Elements of episodic-like memory in animal models

Representations of unique events from one’s past constitute the content of episodic memories. A number of studies with non-human animals have revealed that animals remember specific episodes from their past (referred to as episodic-like memory). The development of animal models of memory holds enormous potential for gaining insight into the biological bases of human memory. Specifically, given the extensive knowledge of the rodent brain, the development of rodent models of episodic memory would open new opportunities to explore the neuroanatomical, neurochemical, neurophysiological, and molecular mechanisms of memory. Development of such animal models holds enormous potential for studying functional changes in episodic memory in animal models of Alzheimer’s disease, amnesia, and other human memory pathologies. This article reviews several approaches that have been used to assess episodic-like memory in animals. The approaches reviewed include the discrimination of what, where, and when in a radial arm maze, dissociation of recollection and familiarity, object recognition, binding, unexpected questions, and anticipation of a reproductive state. The diversity of approaches may promote the development of converging lines of evidence on the difficult problem of assessing episodic-like memory in animals.     

Animal memory: episodic-like memory in rats

Recent experiments with rats on a radial maze indicate that they can remember what foods they encountered, and when and where they encountered them. These findings, and others with food-storing birds, challenge the idea that only humans have episodic memory.     

Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis

Tuberous sclerosis complex (TSC) is a common neurological autosomal-dominant syndrome caused by mutations in the TSC1 or TSC2 genes. TSC starts in early childhood and is characterized by cerebral hamartomas (benign tumours), severe epilepsy and cognitive deficits such as mental retardation and autism. The hamartomas are characterized by loss of the remaining wild-type TSC allele, and clinical data implicate cerebral hamartomas in the generation of epileptic seizures, which may play a significant role in the development of mental retardation. The TSC2 mutation predicts alterations in mitogen-associated protein kinase (MAPK) and, together with the TSC1 mutation, in mammalian target of rapamycin (mTOR) signalling pathways. Both pathways are involved in neuronal plasticity. We therefore hypothesized that the heterozygous mutation itself, besides cerebral hamartomas, contributes to the pathogenesis of cognitive deficits and possibly also epilepsy. Here, we show that young adult TSC2+/- rats, which are virtually free of cerebral hamartomas, exhibit enhanced episodic-like memory and enhanced responses to chemically-induced kindling. The activation of cyclic adenosine monophosphate (cAMP) in the hippocampus results in stronger induction of phospho-p42-MAPK in TSC2+/- rats than in wild-type animals. Thus, the cognitive phenotype and, possibly, epilepsy in TSC patients may result not only from the focal hamartomatous lesions but also, from altered neuronal plasticity in the heterozygous tissue.     

Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease

The question of whether any non-human species displays episodic memory is controversial. Associative accounts of animal learning recognize that behaviour can change in response to single events but this does not imply that animals need or are later able to recall representations of unique events at a different time and place. The lack of language is also relevant, being the usual medium for communicating about the world, but whether it is critical for the capacity to represent and recall events is a separate matter. One reason for suspecting that certain animals possess an episodic-like memory system is that a variety of learning and memory tasks have been developed that, even though they do not meet the strict criteria required for episodic memory, have an 'episodic-like' character. These include certain one-trial learning tasks, scene-specific discrimination learning, multiple reversal learning, delayed matching and non-matching tasks and, most recently, tasks demanding recollection of 'what, where and when' an event happened. Another reason is that the neuronal architecture of brain areas thought to be involved in episodic memory (including the hippocampal formation) are substantially similar in mammals and, arguably, all vertebrates. Third, our developing understanding of activity-dependent synaptic plasticity (which is a candidate neuronal mechanism for encoding memory traces) suggests that its expression reflects certain physiological characteristics that are ideal components of a neuronal episodic memory system. These include the apparently digital character of synaptic change at individual terminals and the variable persistence of potentiation accounted for by the synaptic tag hypothesis. A further value of studying episodic-like memory in animals is the opportunity it affords to model certain kinds of neurodegenerative disease that, in humans, affect episodic memory. An example is recent work on a transgenic mouse that over-expresses a mutation of human amyloid precursor protein (APP) that occurs in familial Alzheimer's disease, under the control of platelet derived (PD) growth factor promoter (the PDAPP mouse). A striking age- and amyloid plaque-related deficit is seen using a task in which the mice have to keep changing their memory representation of the world rather than learn a single fact.     

Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory.

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.     

Hippocampal synaptic activity, pattern separation and episodic-like memory: implications for mouse models of Alzheimer's disease pathology

The present review summarizes converging evidence from animal and human studies that an early target of amyloid pathology is synaptic activity in the DG (dentate gyrus)/CA3 network. We briefly review the computational significance of the DG/CA3 network in the encoding of episodic memory and present new evidence that the CA3/DG pattern of activation is compromised in a mouse model of amyloid pathology. In addition, we present a new behavioural method to test the prediction that amyloid-related synaptic pathology will disrupt the formation of an integrated episodic-like (what, where and when) memory in mice.     

The effect of general anesthesia on memory in experimental animals

Full recovery of short-term memory (maximum time of delayed reactions) and of the structure of situational conditioned reflex and differentiation inhibition in dogs is observed in 1.5-2.5 h after tranquil-anaesthesia (diazepam-ketamine in doses of 0.3-15 mg/kg correspondingly) and dissociative anaesthesia by ketamine (15 mg/kg) in 6-8 h after neuroleptanalgesia (droperidol-fentanyl 2.5-0.05 mg/kg correspondingly), 20-24 h after narcosis by thiopental sodium (30 mg/kg) and by the end of the 3d day after neuroleptanaesthesia (droperidol-ketamine 2.5-15 mg/kg correspondingly). The recovery of the reaction of memory trace reproduction (of conditioned reaction of passive avoidance in rats) after various types of general anaesthesia is observed mainly in the same sequence, but on the average a day later than the short-term memory in dogs.     

Carbon dioxide-oxygen relationships in gas exchange of animals. In memory of Hermann Rahn.

In external gas exchange of vertebrates, behavior of the respiratory gases CO2 and O2 can in many cases adequately be explained by the different physico-chemical properties of the gases, including solubility, chemical combination in blood and tissue, and diffusivity. In particular, the differences in behavior between CO2 and O2 are often of particular relevance. This is demonstrated on a number of examples of gas exchange mechanisms in vertebrates, including (1) exchange ratio after changes in ventilation, (2) local variations of pulmonary ventilation/perfusion ratio, (3) absorption of gas from gas pockets, (4) water vs. air breathing, (5) multimodal breathing, (6) skin breathing, (7) gas exchange of avian eggs, (8) anomalous gas/blood CO2 equilibration, (9) blood/gas CO2 equilibration in avian lungs, (10) pulmonary diffusing capacity, (11) blood/water CO2 equilibration in fish gills, (12) deposition of gas into fish swim bladder.     

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the 'synaptic plasticity and memory (SPM)' hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.     

Transport of animals between rooms: a little-noted aspect of laboratory procedure that may interfere with memory

This study investigated the effects of transporting animals from the experimental room to the animal facility in between experimental sessions, a procedure routinely employed in experimental research, on long-term social recognition memory. By using the intruder-resident paradigm, independent groups of Wistar rats exposed to a 2-h encounter with an adult intruder were transported from the experimental room to the animal facility either 0.5 or 6 h after the encounter. The following day, residents were exposed to a second encounter with either the same or a different (unfamiliar) intruder. Resident's social and non-social behaviors were carefully scored and subjected to Principal Component Analysis, thus allowing to parcel out variance and relatedness among these behaviors. Resident rats transported 6 h after the first encounter exhibited reduced amount of social investigation towards familiar intruders, but an increase of social investigation when exposed to a different intruder as compared to the first encounter. These effects revealed a consistent long-lasting (24 h) social recognition memory in rats. In contrast, resident rats transported 0.5 h after the first encounter did not exhibit social recognition memory. These results indicate that this common, little-noted, laboratory procedure disturbs long-term social recognition memory.     

Using ecology to guide the study of cognitive and neural mechanisms of different aspects of spatial memory in food-hoarding animals

Understanding the survival value of behaviour does not tell us how the mechanisms that control this behaviour work. Nevertheless, understanding survival value can guide the study of these mechanisms. In this paper, we apply this principle to understanding the cognitive mechanisms that support cache retrieval in scatter-hoarding animals. We believe it is too simplistic to predict that all scatter-hoarding animals will outperform non-hoarding animals on all tests of spatial memory. Instead, we argue that we should look at the detailed ecology and natural history of each species. This understanding of natural history then allows us to make predictions about which aspects of spatial memory should be better in which species. We use the natural hoarding behaviour of the three best-studied groups of scatter-hoarding animals to make predictions about three aspects of their spatial memory: duration, capacity and spatial resolution, and we test these predictions against the existing literature. Having laid out how ecology and natural history can be used to predict detailed cognitive abilities, we then suggest using this approach to guide the study of the neural basis of these abilities. We believe that this complementary approach will reveal aspects of memory processing that would otherwise be difficult to discover.