Learning & Memory

The hippocampus is a critical structure involved in many forms of learning and memory. It is also one of the only regions in the adult mammalian brain that continues to generate new neurons throughout adulthood. This process of adult neurogenesis may increase the plasticity of the hippocampus which could be beneficial for learning but has also been demonstrated to decrease the stability of previously acquired memories. Here we test whether increased production of new neurons following the formation of a gradually acquired paired-associates task will result in forgetting of this type of memory. We trained mice in a touchscreen-based object/location task and then increased neurogenesis using voluntary exercise. Our results indicate that mice with increased neurogenesis show poor recall of the previously established memory. When subsequently exposed to a reversal task we also show that mice with increased neurogenesis require fewer correction trials to acquire the new task contingencies. This suggests that prior forgetting reduces perseveration on the now outdated memory. Together our results add to a growing body of literature which indicates the important role of adult neurogenesis in destabilizing previously acquired memories to allow for flexible encoding of new memories.

Functionally active and passive states in working memory have been related to different neural mechanisms. Memoranda in active states might be maintained by persistent neural firing, whereas memoranda in passive states might be maintained through short-term synaptic plasticity. We reasoned that this might make these items differentially susceptible to interference during maintenance, in particular that passively maintained items might be more robust. To test this hypothesis, we gave our participants a working memory task in which one item was prioritised (active) by always probing it first, while the other item was deprioritised (passive) by always probing it second. In two experiments, on half the trials, we presented an interfering task during memory maintenance, in which the stimuli matched either the feature dimension of the memory items (colour or orientation), or their spatial location. Whether the interfering task appeared on a given trial was unpredictable. In a third experiment where participants were given prior knowledge of the interference condition, and finally in a fourth experiment we used a reward-based prioritisation cue. Across experiments, we found that both active and passive memory items were affected by interference to a similar extent, with overall performance being closely matched in all experiments. We further investigated precision and probability of target response parameters from the standard mixture model, which also showed no differences between states. We conclude that active and passive items, although potentially stored in different neuronal states, do not show differential susceptibility to interference. Public significance statementThe ability to briefly remember information is critical to human cognition. Our so-called working memory is nevertheless rather limited, able to hold only a few items at any one time, and prone to forgetting when we are briefly distracted. Yet, there is reason to believe that not all information in working memory is equally vulnerable. Items that are more passively stored, because they will only be required after some time, might be more resilient to interference. Items that are stored actively, for more immediate recall, might be more easily disrupted. Here, we investigated the effect of an interference task on the retention of both active and passive items in working memory. Our results showed that active and passive items are equally affected by interference, suggesting that resilience in working memory does not depend on the functional state of the items therein.

In humans, awareness of an upcoming memory test enhances intentional encoding and improves memory recall. Here, we investigated whether dolphins exhibit similar future-oriented encoding of information known to be needed in the future. Dolphins were trained to remember specific, randomly assigned actions for later re-enactment, with either immediate or delayed recall. When an unexpected delay was introduced in trials anticipating immediate recall, memory was retained for only 13 seconds, suggesting working memory encoding. However, when instructed to expect delayed recall, dolphins accurately reproduced actions after delays even after 16 hours. These results suggest that dolphins, anticipating future need, intentionally encode actions to be performed in the future into long-term memory, implying prospective encoding and prospective memory capacities. Their memory also displayed key features of episodic memory: encoding occurred in a single episode, and memory was declarative, as the action itself declared its content. Moreover, dolphins more effectively recalled self-performed actions compared to gestural codifications of the same actions, mirroring the human-typical "enactment effect" and supporting episodic-like memory over semantic memory. Our findings indicate that dolphins show awareness of future memory demands and seem to use a future-oriented, episodic-like memory system, capable of storing prospectively encoded, intended actions in long-term memory.

Aversive associative learning paradigms such as inhibitory avoidance (IA) are frequently used to examine episodic-like memories in rodents. In IA, rodents learn to associate a context with a footshock, followed by testing for memory strength in the original training context and for memory precision in a similar yet distinct neutral context. The present work assessed the effects of different contextual exposure procedures on memory strength and precision in IA at both recent and remote time points using male and female Long-Evans rats. An initial experiment found that rats kept in the lit (non-shock) compartment of the IA apparatus for 60 s during training, as opposed to 10 s, displayed enhanced memory strength, with discrimination between both chambers at the recent retention test and generalization at the remote retention test. Subsequent experiments investigated the effects of contextual pre-exposure the day before training. The results indicate that pre-exposure to the neutral context promoted generalization without altering memory strength compared to the first experiment. In contrast, pre-exposure to the aversive chamber promoted discrimination and enhanced memory strength. Notably, the different procedures yielded similar effects in both sexes. However, the results also indicate an overall pattern of greater contextual discrimination in females compared to males. These findings provide evidence for how different contextual exposures influence the degree of encoding at the time of training and a behavioral foundation for future studies examining the neurobiological mechanisms underlying memory strength and precision in IA, while highlighting the importance of using both sexes in initial behavioral work. Significance StatementStrength and precision are two fundamental properties of memory that can be simultaneously measured using inhibitory avoidance (IA), a type of context-footshock association task. However, little is known about how different context exposures alter rats encoding of these memories, thereby influencing subsequent memory strength and precision. Here, we found that pre-exposure to the neutral IA chamber decreased memory precision, whereas pre-exposure to the aversive IA chamber promoted memory strength and precision. Additionally, females demonstrated overall enhanced memory precision compared to males. These results indicate that different types of contextual exposures influence initial IA encoding and add to a limited body of research examining memory strength and precision in IA in both sexes.

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67-97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, does not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.

Physical stress, such as from the cold-pressor test, has been robustly associated with altered memory retrieval, but it is not yet clear whether the same happens following psychosocial stress. Studies using psychosocial stressors report mixed effects on memory, leading to uncertainty about the common cognitive impact of both forms of stress. The current study uses a stepped replication design, with four near-identical experiments, each differing by a single critical factor. In three experiments we induced psychosocial stress after participants encoded word stimuli, then assessed retrieval after a prolonged delay. These experiments found no group level influence of postencoding stress on recognition of neutral words or cued recall of word-pairs, but a small effect on recollection of semantically-related words. There was, however, some indication of positive relationships within the stress group between measures of stress (cortisol in experiment 1 and self-reported-anxiety in experiment 3) and recollection of single word stimuli. In the fourth experiment, we found that psychosocial stress immediately before retrieval did not influence word recognition. Overall, our findings demonstrate that psychosocial stress has a typically modest impact on memory, lower than previously claimed, but that individual differences in stress responsivity, particularly for tasks that tap recollection, may help to explain variability in previous findings.

Stress and emotional arousal interfere with encoding of temporal context memory for episodic events. However, it remains unclear how stress affects more fine-grained temporal memory, such as episodic events sequences and event times. Here, 86 healthy participants (M age = 22.5; 46% women, 54% men) were subjected to either a stress condition (socially evaluated cold pressor test) or a control condition, directly after or at a delay of 30 minutes they were presented the temporal structure of four virtual days. In these virtual days, time was scaled and participants could use clock cues to construe the passage of time within a day. We examined whether acute stress would interfere with encoding of episodic event sequences and temporal memory. Our results show that when learning took place directly after a stressor, virtual time estimates were more strongly biased towards a generalized timeline but temporal memory overall was not differentially affected between the stress and control groups. Exploratory analyses suggest that memory accuracy improved in men and deteriorated in women as a function of subjective stress levels following acute stress. In conclusion, acute stress amplified memory generalization but we found no stress related differences in memory accuracy across levels of temporal granularity.

Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as context) and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and - for those who design a new experiment or carry out pilot experiments - the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations to create more consensus in the set-up, procedure and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.

When attempting to recall previously seen visual information, people often move their eyes to the same locations where they initially viewed it. These eye-movements are thought to serve a role in enhancing memory retrieval, although the exact mechanism underlying this effect is yet unknown. To investigate this link between eye-movements and memory, we conducted an experiment with 80 adult participants. Participants were asked to perform a memory retrieval task, while viewing either the same visual context as during encoding or an altered one. Results showed that the benefit of eye movements to memory retrieval was dependent on the visual input. This suggests that the contribution of eye-movements to memory may not be from the motor behavior itself, but from its visual consequences. Our findings thus challenge the hypothesis that eye movements act as a motor retrieval cue and support the view that their visual consequences act as a sensory one. Statement of RelevanceAn intriguing question in cognition is how humans encode memorized material and what helps them retrieve it. It is known that when an action or stimulus is repeated both when information is encoded and when it is retrieved, this can act as a retrieval cue and enhance memory performance. It is also known that people tend to reenact the same eye movements during retrieval as they did during encoding, and this behavior is associated with higher memory performance. This has led to the hypothesis that eye movements act as a retrieval cue. However, we challenge this hypothesis by showing that the visual consequences of eye movements, rather than the motor action that accompanies them, is the key factor for memory enhancement. Understanding the factors that influence memory provides crucial insight into the relationship between external behaviors and internal memory processes, leading to significant implications for the educational and clinical settings.

Although we can all agree that interference induces forgetting, there is surprisingly little consensus regarding what type of interference most likely disrupts memory. We previously proposed that the similarity of interference differentially impacts the representational detail of color memory. Here, we extend this work by applying the Validated Circular Shape Space (Li et al., 2020) for the first time to a continuous retrieval task, in which we quantified both the visual similarity of distracting information as well as the representational detail of shape memory. We found that the representational detail of memory was systematically and differentially altered by the similarity of distracting information. Dissimilar distractors disrupted both fine- and coarse-grained information about the target, akin to memory erasure. In contrast, similar distractors disrupted fine-grained target information but increased reliance on coarse-grained information about the target, akin to memory blurring. Notably, these effects were consistent across two mixture models that each implemented a different scaling metric (either angular distance or perceived target similarity), as well as a parameter-free analysis that did not fit the mixture model. These findings suggest that similar distractors will help memory in cases where coarse-grained information is sufficient to identify the target. In other cases where precise fine-grained information is needed to identify the target, similar distractors will impair memory. As these effects have now been observed across both stimulus domains of shape and color, and were robust across multiple scaling metrics and methods of analyses, we suggest that these results provide a general set of principles governing how the nature of interference impacts forgetting.

The hippocampus plays a critical role in storing and retrieving spatial information. By targeting the dorsal hippocampus and manipulating specific "candidate" molecules using pharmacological and genetic manipulations, we have previously discovered that long-term active place avoidance memory requires transient activation of particular molecules in dorsal hippocampus. These molecules include amongst others, the persistent kinases Ca-calmodulin kinase II (CaMKII) and the atypical protein kinase C isoform PKC{iota} /{lambda} for acquisition of the conditioned behavior, whereas persistent activation of the other atypical PKC, protein kinase M zeta (PKM{zeta}) is necessary for maintaining the memory for at least a month. It nonetheless remains unclear what other molecules and their interactions maintain active place avoidance long-term memory, and the candidate molecule approach is both impractical and inadequate to identify new candidates since there are so many to survey. Here we use a complementary approach to identify candidates by transcriptional profiling of hippocampus subregions after formation of the long-term active place avoidance memory. Interestingly, 24-h after conditioning and soon after expressing memory retention, immediate early genes were upregulated in the dentate gyrus but not Ammons horn of the memory expressing group. In addition to determining what genes are differentially regulated during memory maintenance, we performed an integrative, unbiased survey of the genes with expression levels that covary with behavioral measures of active place avoidance memory persistence. Gene Ontology analysis of the most differentially expressed genes shows that active place avoidance memory is associated with activation of transcription and synaptic differentiation in dentate gyrus but not CA3 or CA1, whereas hypothesis-driven candidate molecule analyses identified insignificant changes in the expression of many LTP-associated molecules in the various hippocampal subfields, nor did they covary with active place avoidance memory expression, ruling out strong transcriptional regulation but not translational regulation, which was not investigated. These findings and the data set establish an unbiased resource to screen for molecules and evaluate hypotheses for the molecular components of a hippocampus-dependent, long-term active place avoidance memory.

ABSTRACTRecalling the past, thinking about the future and navigating in the world are linked with a brain structure called the hippocampus. Precisely how the hippocampus enables these critical cognitive functions is still debated. The strategies people use to perform tasks associated with these functions have been under-studied, and yet such information could augment our understanding of the associated cognitive processes and neural substrates. Here, we devised and deployed an in-depth protocol to examine the explicit strategies used by 217 participants to perform four naturalistic tasks widely acknowledged to be hippocampal-dependent, namely, those assessing scene imagination, autobiographical memory recall, future thinking and spatial navigation. In addition, we also investigated strategy use for three laboratory-based memory tasks, one of which is held to be hippocampal-dependent – concrete verbal paired associates – and two tasks which are likely hippocampal-independent – abstract verbal paired associates and the dead or alive semantic memory test. We found that scene visual imagery was the dominant strategy not only when mentally imagining scenes, but also during autobiographical memory recall, when thinking about the future and during navigation. Moreover, scene visual imagery strategies were used most frequently during the concrete verbal paired associates task, whereas verbal strategies were most prevalent for the abstract verbal paired associates task and the dead or alive semantic memory task. The ubiquity of specifically scene visual imagery use across a range of tasks may attest to its, perhaps underappreciated, importance in facilitating cognition, whilst also aligning with perspectives that emphasise a key role for the hippocampus in constructing scene imagery.Competing Interest StatementThe authors have declared no competing interest.View Full Text

Memories of past events can be recalled long after the event, indicating stability. But new experiences are also integrated into existing memories, indicating plasticity. In the hippocampus, spatial representations are known to remain stable, but have also been shown to drift over long periods of time. We hypothesized that experience, more than the passage of time, is the driving force behind memory plasticity. We compared the stability of place cells in the hippocampus of mice traversing two similar, familiar tracks for different durations. We found that the more time spent in an environment, the greater the representational drift, regardless of the total elapsed time. Our results suggest that spatial representation is a dynamic process, related to the ongoing experiences within a specific context, and is related to the accumulation of new memories rather than to passive forgetting. HighlightsO_LIRepresentational drift is related to experience within an environment. C_LIO_LIRepresentational drift is a dynamic context-wide process. C_LIO_LIPlace cell number decreases with experience, spatial information content increases. C_LI

Forming a long-term memory requires changes in neuronal transcription. What happens, though, as the memory is forgotten? And how does the transcriptional state relate to the maintenance and recall of the long-term memory? To answer these questions we have been systematically tracing the time-course of transcriptional changes evoked by long-term sensitization in the marine mollusk Aplysia californica. Our approach captures transcriptional changes in neurons of known behavioral relevance using a within-subjects design, delineating patterns of transcriptional change that are comprehensive and reproducible. We have previously reported that within 1 day of long-term sensitization training there is a widespread transcriptional response involving robust changes in over 5% of tested transcripts (1,252 of [~]22k; Conte, 2017). Within 1 week, however, memory strength fades and nearly all transcriptional changes relapse to baseline (Perez, 2018). Here we report microarray analysis (N = 16) of transcriptional changes 5 days post-learning, a time-point when memory strength has weakened but is still robust. Remarkably, we find that at this intermediate behavioral stage nearly all transcriptional changes have fully decayed, even in subsets of animals that have shown very little forgetting. Thus, most transcriptional changes seem to decay more rapidly than memory expression. We discuss several possible ways that memory expression could become decoupled from detectable transcriptional regulation. HighlightsO_LILong-term sensitization training produces a memory that then fades over the course of a week, with behavioral expression at 5 days at an intermediate stage of partly forgotten with continued clear sensitization and considerable variety across animals. C_LIO_LIThe transcriptional response to sensitization training fades more quickly than behavioral expression, with nearly all transcripts regulated 1 day after training showing a statistically significant decline in regulation, even amongst animals that had shown little forgetting. C_LIO_LITranscription does not seem to have a straightforward relationship with the expression of sensitization memory, with a small set of transcripts consistently regulated even as behavioral expression changes and strong behavioral expression possible without most of the transcriptional changes observed during early maintenance. C_LI

Most of the current models of long-term memory consolidation require prior establishment of short-term memory. Here, we show that optogenetic or genetic inhibition of CaMKII, a kinase important for synaptic plasticity, in an inhibitory avoidance task impairs short-term memory at 1 h but not long-term memory at 1 d. Similarly, cortico-amygdala synaptic potentiation was more sensitive to CaMKII inhibition at 1 h but not at 1 d. These results strongly suggest that long-term memory does not require the prior formation of short-term memory and that CaMKII-dependent synaptic plasticity specifically regulates short-term memory, but not long-term memory, for avoidance memory.

The discovery of the Kamin blocking effect suggested that surprise or prediction errors are necessary for associative learning. This suggestion led to the development of a new theoretical framework for associative learning relying on prediction error rather than just temporal contiguity between events. However, many recent studies have failed to replicate the blocking effect, questioning the central role of blocking in associative learning theory. Here, we test the expression of Kamin blocking in rats that either approach and interact with the conditioned cue (sign trackers) or approach and interact with the reward location (goal trackers) during appetitive classical conditioning. The behavioral task involved three phases: classical conditioning of a lever cue, conditioning of a compound of the lever cue plus an auditory cue, and testing response to presentation of the auditory cue in extinction. The results show that only sign trackers express the blocking effect. Thus, groups that include goal trackers are less likely to be able to replicate the blocking effect. Our findings support the idea that sign and goal tracking responses arise as a result of distinct parallel learning processes. Psychological theories of learning that incorporate these parallel learning processes and their interactions will provide a better framework for understanding the blocking effect and related associative learning phenomena.

Everyday activities often require learning sequences that necessitate the involvement of both the declarative and the procedural memory domains. Previous research has shown that a learning structure that is common across tasks from different domains can improve learning and resistance to interference. However, it remains unknown whether such shared learning structure can enhance longer-term memory retention. To address this question, forty-eight healthy adults participated in a pre-registered study in which they learned both an object sequence task (declarative learning) and a motor sequence task (procedural learning) in two separate sessions separated by 4h. Participants were assigned to either an associated group, where the two tasks shared a common learning structure - that consisted of a specific mapping between finger movements and object categories across learning sessions - or an unassociated group with no such cross-domain shared structure. Memory retention was assessed with a 24h retest session on both tasks. Contrary to our predictions, a shared higher-order structure between tasks from different domains did not enhance memory retention. Exploratory follow-up analyses revealed that the order the tasks were learned (i.e., object or motor first), rather than their structural overlap, influenced performance. Specifically, learning the motor task before the object task impaired the consolidation of the object task irrespective of whether the tasks shared a common learning structure or not. This effect was unidirectional as learning the object task before the motor task had no effect on the consolidation of the motor task. Altogether, the current findings suggest that the order of cross-domain learning experiences rather than their structure influences memory consolidation.

Over past couple of decades our understanding of visual working memory (VWM), and working memory in general, has been predominantly in line with the capacity debate. We recently opened a new line of inquiry regarding the recall of a single object to go beyond the capacity debate, and showed that a series of feature probe questions about a single object yields poorer recall later in the sequence (Sengupta et al, 2020). In the current work we focused on another aspect of sequential feature recall - mainly regarding whether recall can be improved by asking the same question twice. To that end, we chose to focus on two features - color and location, and we contrasted repeat and non-repeat (from the standpoint of feature questions) trials in a series of two experiments. In repeat trials either color or location would be probed twice consecutively. In non-repeat trials color and location probes were presented one after the other in random order. In all trials the stimulus was a small colored oriented line presented for 1 sec in a location within 4o of visual angle. The recall of color and location were mapped onto continuous variable like Sengupta et al, 2020 - for instance, color recall was mapped onto a color wheel. In the first experiment, we used an unaltered color wheel when the color question was repeated. For the second experiment, we used a rotated color wheels for two consecutive color recall trials. We observed an increase in recall error for both repeat and non-repeat condition for location when the probe was at the second question in both experiments. However, color recall error did not increase for second repeat question condition in Experiment 1 as opposed to the non-repeat condition. On the other hand, in Experiment 2 we observed the expected increase in recall error for both repeat and non repeat condition for color probe at the second question. This maybe due to the fact that participants used an anchoring strategy in Experiment 1 by remembering where they clicked on the color wheel in the first question. The rotation of color wheel in second experiment destroys the anchor leading to the aforementioned result. The results show that trying to recall the same feature again leads to degradation of recall accuracy for both color and location, and human beings may use different strategies for recall in working memory tasks.

Computational modeling has revealed that human research participants use both rapid working memory (WM) and incremental reinforcement learning (RL) (RL+WM) to solve a simple instrumental learning task, relying on WM when the number of stimuli is small and supplementing with RL when the number of stimuli exceeds WM capacity. Inspired by this work, we examined which learning systems and strategies are used by adolescent and adult mice when they first acquire a conditional associative learning task. In a version of the human RL+WM task translated for rodents, mice were required to associate odor stimuli (from a set of 2 or 4 odors) with a left or right port to receive reward. Using logistic regression and computational models to analyze the first 200 trials per odor, we determined that mice used both incremental RL and stimulus-insensitive, one-back strategies to solve the task. While these one-back strategies may be a simple form of short-term or working memory, they did not approximate the boost to learning performance that has been observed in human participants using WM in a comparable task. Adolescent and adult mice also showed comparable performance, with no change in learning rate or softmax beta parameters with adolescent development and task experience. However, reliance on a one-back perseverative, win-stay strategy increased with development in males in both odor set sizes. Our findings advance a simple conditional associative learning task and new models to enable the isolation and quantification of reinforcement learning alongside other strategies mice use while learning to associate stimuli with rewards within a single behavioral session. These data and methods can inform and aid comparative study of reinforcement learning across species. Author summaryHere we studied the strategies and mechanisms mice use to learn a simple two choice odor based task in a single session. Using a set size manipulation and computational models we find evidence that mice use incremental reinforcement learning as well as several short-term (one-back) strategies to earn water reward. Our data and models clarify how mice learn a simple task and establish methods by which mouse and human reinforcement learning may be isolated for cross-species comparison of learning.

While forgetting has been studied extensively in various organisms, its precise nature has often been unclear. Here, we used behavioral experiments in Drosophila to determine that a significant aspect of forgetting consists of a decrease in the ability of a memory to induce an appropriate behavior. We tested flies for memory retention at various times after training and then separately retested both flies that chose correctly and those that chose incorrectly. Although the ability to choose correctly decreased over time, we could not measure any differences in memory between flies that initially chose correctly and those that chose incorrectly upon retest. This suggests that forgetting is unlikely to consist of a spontaneous loss of a memory but instead consists of a decrease in the probability of flies that remember choosing the correct behavioral response. Thus, although flies maintain memory over time, there is an increase in uncertainty associated with this memory. We find that forgetting of long-term memories and accelerated forgetting in old flies occur in a similar manner.