditioned foot-shock. The animal associates the aversive stimulus with the new context as well as the tone. Creating a contextual conditioned stimulus in this way involves declarative memory processes, as the animal must form an integrated, multisensory representation of the event.^[28]

In the testing phase, animals are placed again in the original conditioning cage after a delay of 24 hours or more, and freezing responses are measured. Contextual fear conditioning initially relies primarily on the hippocampus, but over several weeks shifts to becoming primarily reliant on cortical regions. This task is impaired in transgenic Alzheimer’s mice who show neuropathology in the hippocampal formation and cortical areas. To this end, it has the advantage of having high intrinsic validity in addition to being reliable and automatable.^[29]

Repeated Reversal and Radial Arm Maze Tasks

The repeated reversal task is analogous to a delayed matching to place task adapted for mice. In this task, mice learn a series of spatial locations in a classic Morris Water Maze context. They learn to reliably escape onto a hidden platform at a given location, and then the platform is moved to a new location. With daily platform location changes, the old memory trace for the earlier location must be suppressed. As such, earlier locations are encoded in long-term memory as unique events and may cause interference with new platform locations. Less precise memory for new platform locations may therefore show up as an inability to quickly learn the new platform location or an incapability to inhibit the long-term memories associated with the previous platform locations.^[30]

New platform location learning is characterized by saving scores, that is, differences in latency to find the platform between the beginning and end of daily training. Transgenic Alzheimer’s mice (APPswe/ PS1dE9 and PDAPP strains) show less preference for new platform locations and slower overall learning of successive platform locations compared to healthy controls. This is exhibited as more time spent around the old (reference) platform location over successive days.^[31]

In the Radial Water Maze task, a 6-arm radial arm maze is placed in the same open pool used in the Morris water maze. Over repeated trials of this task, mice learn to return to the arm that contains the hidden platform. Such a win-stay strategy increases the demands on the hippocampal-dependent working memory system of the animals. Additionally, it assesses spatial memory in a situation where an inhibition of reference memory is not required, as seen in the repeated reversal task.^[31]

When the animal swims into an arm that doesn’t contain a submerged platform, this counts as an error. The platform location is typically changed across days, but stays constant over the multiple trials of a single day. Therefore, mice will learn the rule that the platform is contained in a single arm on each trial within a day, but in a different arm each day.^[32]

Since episodic memory performance impairment is one of the first cognitive symptoms to show up in a wide range of amnestic disorders, episodic memory is a sensitive indicator of early brain pathology.

In this section, we will overview how various syndromes and diseases impact episodic memory performance in humans and murine models.

Fragile X syndrome

Fragile X syndrome is an inherited intellectual disability caused by a mutation in the FMR1 gene. It is the most common genetic cause of autism, a developmental disorder characterized by behavioral and learning challenges. The FMR1 gene is transcribed most prominently in two areas crucial for memory encoding and attention: the hippocampus and basal forebrain. Individuals with Fragile X syndrome show less activation in these areas during episodic memory encoding.^[33]

The Fmr1-KO Mouse Model of Fragile X Syndrome

The FMR1-knockout model is a valuable tool for exploring the physiological role of FMR1. Using this model, Wang and colleagues found impairments in episodic-like memory in mice, as assessed within a serial odor task paradigm. The FMR1 knockout mice show impairments in the acquisition of information in an episodic context, demonstrated as reduced time spent sampling the novel odor in the serial odor task.^[27] Additionally, the knockout mice showed reduced synaptic plasticity in a part of the hippocampal formation important for processing cue identity information within a sequence, namely, the lateral perforant pathway. This pathway projects from the lateral entorhinal cortex to the dentate gyrus.^[27]

Down’s Syndrome

Down syndrome, also known as trisomy 21, is a genetic disorder caused by an extra copy (either in full or in part) of chromosome 21. Individuals with Down’s syndrome have deficits in verbal short-term memory and explicit long-term memory but show preserved visuospatial short-term memory, associative learning, and implicit long-term memory.^[34]

The Ts65Dn Mouse Model of Down’s Syndrome

The Ts65Dn mouse model is the most commonly used rodent model to elucidate the cognitive dysfunction of Down’s syndrome. These mice are segmentally trisomic at chromosome 16, which is homologous to human chromosome 21. They show many features that characterize Down’s syndrome, including cerebellar and craniofacial abnormalities and neurodegeneration later in life.^[35]

Ts65Dn mice perform at normal levels in procedural tasks but show deficits in declarative tasks involving conscious recollection of information, especially within the context of spatial tasks. In an episodic-like memory paradigm, Ts65Dn mice demonstrate normal performance in novel object recognition and object displacement tasks over short time periods of a few minutes, but impairments in detecting object novelty over long time periods of 24 hours.^[35]

Korsakoff’s Syndrome

Korsakoff’s syndrome is an amnestic disorder caused by a thiamine or vitamin B1 deficiency. Thiamine is a necessary cofactor in biochemical reactions producing cellular energy. When chronically deficient, this results primarily in gliosis, hemorrhage, and bleeding in the mammillary bodies and lesions within the diencephalic regions.^[36] This disorder is most commonly a result of heavy, chronic alcohol consumption and severe malnutrition.

Korsakoff’s syndrome is characterized primarily by amnesia, memory loss, confabulation, and disordered temporal sequencing. While implicit spatial, verbal, and procedural memory are largely preserved, individuals with Korsakoff’s syndrome show impaired declarative memory, executive function, and deficits in the processing of spatial and temporal components of episodic memory. Anterograde memory processes appear to be more severely affected than retrograde memory processes.^[36]

The Pyrithiamine-induced Thiamine Deficiency Murine Model of Korsakoff’s Syndrome

Korsakoff’s syndrome has been modeled in rodents either through the use of thiamine-deficient diets or, more commonly, with the pyrithiamine-induced thiamine deficiency (PTD) model.^[12] This model utilizes pyrithiamine, a thiamine antagonist, in conjunction with a thiamine-deficient diet. The PTD model induces lesions predominantly in the diencephalic areas, but also the basal forebrain, cortical areas, and mammillary bodies.^[37] As a consequence, performance on tasks assessing episodic working memory are impaired. Specifically, PTD rats show impaired formation of hippocampal-dependent spatial and avoidance memories, as measured in water maze and contextual fear conditioning tasks.^[38]

Alzheimer’s Disease

Alzheimer’s disease affects approximately one in every 10 people over the age of 65. It is characterized by the accumulation of neurotoxic extracellular amyloid-beta plaques and intracellular neurofibrillary tangles that disrupt neural communication, causing widespread neuronal death. Since the amyloid plaques and neurofibrillary tangles accumulate at a relatively slow rate, Alzheimer’s disease contains a long preclinical period where clinicians can detect episodic memory deficits stably up to three years prior to a diagnosis.^[39]

Alzheimer’s disease patients show medial temporal lobe pathology early in the disease course, as well as deterioration of other important cortical hubs of episodic memory such as the parietal and temporal lobes. Alzheimer’s disease creates dysfunctions in several tests of episodic memory, including the ability to discriminate old from new (recognition memory tests), delayed free recall, and prose recall.^[39]

3xTg Mouse Transgenic Model of Alzheimer’s Disease

One of the most popular models of Alzheimer’s disease in murine models is the 3xTg transgenic model. 3xTg mice develop amyloid beta pathology throughout the medial temporal lobe and neocortex in a similar manner to Alzheimer’s disease progression in humans.

Compared to control mice, 3xTg AD mice at six months of age showed impairments in identifying a novel what-where-which occasion in an open field what-where-which task.^[40]

APPswe/Ps1dE9 Transgenic Model of Alzheimer’s Disease

The APPswe/Ps1dE9 model is an aggressive double-transgenic model of familial Alzheimer’s disease. Since mice expressing APPswe alone don’t show amyloidosis until after 24 months of age, the cross with Ps1dE9 significantly elevates amyloid-beta levels in the brain. Indeed, plaque deposits may begin to appear as early as five months of age.^[32]

By 6 months of age, mice expressing amyloid precursor protein (APP) with mutant presenilin 1 (PS1) show deficits in episodic-like memory. This has been measured as impairments in learning the new platform location in the repeated reversal task and decreased performance in the radial arm water maze working memory task compared to healthy controls.^[31]

The Aβ_1-42 Injection Model

The Aβ_1-42 Injection Model involves injections (commonly intracerebroventricularly) of toxic soluble species of amyloid beta, including fibrils, protofibrils, and oligomers. This non-transgenic model produces typical features of Alzheimer’s disease pathology, including deficits in episodic-like memory. In 2012, Ceccom and colleagues utilized this model and demonstrated episodic-like memory impairments in mice after a 21-day delay, expressed as impaired freezing in a contextual fear memory assay.^[29]

This model may be best suited for short-term studies that are interested in the effects of amyloid-beta on a particular brain region, or to rapidly screen pharmacological candidates. It has the advantage of being easy to implement, reliable, and highly reproducible.^[29]

Schizophrenia

Episodic memory impairments are prevalent in schizophrenia along with other negative cognitive symptoms such as hallucinations, delusions, and paranoia.

Schizophrenia patients show abnormalities in crucial brain regions involved in episodic memory, including the hippocampal, parahippocampal, frontal, and temporal regions.

Additionally, schizophrenia is characterized by less prefrontal activation than control subjects during encoding and retrieval of episodic memory.^[41]

Df(16)A+/- Murine Model of Schizophrenia

In a recent 2018 study, Gogos and Losonczy investigated episodic-like memory impairments in mice using a genetic murine model of schizophrenia known as Df(16)A+/-. This animal model has a deletion of chromosome 22q11.2, a common genetic risk factor for schizophrenia.

The researchers used real time 2-photon microscopy to record place cells in the CA1 subfield of the hippocampus, a crucial area that encodes the spatial component of episodic memories. The mice were tasked to navigate familiar and novel environments on a Treadmill, including adapting to environment alterations.

While the control mice showed stable spatial maps and adaptable place cells that reorganized based on environmental context, the Df(16)A+/- mice showed impairments in adapting to environmental changes and deficits in recalling familiar environments. The schizophrenic mice, therefore, showed impairments in their episodic memory as evidenced by less stable cognitive maps and less adaptable goal-directed place cell activity.^[42]

Traumatic Brain Injury

An estimated 2.8 million people in the US alone suffer a TBI annually as a result of sports injuries, car accidents, or other concussive head injuries.

TBIs are associated with memory impairments as well as deficits in cognitive processes such as executive functioning, attention, and processing speed. TBIs can produce subdural hematomas and widespread white matter lesions in susceptible areas such as the frontal and temporal lobes, expressed as a diffuse axonal injury.

As a result these injuries can result in serious disruptions in the connectivity between the many regions that support episodic memory. For example, TBIs involving predominantly the frontal lobes can impair episodic memory by disrupting encoding strategies, effortful retrieval, source monitoring, and temporal order memory.

One meta-review analyzing the effects of moderate-to-severe TBIs in humans  found that the largest effect on episodic memory was seen with regards to verbal memory, specifically verbal recall within the context of delayed testing.^[43]

Lateral Fluid Percussion Injury Model

Traumatic brain injuries in rats can be effectively modeled using lateral fluid percussion injury (LFPI). To induce TBI using LFPI, researchers use a pressure pulse targeted at the intact dura via a craniotomy. In 2013, Gurkoff and colleagues utilized this model to test the “when” component of episodic memory via a temporal ordering task. The rats were exposed to an odor sequence and then were assessed on their ability to discriminate that sequence from a novel sequence after a delay of an hour or more. The researchers found that injured animals demonstrated no preference for either sequence, while the control animals preferred the initial sequence, as this sequence is more easily remembered due to the primacy effect.^[44]

To test the spatial component of episodic memory,  Gurkoff and colleagues used topological tasks such as object-location recognition tasks, where the rats must distinguish when two objects have switched positions in space. LFPI rats show deficits in this task at long time windows (>1 hour), and were unable to discriminate the new location from the old location.^[44]

Cognitive Aging

A major feature of cognitive aging involves a decline in episodic memory performance and functioning.

Aged rats (22-24 months old) show impaired performance selectively on tests of episodic memory recollection, with relative sparing of familiarity. Similar to schizophrenia-like rats, aged rats show inflexible cognitive maps compared to young rats (6-8 months old), as hippocampal place cells fail to adapt when aged animals are exposed to a novel environment.^[45]

This is seen mostly as impairments in hippocampal-dependent spatial memory assessed in Morris Water Maze learning. Inflexible cognitive maps, therefore, imply the hippocampus isn’t able to effectively encode subtle differences in context that may vary across multiple experiences, such as the sequence of trials in the Morris water maze.^[45]

Episodic memory impairments due to aging is tightly linked to dysfunctions in the hippocampus. An Alzheimer’s disease mimic known as hippocampal sclerosis of aging is a known causative factor, resulting in hippocampal formation cell loss and gliosis due to a combination of advanced age and cerebrovascular pathology.^[46]

Donepezil Improves Episodic Memory in Sleep Deprivation

Donepezil is a psychotropic medication prescribed to treat Alzheimer’s disease. It is an acetylcholinesterase inhibitor, so it exerts its action by binding and reversibly inactivating the enzyme acetylcholinesterase from breaking down acetylcholine. This increases the levels and duration of acetylcholine at cholinergic synapses.

Sleep is fundamentally important for hippocampal-dependent episodic memory processes, especially after episodic encoding. Sleep deprivation, even as little as 24 hours, disrupts episodic memory performance by interfering with consolidation and retrieval processes. One study found that a daily dose of 5mg of donepezil improved episodic memory deficits in sleep-deprived individuals within a delayed word recognition task. The researchers found that it improved delayed recognition through an improvement in attention and memory encoding.^[47]

DHEA Increases Recollection Accuracy

DHEA, or dehydroepiandrosterone, is a steroid hormone produced naturally by the adrenal glands and brain, but also found in supplement form. DHEA has been found in humans and rodents to exert cognition and memory-enhancing effects through multiple mechanisms. It acts as a glucocorticoid antagonist, thereby ameliorating the negative effects of glucocorticoids like cortisol on cognition. Additionally, rodent studies have shown that DHEA affects synaptic plasticity in the hippocampus through antagonism of the GABA-A receptor and agonism of the sigma-1 receptor.^[48]

One 2006 study investigated the effects of DHEA on cortisol levels and episodic memory retrieval in 24 healthy individuals. The subjects were on a 7-day course of 150mg DHEA, and episodic memory was assessed through a task measuring recognition of spoken words and corresponding associations shown during the learning phase.

The researchers found DHEA administration led to decreased levels of evening cortisol and higher recollection accuracy in the episodic memory task. Concurrent electromagnetic tomography revealed hippocampal activation and an early activation of the anterior cingulate cortex in the DHEA group. The anterior cingulate cortex is a cortical region that is sensitive to steroids and is involved in pre-hippocampal processing.^[49]

Through the use of DHEA, the researchers established that intervening to decrease cortisol levels ultimately leads to higher recollection accuracy. Such findings suggest that cortisol is involved and can influence episodic memory processes and performance.

Marijuana’s Amnesic Properties

While hundreds of cannabinoids are present in the marijuana plant, the main chemical responsible for marijuana’s psychoactive effects is tetrahydrocannabinol (THC). THC’s effects are a result of its agonism of CB1 and CB2 receptors, the neuromodulatory cannabinoid receptors found in the brain and peripheral tissues, respectively.

A high quantity of CB receptors are found in brain regions supporting episodic memory. including the medial temporal lobe and cerebral cortex. Cannabinoids inhibit the release of several neurotransmitters in these areas, including glutamate, acetylcholine, and epinephrine, which collectively decrease neuronal activity and contribute to its amnesic properties.^[50]

Cannabis users show reduced activation in regions involved with memory processing, including the lateral and medial temporal lobe as well as parietal and frontal regions involved in attention and performance monitoring. Cannabis impairs episodic memory encoding, consolidation, and retrieval and verbal recall during intoxication, with residual effects that can linger for days after the most recent use in heavy users.^[51] Specifically, THC transiently impairs immediate and delayed free recall of information presented before, but not after, drug administration in a dose-and delay-dependent manner. The tasks include recall of word lists, digits, and prose.^[51]

One study found that a past history of cannabis use disorder causes episodic memory impairments and abnormalities in hippocampal morphology relative to non-users. The structural abnormalities include reduced hippocampal volume correlated to the amount of cannabis used.^[51]

Assessing Effects of Cannabis on Episodic Memory in Mice

Rodent studies surveying the effects of cannabinoids on memory commonly utilize WIN 55,212-2, a synthetic CB1/CB2 receptor agonist with similar effects as THC. In 2017, Mouro and colleagues found that mice administered this drug showed deficits in long-term episodic memory as assessed in a novel object recognition memory task. This was demonstrated as equal time spent exploring both the familiar and novel object in an open field arena 24 hours after training.^[52]

Interestingly, the researchers found that blocking adenosine (A_2A) receptors abolishing the memory-impairing effects of the CB1 receptor agonist. Thus, A_2A receptors may be a future pharmacological target to prevent the cognitive side effects associated with cannabinoid receptor drugs.^[52]

Ketamine Disrupts Long-Term Memory Encoding

Ketamine is a non-competitive NMDA antagonist that is used as an anesthetic and recreationally as a dissociative hallucinogen. Since episodic recall is largely mediated by glutamatergic transmission in the hippocampus that relies on NMDA receptors, ketamine produces a dose-dependent impairment of episodic memory performance.^[53]

Ketamine exerts its effects on key brain regions involved in episodic memory, including the hippocampal formation and frontal regions.^[53] Ketamine, and NMDA receptor antagonists generally, disrupt long term potentiation in the hippocampus, a crucial mechanism underlying learning and long-term memory.

According to one 2000 study conducted by Hellem and colleagues, one acute ketamine infusion impaired performance in free recall and recognition of words presented during, but not before, the infusion. It was found to impair episodic memory at the level of encoding but not retrieval, similar to the memory deficits seen in acute schizophrenia.^[54][55]

Donepezil and Memantine Reverse Age-induced Memory Impairment

Donepezil and memantine are two compounds used in the treatment of Alzheimer’s disease. Memantine is an NMDA antagonist used to treat moderate to severe forms of Alzheimer’s disease. Donepezil, on the other hand, is an acetylcholinesterase inhibitor used to treat mild to moderate forms of Alzheimer’s. It is also used to treat cognitive impairments in sleep-deprived individuals, as mentioned previously.

Using the contextual and serial discrimination (CSD) task, Tronche and colleagues found these that these two compounds can lead to significant memory-enhancing effects on contextual memory performance.

Notably, 0.3mg/kg of donepezil reversed memory impairments induced by aging in 14-15 month mice, mostly by reducing the number of interfering responses (wrong context responses). In aged mice (18-19 months), memantine at a dose of 3.0mg/kg had a memory-enhancing effect, also seen as an increase in correct responses in the CSD task.^[26]

Since the CSD task can detect early age-dependent cognitive impairments, the researchers concluded that the CSD task is a reliable tool to identify pharmacological targets in the treatment of age-related amnesia.^[26]

Copper Chelator Agents Recover Episodic Memory in Alzheimer’s Mouse Model

Copper ions are known to accumulate in amyloid plaques, one of the major pathological features of Alzheimer’s disease caused by the clumping of extracellular beta-amyloid proteins. These ions are thought to in part mediate the toxicity and the oxidative stress induced by the plaques.

Copper chelator agents are small molecules that are able to bind to and shuttle copper out of amyloid plaques and restore normal circulation of copper ions. The copper chelators PA1637 and Clioquinol have been found to successfully rescue episodic-like memory deficits in a non-transgenic mouse model of Alzheimer’s disease (see the Aβ1-42 Injection Model discussed above).^[29]

More specifically,untreated amyloid mice show a significant decrease in freezing  responses within a contextual fear memory assay. On the other hand, Alzheimer’s mice given copper chelator agents show significant improvement  in their freezing scores, indicating a reversal of memory deficits induced by beta amyloid pathology.^[29]

HDAi Restore Contextual Memory Deficits in Alzheimer’s Mice

Histone deacetylase are enzymes that remove acetyl groups from histone proteins on DNA, which alters chromatin structure and downregulates gene transcription. Ultimately, this allows DNA to wrap around histones. Thus, histone deacetylases have an important molecular role.

Histone deacetylase inhibitors (HDAi) are compounds that inhibit histone deacetylases. Historically, HDAi has been used neurologically to treat seizures, but recent advances have shown its potential in salvaging memory deficits associated with Alzheimer’s disease.

In memory regions of the brain such as the hippocampal formation, histone acetylation has been found to occur in response to contextual learning and hippocampal-dependent memory consolidation. As such, inhibiting histone deacetylases is a promising molecular target to artificially increase acetylation and gene transcription in these regions, leading to enhanced hippocampal-dependent memory consolidation and cognitive performance.^[56]

In 2010, Kilgore and colleagues found that systemic HDAi improved contextual memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Specifically, chronic treatment with HDAi rescued freezing deficits in a contextual fear conditioning task. The authors concluded that HDACi treatment restores memory consolidation and facilitates the storage of information in this context, possibly by enhancing dendritic growth, synaptogenesis, and long-term potentiation at hippocampal synapses.^[56]

Episodic memory is crucial for humans and rodents to learn about and normally function in everyday life.

In the lab, this multidimensional memory system can be best assessed when the subject animal relies on memory for what an object is, where it is located, and when or in which context it occurs.

In humans, episodic memory is assessed in a wide variety of clinical tests, including learning tests, self-report tests, recall tasks, and, more recently, virtual reality tasks.

In light of how fragile and vulnerable to dysfunction episodic memory is from a wide variety of disorders, syndromes, and conditions, animal models are key tools for understanding and improving episodic memory. Thus, the generation of animal models of episodic-like memory holds tremendous potential for elucidating the underlying mechanisms of human memory processes and for finding pharmaceutical treatments to improve ailed episodic memory.

• According to Tulving, episodic memory is a memory system that “receives and stores information about temporally dated episodes or events, and temporal-spatial relations among these events”.
• Episodic memory is subserved by a widely distributed network of cortical and subcortical brain regions that is shared among other memory systems.
• The hippocampal formation and the surrounding parahippocampal cortices are foundational to a properly functioning episodic memory system.
• The perirhinal cortex is important in coding for the “what” quality of episodic memory, including familiarity-based knowing and individual object recognition.
• The parahippocampal cortex is important for the processing of contextual associations by binding memory items within a particular context.
• The entorhinal cortex is the relay center between the hippocampus and cortex and codes for both spatial and non-spatial aspects of episodic memory.
• The hippocampus combines information from multiple cortical streams to form an integrated, multisensory representation of episodes.
• The hippocampus is thought to code for spatial aspects of episodic memory with place cells, which fire when an animal is at a particular location in space
• The hippocampus is thought to code for temporal aspects of episodic memory with time cells, which fire at specific time periods in a temporally-structured experience
• The prefrontal cortex is important for using controlled processes during memory retrieval, such as searching and monitoring. Lesions to the PFC causes selective deficits in recollection and produces disorganized learning.
• The amygdala, the main brain area of the limbic system that is involved in processing emotions such as fear, modulates the encoding and consolidation of hippocampal-dependent memories.
• The mammillary bodies are an important region for episodic memory recollection and spontaneous retrieval strategies. This area is commonly damaged in Korsakoff’s syndrome and Alzheimer’s disease.
• Episodic memory in humans is measured using recall tasks, self-reports or interviews, verbal learning tests, and virtual reality
• Episodic memory in rodents is measured most accurately in the lab within the context of where-what-which and where-what-when paradigms.
• Episodic memory is vulnerable to a wide array of syndromes, disorders and neuropsychiatric conditions, including Fragile X syndrome, Down’s syndrome, Korsakoff’s syndrome, schizophrenia, traumatic brain injury, Alzheimer’s disease, and cognitive aging.
• Donepezil may improve episodic memory by increasing levels of acetylcholine at cholinergic synapses.
• DHEA may improve episodic memory by enhancing activity in episodic memory-supporting regions and decreasing cortisol levels.
• Marijuana and ketamine dose-dependently impair episodic memory by interfering with and decreasing activity in crucial brian regions supporting episodic memory.
• Copper chelator agents and histone deacetylase inhibitors rescue episodic-like memory deficits in murine models of Alzheimer’s disease.

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