What,where and when: deconstructing memory

The ability of animals to remember the what, where and when of a unique past event is used as an animal equivalent to human episodic memory. We currently view episodic memory as reconstructive, with an event being remembered in the context in which it took place. Importantly, this means that the components of a what, where, when memory task should be dissociable (e.g. what would be remembered to a different degree than when). We tested this hypothesis by training hummingbirds to a memory task, where the location of a reward was specified according to colour (what), location (where), and order and time of day (when). Although hummingbirds remembered these three pieces of information together more often than expected, there was a hierarchy as to how they were remembered. When seemed to be the hardest to remember, while errors relating to what were more easily corrected. Furthermore, when appears to have been encoded as a combination of time of day and sequence information. As hummingbirds solved this task using reconstruction of different memory components (what, where and when), we suggest that similar deconstructive approaches may offer a useful way to compare episodic and episodic-like memories.     

Rats answer an unexpected question after incidental encoding

A fundamental aspect of episodic memory is that retrieval of information can occur when encoding is incidental and memory assessment is unexpected. These features are difficult to model in animals because behavioral training likely gives rise to well-learned expectations about the sequence of events. Thus, the possibility remains that animals may solve an episodic memory test by using well-learned semantic rules without remembering the episode at memory assessment. Here we show that rats can answer an unexpected question after incidental encoding in a hippocampal-dependent manner, consistent with the use of episodic memory. Rats were initially trained to report about a recent event (food versus no food) and separately searched for food where there was no expectation of being asked about the presence of food. To test episodic memory, we gave rats the opportunity to incidentally encode the presence or absence of food and unexpectedly asked them to report about the recent event. Temporary inactivation of the CA3 region of the hippocampus with bilateral infusions of lidocaine selectively eliminated the ability of rats to answer the unexpected, but not the expected, question. Our studies suggest that rats remember an earlier episode after incidental encoding based upon hippocampal-dependent episodic memory.     

Neonatal representation of odour objects: distinct memories of the whole and its parts

Extraction of relevant information from highly complex environments is a prerequisite to survival. Within odour mixtures, such information is contained in the odours of specific elements or in the mixture configuration perceived as a whole unique odour. For instance, an AB mixture of the element A (ethyl isobutyrate) and the element B (ethyl maltol) generates a configural AB percept in humans and apparently in another species, the rabbit. Here, we examined whether the memory of such a configuration is distinct from the memory of the individual odorants. Taking advantage of the newborn rabbit''s ability to learn odour mixtures, we combined behavioural and pharmacological tools to specifically eliminate elemental memory of A and B after conditioning to the AB mixture and evaluate consequences on configural memory of AB. The amnesic treatment suppressed responsiveness to A and B but not to AB. Two other experiments confirmed the specific perception and particular memory of the AB mixture. These data demonstrate the existence of configurations in certain odour mixtures and their representation as unique objects: after learning, animals form a configural memory of these mixtures, which coexists with, but is relatively dissociated from, memory of their elements. This capability emerges very early in life.     

Norway rats reciprocate help according to the quality of help they received

Direct reciprocity, according to the decision rule ‘help someone who has helped you before’, reflects cooperation based on the principle of postponed benefits. A predominant factor influencing Homo sapiens'' motivation to reciprocate is an individ­ual''s perceived benefit resulting from the value of received help. But hitherto it has been unclear whether other species also base their decision to cooperate on the quality of received help. Previous experiments have demonstrated that Norway rats, Rattus norvegicus, cooperate using direct reciprocity decision rules in a variant of the iterated Prisoner''s Dilemma, where they preferentially help cooperators instead of defectors. But, as the quality of obtained benefits has not been varied, it is yet unclear whether rats use the value of received help as decision criterion to pay help back. Here, we tested whether rats distinguish between different cooperators depending purely on the quality of their help. Our data show that a rat''s propensity to reciprocate help is, indeed, adjusted to the perceived quality of the partner''s previous help. When cooperating with two conspecific partners expending the same effort, rats apparently rely on obtained benefit to adjust their level of returned help.     

Sleep Improves Prospective Remembering by Facilitating Spontaneous-Associative Retrieval Processes

Memories are of the past but for the future, enabling individuals to implement intended plans and actions at the appropriate time. Prospective memory is the specific ability to remember and execute an intended behavior at some designated point in the future. Although sleep is well-known to benefit the consolidation of memories for past events, its role for prospective memory is still not well understood. Here, we show that sleep as compared to wakefulness after prospective memory instruction enhanced the successful execution of prospective memories two days later. We further show that sleep benefited both components of prospective memory, i.e. to remember that something has to be done (prospective component) and to remember what has to be done (retrospective component). Finally, sleep enhanced prospective remembering particularly when attentional resources were reduced during task execution, suggesting that subjects after sleep were able to recruit additional spontaneous-associative retrieval processes to remember intentions successfully. Our findings indicate that sleep supports the maintenance of prospective memory over time by strengthening intentional memory representations, thus favoring the spontaneous retrieval of the intended action at the appropriate time.     

Ants adjust their pheromone deposition to a changing environment and their probability of making errors

Animals must contend with an ever-changing environment. Social animals, especially eusocial insects such as ants and bees, rely heavily on communication for their success. However, in a changing environment, communicated information can become rapidly outdated. This is a particular problem for pheromone trail using ants, as once deposited pheromones cannot be removed. Here, we study the response of ant foragers to an environmental change. Ants were trained to one feeder location, and the feeder was then moved to a different location. We found that ants responded to an environmental change by strongly upregulating pheromone deposition immediately after experiencing the change. This may help maintain the colony''s foraging flexibility, and allow multiple food locations to be exploited simultaneously. Our treatment also caused uncertainty in the foragers, by making their memories less reliable. Ants which had made an error but eventually found the food source upregulated pheromone deposition when returning to the nest. Intriguingly, ants on their way towards the food source downregulated pheromone deposition if they were going to make an error. This may suggest that individual ants can measure the reliability of their own memories and respond appropriately.     

Evidence for Transceptor Function of Cellodextrin Transporters in Neurospora crassa

Neurospora crassa colonizes burnt grasslands and metabolizes both cellulose and hemicellulose from plant cell walls. When switched from a favored carbon source to cellulose, N. crassa dramatically up-regulates expression and secretion of genes encoding lignocellulolytic enzymes. However, the means by which N. crassa and other filamentous fungi sense the presence of cellulose in the environment remains unclear. Previously, we have shown that a N. crassa mutant carrying deletions of three β-glucosidase enzymes (Δ3βG) lacks β-glucosidase activity, but efficiently induces cellulase gene expression and cellulolytic activity in the presence of cellobiose as the sole carbon source. These observations indicate that cellobiose, or a modified version of cellobiose, functions as an inducer of lignocellulolytic gene expression and activity in N. crassa. Here, we show that in N. crassa, two cellodextrin transporters, CDT-1 and CDT-2, contribute to cellulose sensing. A N. crassa mutant carrying deletions for both transporters is unable to induce cellulase gene expression in response to crystalline cellulose. Furthermore, a mutant lacking genes encoding both the β-glucosidase enzymes and cellodextrin transporters (Δ3βGΔ2T) does not induce cellulase gene expression in response to cellobiose. Point mutations that severely reduce cellobiose transport by either CDT-1 or CDT-2 when expressed individually do not greatly impact cellobiose induction of cellulase gene expression. These data suggest that the N. crassa cellodextrin transporters act as “transceptors” with dual functions - cellodextrin transport and receptor signaling that results in downstream activation of cellulolytic gene expression. Similar mechanisms of transceptor activity likely occur in related ascomycetes used for industrial cellulase production.     

Cellulose-degrading bacteria associated with the invasive woodwasp Sirex noctilio

Sirex noctilio is an invasive wood-feeding wasp that threatens the world''s commercial and natural pine forests. Successful tree colonization by this insect is contingent on the decline of host defenses and the ability to utilize the woody substrate as a source of energy. We explored its potential association with bacterial symbionts that may assist in nutrient acquisition via plant biomass deconstruction using growth assays, culture-dependent and -independent analysis of bacterial frequency of association and whole-genome analysis. We identified Streptomyces and γ-Proteobacteria that were each associated with 94% and 88% of wasps, respectively. Streptomyces isolates grew on all three cellulose substrates tested and across a range of pH 5.6 to 9. On the basis of whole-genome sequencing, three Streptomyces isolates have some of the highest proportions of genes predicted to encode for carbohydrate-active enzymes (CAZyme) of sequenced Actinobacteria. γ-Proteobacteria isolates grew on a cellulose derivative and a structurally diverse substrate, ammonia fiber explosion-treated corn stover, but not on microcrystalline cellulose. Analysis of the genome of a Pantoea isolate detected genes putatively encoding for CAZymes, the majority predicted to be active on hemicellulose and more simple sugars. We propose that a consortium of microorganisms, including the described bacteria and the fungal symbiont Amylostereum areolatum, has complementary functions for degrading woody substrates and that such degradation may assist in nutrient acquisition by S. noctilio, thus contributing to its ability to be established in forested habitats worldwide.     

Identification of Genes That Promote or Inhibit Olfactory Memory Formation in Drosophila

Genetic screens in Drosophila melanogaster and other organisms have been pursued to filter the genome for genetic functions important for memory formation. Such screens have employed primarily chemical or transposon-mediated mutagenesis and have identified numerous mutants including classical memory mutants, dunce and rutabaga. Here, we report the results of a large screen using panneuronal RNAi expression to identify additional genes critical for memory formation. We identified >500 genes that compromise memory when inhibited (low hits), either by disrupting the development and normal function of the adult animal or by participating in the neurophysiological mechanisms underlying memory formation. We also identified >40 genes that enhance memory when inhibited (high hits). The dunce gene was identified as one of the low hits and further experiments were performed to map the effects of the dunce RNAi to the α/β and γ mushroom body neurons. Additional behavioral experiments suggest that dunce knockdown in the mushroom body neurons impairs memory without significantly affecting acquisition. We also characterized one high hit, sickie, to show that RNAi knockdown of this gene enhances memory through effects in dopaminergic neurons without apparent effects on acquisition. These studies further our understanding of two genes involved in memory formation, provide a valuable list of genes that impair memory that may be important for understanding the neurophysiology of memory or neurodevelopmental disorders, and offer a new resource of memory suppressor genes that will aid in understanding restraint mechanisms employed by the brain to optimize resources.     

Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aβ1–42-infused mouse model of Alzheimer's disease

Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of central nervous system (CNS) and are currently being tested in clinical trials for neurological disorders, but preventive mechanisms of placenta-derived MSCs (PD-MSCs) for Alzheimer''s disease are poorly understood. Herein, we investigated the inhibitory effect of PD-MSCs on neuronal cell death and memory impairment in Aβ_1–42-infused mice. After intracerebroventrical (ICV) infusion of Aβ_1–42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. Our results showed that the transplantation of PD-MSCs into Aβ_1–42-infused mice significantly improved cognitive impairment, and behavioral changes attenuated the expression of APP, BACE1, and Aβ, as well as the activity of β-secretase and γ-secretase. In addition, the activation of glia cells and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by the transplantation of PD-MSCs. Furthermore, we also found that PD-MSCs downregulated the release of inflammatory cytokines as well as prevented neuronal cell death and promoted neuronal cell differentiation from neuronal progenitor cells in Aβ_1–42-infused mice. These data indicate that PD-MSC mediates neuroprotection by regulating neuronal death, neurogenesis, glia cell activation in hippocampus, and altering cytokine expression, suggesting a close link between the therapeutic effects of MSCs and the damaged CNS in Alzheimer''s disease.     

Some characteristics of spatial associative memory in the pigeon, Columba livia

Willson and Wilkie (1993) developed a novel procedure to assess pigeons' memory for the spatial location of food. Only one of four locations provided food each daily session. Each location consisted of an illuminated pecking key and grain feeder. Over different days different locations, randomly selected, provided food during a 16-min session. The pigeons tended to revisit the location at which food was found on the previous day thereby demonstrating memory for food-spatial location associations over 24 h. Three experiments were conducted to further investigate this phenomenon. In Experiment 1 the session duration was varied between 4 and 32 min. Longer sessions had no detectable effect on their ability to remember the rewarded location 24 h later, a result that suggests that only brief encounters with food at a particular location are necessary for recall. In Experiment 2 the necessity of an active search for the day's rewarded location was removed; a 5-min period in which only the rewarded key was lit preceded the regular 16-min session. Pecks to the lit key in this 5-min period produced grain on the standard schedule. This manipulation facilitated the pigeons' discovery of food but did not affect their ability to remember the rewarded location, suggesting that the process of search and discovery is not essential to the associative memory process. In Experiment 3, food was available during the complete session (non-depleting condition) or was available only during the first half of the session (depleting condition). No detectable differences in the birds' memory of yesterday's profitable location were found. This suggests that non-depletion of food is not a necessary condition for day-to-day recall of food location. Taken together these findings enlarge our understanding of the spatial associative memory process.     

Linking predator risk and uncertainty to adaptive forgetting: a theoretical framework and empirical test using tadpoles

Hundreds of studies have examined how prey animals assess their risk of predation. These studies work from the basic tennet that prey need to continually balance the conflicting demands of predator avoidance with activities such as foraging and reproduction. The information that animals gain regarding local predation risk is most often learned. Yet, the concept of ‘memory’ in the context of predation remains virtually unexplored. Here, our goal was (i) to determine if the memory window associated with predator recognition is fixed or flexible and, if it is flexible, (ii) to identify which factors affect the length of this window and in which ways. We performed an experiment on larval wood frogs, Rana sylvatica, to test whether the risk posed by, and the uncertainty associated with, the predator would affect the length of the tadpoles'' memory window. We found that as the risk associated with the predator increases, tadpoles retained predator-related information for longer. Moreover, if the uncertainty about predator-related information increases, then prey use this information for a shorter period. We also present a theoretical framework aiming at highlighting both intrinsic and extrinsic factors that could affect the memory window of information use by prey individuals.     

A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission

Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-β precursor protein (APP), whose mutations cause familial forms of Alzheimer''s disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2b^D rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid β (Aβ), a proteolytic product of APP, to AD, Itm2b^D rats were engineered to express two humanized App alleles and produce human Aβ. Here, we studied young Itm2b^D rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2b^D rats not only present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia.     

Hibernation does not affect memory retention in bats

Long-term memory can be critically important for animals in a variety of contexts, and yet the extreme reduction in body temperature in hibernating animals alters neurochemistry and may therefore impair brain function. Behavioural studies on memory impairment associated with hibernation have been almost exclusively conducted on ground squirrels (Rodentia) and provide conflicting results, including clear evidence for memory loss. Here, we for the first time tested memory retention after hibernation for a vertebrate outside rodents—bats (Chiroptera). In the light of the high mobility, ecology and long life of bats, we hypothesized that maintenance of consolidated memory through hibernation is under strong natural selection. We trained bats to find food in one out of three maze arms. After training, the pre-hibernation performance of all individuals was at 100 per cent correct decisions. After this pre-test, one group of bats was kept, with two interruptions, at 7°C for two months, while the other group was kept under conditions that prevented them from going into hibernation. The hibernated bats performed at the same high level as before hibernation and as the non-hibernated controls. Our data suggest that bats benefit from an as yet unknown neuroprotective mechanism to prevent memory loss in the cold brain.     

Knower–guesser differentiation in ravens: others' viewpoints matter

Differentiating between individuals with different knowledge states is an important step in child development and has been considered as a hallmark in human evolution. Recently, primates and corvids have been reported to pass knower–guesser tasks, raising the possibility of mental attribution skills in non-human animals. Yet, it has been difficult to distinguish ‘mind-reading’ from behaviour-reading alternatives, specifically the use of behavioural cues and/or the application of associatively learned rules. Here, I show that ravens (Corvus corax) observing an experimenter hiding food are capable of predicting the behaviour of bystanders that had been visible at both, none or just one of two caching events. Manipulating the competitors'' visual field independently of the view of the test-subject resulted in an instant drop in performance, whereas controls for behavioural cues had no such effect. These findings indicate that ravens not only remember whom they have seen at caching but also take into account that the other''s view was blocked. Notably, it does not suffice for the birds to associate specific competitors with specific caches. These results support the idea that certain socio-ecological conditions may select for similar cognitive abilities in distantly related species and that some birds have evolved analogous precursors to a human theory-of-mind.     

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1–42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNEL-positive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1–42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.     

A Novel Paradigm for Nonassociative Long-Term Memory in Drosophila: Predator-Induced Changes in Oviposition Behavior

Learning processes in Drosophila have been studied through the use of Pavlovian associative memory tests, and these paradigms have been extremely useful in identifying both genetic factors and neuroanatomical structures that are essential to memory formation. Whether these same genes and brain compartments also contribute to memory formed from nonassociative experiences is not well understood. Exposures to environmental stressors such as predators are known to induce innate behavioral responses and can lead to new memory formation that allows a predator response to persist for days after the predator threat has been removed. Here, we utilize a unique form of nonassociative behavior in Drosophila where female flies detect the presence of endoparasitoid predatory wasps and alter their oviposition behavior to lay eggs in food containing high levels of alcohol. The predator-induced change in fly oviposition preference is maintained for days after wasps are removed, and this persistence in behavior requires a minimum continuous exposure time of 14 hr. Maintenance of this behavior is dependent on multiple long-term memory genes, including orb2, dunce, rutabaga, amnesiac, and Fmr1. Maintenance of the behavior also requires intact synaptic transmission of the mushroom body. Surprisingly, synaptic output from the mushroom body (MB) or the functions of any of these learning and memory genes are not required for the change in behavior when female flies are in constant contact with wasps. This suggests that perception of this predator that leads to an acute change in oviposition behavior is not dependent on the MB or dependent on learning and memory gene functions. Because wasp-induced oviposition behavior can last for days and its maintenance requires a functional MB and the wild-type products of several known learning and memory genes, we suggest that this constitutes a paradigm for a bona fide form of nonassociative long-term memory that is not dependent on associated experiences.     

The learning abilities of the white cabbage butterfly,Pieris rapae,foraging for flowers

This study examines the role of learning and memory in the butterflyPieris rapae crucivora Boisduval during foraging for flowers. In an outdoor cage with 6 flower species,P. rapae showed various visiting patterns: some visited only one species, while others visited several species in a day. The foraging process for flowers ofErigeron annuus (L.) Pers. could be divided into two successive steps: (1) landing on the nectaring caputs, and (2) finding the source of nectar in the caput. Butterflies learned to proceed through the two steps more efficiently with successive attempts: they gradually decreased landings on nectarless caputs and probings on the nectarless petals of ligulate flowers respectively. As a result, handling time per unit caputs became shorter, and apparent rewards per unit time, i.e. the efficiency of collecting nectar, increased. In addition, once learned,P. rapae could remember a rewarding flower color for 3 days, which was not interfered with by learning another flower color. This indicates thatP. rapae keeps memory for a period longer than 3 days, and that they can remember at least two flower species as suitable flower resources. Furthermore, data indicated that they sometimes can apply the foraging skills obtained on other flower species to a novel one. These abilities could enable butterflies to easily switch flower species, or to enhance labile preference. It has been known thatP. rapae also shows flower constancy, which may be due to memory constraints. Therefore, they may appropriately use two foraging tactics: visit consistency and labile preference, to get enough nectar according to their circumstances.     

Commentary: Spermidine-triggered autophagy ameliorates memory during aging

The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies’ age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.