Human Declarative Memory Research Articles

Forget me not: The effect of doxycycline on human declarative memory

Investigations into neuroprotective drugs are in high demand for the treatment of neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, but also psychiatric disorders, such as depression, trauma, and substance use. One potential drug class being investigated are tetracyclines impacting on a variety of neuroprotective mechanisms. At the same time, tetracyclines like doxycycline have been suggested to affect human fear and spatial memory as well as reducing declarative memory retention. Based on the assumed necessity for synaptic consolidation in hippocampus-dependent learning, we hypothesised declarative memory may be similarly impaired by doxycycline as fear and spatial memory. Therefore, in this study we investigate the potential diminishing effects of doxycycline on consolidation of declarative memory in healthy humans. Additionally, to test for effect specificity we assessed motor memory, sustained attention, and processing speed. We administered a neuropsychological test battery in three independent randomized placebo-controlled double-blind trials (RCTs), in which healthy young volunteers (total N = 252) either received a single oral dose doxycycline (200 mg, n = 126) or placebo (n = 126) in a between-subject design. We found no evidence for a detrimental effect of doxycycline on declarative memory; instead, doxycycline improved declarative learning (p-value=0.022, Cohen's d=0.15) and memory consolidation (p=0.040, d=0.26). Contrarily, doxycycline slightly reduced motor learning (p=0.001, d=0.10) but subtly strengthened long-term motor memory (p=0.001, d=0.10). These results suggest that doxycycline can improve declarative learning and memory without having long term negative effects on other cognitive domains in healthy humans. Our results give hope to further investigate doxycycline in neuroprotective treatment applications.

A visual paired associate learning (vPAL) paradigm to study memory consolidation during sleep.

Sleep improves the consolidation and long-term stability of newly formed memories and associations. Most research on human declarative memory and its consolidation during sleep uses word-pair associations requiring exhaustive learning. In the present study, we present the visual paired association learning (vPAL) paradigm, in which participants learn new associations between images of celebrities and animals. The vPAL is based on a one-shot exposure that resembles learning in natural conditions. We tested if vPAL can reveal a role for sleep in memory consolidation by assessing the specificity of memory recognition, and the cued recall performance, before and after sleep. We found that a daytime nap improved the stability of recognition memory and discrimination abilities compared to identical intervals of wakefulness. By contrast, cued recall of associations did not exhibit significant sleep-dependent effects. High-density electroencephalography during naps further revealed an association between sleep spindle density and stability of recognition memory. Thus, the vPAL paradigm opens new avenues for future research on sleep and memory consolidation across ages and heterogeneous populations in health and disease.

Reminder-dependent alterations in long-term declarative memory expression

The reminder of a previously-learned memory can render that memory vulnerable to disruption or change in expression. Such memory alterations have been viewed as supportive of the framework of memory reconsolidation. However, alternative interpretations and inconsistencies in the replication of fundamental findings have raised questions particularly in the domain of human declarative memory. Here we present a series of related experiments, all of which involve the learning of a declarative memory, followed 1–2 days later by memory reminder. Post-reminder learning of interfering material did result in modulation of subsequent recall at test, but the precise manifestation of that interference effect differed across experiments. With post-reminder performance of a visuospatial task, a quantitative impairment in test recall performance was observed within a visual list-learning paradigm, but not in a foreign vocabulary learning paradigm. These results support the existence of reminder-induced memory processes that can lead to the alteration of subsequent memory performance by interfering tasks. However, it remains unclear whether these effects are reflective of modulation or impairment of the putative memory reconsolidation process.

Effects of exploring a novel environment on memory across the lifespan

Exploration of a novel environment has been shown to promote memory formation in healthy adults. Studies in animals have suggested that such novelty-induced memory boosts are mediated by hippocampal dopamine. The dopaminergic system is known to develop and deteriorate over the lifespan, but so far, the effects of novelty on memory across the lifespan have not yet been investigated. In the current study, we had children, adolescents, younger, and older adults (n = 439) explore novel and previously familiarized virtual environments to pinpoint the effects of spatial novelty on declarative memory in humans across different age groups. After exploration, words were presented while participants performed a deep or shallow encoding task. Incidental memory was quantified in a surprise test. Results showed that participants in the deep encoding condition remembered more words than those in the shallow condition, while novelty did not influence this effect. Interestingly, however, children, adolescents and younger adults benefitted from exploring a novel compared to a familiar environment as evidenced by better word recall, while these effects were absent in older adults. Our findings suggest that the beneficial effects of novelty on memory follow the deterioration of neural pathways involved in novelty-related processes across the lifespan.

A predictive account of how novelty influences declarative memory

A rich body of studies in the human and non-human literature has examined the question how novelty influences memory. For a variety of different stimuli, ranging from simple objects and words to vastly complex scenarios, the literature reports that novelty improves memory in some cases, but impairs memory in other cases. In recent attempts to reconcile these conflicting findings, novelty has been divided into different subtypes, such as relative versus absolute novelty, or stimulus versus contextual novelty. Nevertheless, a single overarching theory of novelty and memory has been difficult to attain, probably due to the complexities in the interactions among stimuli, environmental factors (e.g., spatial and temporal context) and level of prior knowledge (but see Duszkiewicz et al., 2019; Kafkas & Montaldi, 2018b; Schomaker & Meeter, 2015). Here we describe how a predictive coding framework might be able to shed new light on different types of novelty and how they affect declarative memory in humans. More precisely, we consider how prior expectations modulate the influence of novelty on encoding episodes into memory, e.g., in terms of surprise, and how novelty/surprise affect memory for surrounding information. By reviewing a range of behavioural findings and their possible underlying neurobiological mechanisms, we highlight where a predictive coding framework succeeds and where it appears to struggle.

EP300 and CREBBP histone acetyltransferases modulate individuals’ episodic memory

Declarative memory, including episodic and semantic memories, enables us to connect the present things with the past experiences. E1A binding protein p300 (EP300) and cAMP response element binding-binding protein (CREBBP), two important histone acetyltransferases (HATs) of KAT3 family, are involved in the development of cognitive aging such as the decreasing in episodic memory. However, no evidence suggested their potential roles in individual difference in declarative memories of youth. In the present study, we investigated whether EP300 and CREBBP genes modulated individual difference in declarative memory among youth subjects by using Remember (R)/Know (K) paradigm. The results showed that rs4822004 in EP300 modulated R responses (episodic memory) as controlling K responses (β = 0.076, R2 = 0.385, F = 180.322, p = 0.020). Moreover, we also found that rs130032 in CREBBP also modulated the performance of R responses after controlling K responses (β = 0.068, R2 = 0.384, F = 178.483, p = 0.038). The study suggests that EP300 and CREBBP genes contribute to the individuals’ difference in episodic memory, which provides evidence on the roles of histone acetylation activity in human declarative memory.

Postretrieval Relearning Strengthens Hippocampal Memories via Destabilization and Reconsolidation.

Memory reconsolidation is hypothesized to be a mechanism by which memories can be updated with new information. Such updating has previously been shown to weaken memory expression or change the nature of the memory. Here we demonstrate that retrieval-induced memory destabilization also allows that memory to be strengthened by additional learning. We show that for rodent contextual fear memories, this retrieval conditioning effect is observed only when conditioning occurs within a specific temporal window opened by retrieval. Moreover, it necessitates hippocampal protein degradation at the proteasome and engages hippocampal Zif268 protein expression, both of which are established mechanisms of memory destabilization-reconsolidation. We also demonstrate a conceptually analogous pattern of results in human visual paired-associate learning. Retrieval-relearning strengthens memory performance, again only when relearning occurs within the temporal window of memory reconsolidation. These findings link retrieval-mediated learning in humans to the reconsolidation literature, and have potential implications both for the understanding of endogenous memory gains and strategies to boost weakly learned memories.SIGNIFICANCE STATEMENT Memory reconsolidation allows existing memories to be updated with new information. Previous research has demonstrated that reconsolidation can be manipulated pharmacologically and behaviorally to impair problematic memories. In this article, we show that reconsolidation can also be exploited to strengthen memory. This is shown both in rats, in a fear memory setting, and in a human declarative memory setting. For both, the behavioral conditions necessary to observe the memory strengthening match those that are required to trigger memory reconsolidation. There are several behavioral approaches that have previously been shown convincingly to strengthen memory. The present demonstration that reconsolidation can underpin long-lasting memory improvements may both provide an underlying mechanism for such approaches and provide new strategies to boost memories.

Enhancing memory with stress: Progress, challenges, and opportunities

Stress can strongly influence what we learn and remember, including by making memories stronger. Experiments probing stress effects on hippocampus-dependent memory in rodents have revealed modulatory factors and physiological mechanisms by which acute stress can enhance long-term memory. However, extending these findings and mechanisms to understand when stress will enhance declarative memory in humans faces important challenges. This review synthesizes human and rodent studies of stress and memory, examining translational gaps related to measurements of declarative memory and stress responses in humans. Human studies diverge from rodent research by assessing declarative memories that may not depend on the hippocampus and by measuring peripheral rather than central stress responses. This highlights opportunities for future research across species, including assessing stress effects on hippocampal-dependent memory processes in humans and relating peripheral stress responses to stress effects on the function of memory-related brain regions in rodents. Together, these investigations will facilitate the translation of stress effects on memory function from rodents to humans and inform interventions that can harness the positive effects of stress on long-term memory.

Reporting Guidelines and Issues to Consider for Using Intracranial Brain Stimulation in Studies of Human Declarative Memory.

Participants with stimulating and recording electrodes implanted within the brain for clinical evaluation and treatment provide a rare opportunity to unravel the neuronal correlates of human memory, as well as offer potential for modulation of behavior. Recent intracranial stimulation studies of memory have been inconsistent in methodologies employed and reported conclusions, which renders generalizations and construction of a framework impossible. In an effort to unify future study efforts and enable larger meta-analyses we propose in this mini-review a set of guidelines to consider when pursuing intracranial stimulation studies of human declarative memory and summarize details reported by previous relevant studies. We present technical and safety issues to consider when undertaking such studies and a checklist for researchers and clinicians to use for guidance when reporting results, including targeting, placement, and localization of electrodes, behavioral task design, stimulation and electrophysiological recording methods, details of participants, and statistical analyses. We hope that, as research in invasive stimulation of human declarative memory further progresses, these reporting guidelines will aid in setting standards for multicenter studies, in comparison of findings across studies, and in study replications.

Brain histamine modulates recognition memory: possible implications in major cognitive disorders.

Several behavioural tests have been developed to study and measure emotionally charged or emotionally neutral memories and how these may be affected by pharmacological, dietary or environmental manipulations. In this review, we describe the experimental paradigms used in preclinical studies to unravel the brain circuits involved in the recognition and memorization of environmentally salient stimuli devoid of strong emotional value. In particular, we focus on the modulatory role of the brain histaminergic system in the elaboration of recognition memory that is based on the judgement of the prior occurrence of an event, and it is believed to be a critical component of human declarative memory. The review also addresses questions that may help improve the treatment of impaired declarative memory described in several affective and neuropsychiatric disorders such as ADHD, Alzheimer's disease and major neurocognitive disorder. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Direct electrical stimulation of the amygdala enhances declarative memory in humans

Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies.

The role of GABAA in the expression of updated information through the reconsolidation process in humans

Consolidated memory can be again destabilized by the presentation of a memory cue (reminder) of the previously acquired information. During this process of labilization/restabilization memory traces can be either impaired, strengthened or updated in content.Here, we study if a consolidated memory can be updated by linking one original cue to two different outcomes and whether this process was modulated by the GABAergic system. To aim that, we designed two experiments carried out in three consecutive days. All participants learned a list of non-sense syllable pairs on day 1. On day 2 the new information was introduced after the reminder or no-reminder presentation. Participants were tested on day 3 for the updated or original list (Exp. 1). In Exp. 2 we tested whether this new information was incorporated by an inhibitory process mediated by the GABAergic system. For that, participants retrieved the original information before being taken Clonazepam 0.25mg (GABAA agonist) or Placebo pill.We found that the groups that received the reminder correctly recalled the old and new information. However, the no reminder groups only correctly recalled the original information. Furthermore, when testing occurred in the presence of Clonazepam, the group that received the reminder plus the new information showed an impaired original memory performance compared to the group that received only Clonazepam (without reminder) or the reminder plus Placebo pill.These results show that new information can be added to a reactivated declarative memory in humans by linking one cue to two different outcomes. Furthermore, we shed light on the mechanisms of memory updating being the GABAergic system involved in the modulation of the old and new information expression.

Retrieval under stress decreases the long-term expression of a human declarative memory via reconsolidation

Acute stress impairs memory retrieval of several types of memories. An increase in glucocorticoids, several minutes after stressful events, is described as essential to the impairing retrieval-effects of stressors. Moreover, memory retrieval under stress can have long-term consequences. Through what process does the reactivated memory under stress, despite the disrupting retrieval effects, modify long-term memories? The reconsolidation hypothesis proposes that a previously consolidated memory reactivated by a reminder enters a vulnerability phase (labilization) during which it is transiently sensitive to modulation, followed by a re-stabilization phase. However, previous studies show that the expression of memories during reminder sessions is not a condition to trigger the reconsolidation process since unexpressed memories can be reactivated and labilized. Here we evaluate whether it is possible to reactivate-labilize a memory under the impairing-effects of a mild stressor. We used a paradigm of human declarative memory whose reminder structure allows us to differentiate between a reactivated-labile memory state and a reactivated but non-labile state. Subjects memorized a list of five cue-syllables associated with their respective response-syllables. Seventy-two hours later, results showed that the retrieval of the paired-associate memory was impaired when tested 20min after a mild stressor (cold pressor stress (CPS)) administration, coincident with cortisol levels increase. Then, we investigated the long-term effects of CPS administration prior to the reminder session. Under conditions where the reminder initiates the reconsolidation process, CPS impaired the long-term memory expression tested 24h later. In contrast, CPS did not show effects when administered before a reminder session that does not trigger reconsolidation. Results showed that memory reactivation-labilization occurs even when retrieval was impaired. Memory reactivation under stress could hinder -via reconsolidation- the probability of the traces to be expressed in the long term.

Long-term coding of personal and universal associations underlying the memory web in the human brain.

Neurons in the medial temporal lobe (MTL), a critical area for declarative memory, have been shown to change their tuning in associative learning tasks. Yet, it is unclear how durable these neuronal representations are and if they outlast the execution of the task. To address this issue, we studied the responses of MTL neurons in neurosurgical patients to known concepts (people and places). Using association scores provided by the patients and a web-based metric, here we show that whenever MTL neurons respond to more than one concept, these concepts are typically related. Furthermore, the degree of association between concepts could be successfully predicted based on the neurons' response patterns. These results provide evidence for a long-term involvement of MTL neurons in the representation of durable associations, a hallmark of human declarative memory.

Cue-independent memory impairment by reactivation-coupled interference in human declarative memory

Memory is a dynamic process. While memory becomes increasingly resistant to interference after consolidation, a brief reactivation renders it unstable again. Previous studies have shown that interference, when applied upon reactivation, impairs the consolidated memory, presumably by disrupting the reconsolidation of the memory. However, attempts have failed in disrupting human declarative memory, raising a question about whether declarative memory becomes unstable upon reactivation. Here, we used a double-cue/one-target paradigm, which associated the same target with two different cues in initial memory formation. Only one cue/target association was later reactivated and treated with behavioral interference. Our results showed, for the first time, that reactivation-coupled interference caused cue-independent memory impairment that generalized to other cues associated with the memory. Critically, such memory impairment appeared immediately after interference, before the reconsolidation process was completed, suggesting that common manipulations of reactivation-coupled interference procedures might disrupt other processes in addition to the reconsolidation process in human declarative memory.

An Individual's Rate of Forgetting is Stable Over Time but Differs Across Materials.

One of the goals of computerized tutoring systems is to optimize the learning of facts. Over a hundred years of declarative memory research have identified two robust effects that can improve such systems: the spacing and the testing effect. By making optimal use of both and adjusting the system to the individual learner using cognitive models based on declarative memory theories, such systems consistently outperform traditional methods (Van Rijn, Van Maanen, & Van Woudenberg, 2009). This adjustment process is driven by a continuously updated estimate of the rate of forgetting for each item and learner on the basis of the learner's accuracy and response time. In this study, we investigated to what extent these estimates of individual rates of forgetting are stable over time and across different materials. We demonstrate that they are stable over time but not across materials. Even though most theories of human declarative memory assume a single underlying rate of forgetting, we show that, in practice, it makes sense to assume different materials are forgotten at different rates. If a computerized, adaptive fact-learning system allowed different rates of forgetting for different materials, it could adapt to individual learners more readily.

Circadian rhythm. Dysrhythmia in the suprachiasmatic nucleus inhibits memory processing.

Chronic circadian dysfunction impairs declarative memory in humans but has little effect in common rodent models of arrhythmia caused by clock gene knockouts or surgical ablation of the suprachiasmatic nucleus (SCN). An important problem overlooked in these translational models is that human dysrhythmia occurs while SCN circuitry is genetically and neurologically intact. Siberian hamsters (Phodopus sungorus) are particularly well suited for translational studies because they can be made arrhythmic by a one-time photic treatment that severely impairs spatial and recognition memory. We found that once animals are made arrhythmic, subsequent SCN ablation completely rescues memory processing. These data suggest that the inhibitory effects of a malfunctioning SCN on cognition require preservation of circuitry between the SCN and downstream targets that are lost when these connections are severed.

The Novel Object Recognition Test in Rodents in Relation to Cognitive Impairment in Schizophrenia

Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.

New automated procedure to assess context recognition memory in mice.

Recognition memory is an important aspect of human declarative memory and is one of the routine memory abilities altered in patients with amnestic syndrome and Alzheimer's disease. In rodents, recognition memory has been most widely assessed using the novel object preference paradigm, which exploits the spontaneous preference that animals display for novel objects. Here, we used nose-poke units instead of objects to design a simple automated method for assessing context recognition memory in mice. In the acquisition trial, mice are exposed for the first time to an operant chamber with one blinking nose-poke unit. In the choice session, a novel nonblinking nose-poke unit is inserted into an empty spatial location and the number of nose poking dedicated to each set of nose-poke unit is used as an index of recognition memory. We report that recognition performance varies as a function of the length of the acquisition period and the retention delay and is sensitive to conventional amnestic treatments. By manipulating the features of the operant chamber during a brief retrieval episode (3-min long), we further demonstrate that reconsolidation of the original contextual memory depends on the magnitude and the type of environmental changes introduced into the familiar spatial environment. These results show that the nose-poke recognition task provides a rapid and reliable way for assessing context recognition memory in mice and offers new possibilities for the deciphering of the brain mechanisms governing the reconsolidation process.

Stress enhances reconsolidation of declarative memory.

Retrieval of negative emotional memories is often accompanied by the experience of stress. Upon retrieval, a memory trace can temporarily return into a labile state, where it is vulnerable to change. An unresolved question is whether post-retrieval stress may affect the strength of declarative memory in humans by modulating the reconsolidation process. Here, we tested in two experiments whether post-reactivation stress may affect the strength of declarative memory in humans. In both experiments, participants were instructed to learn neutral, positive and negative words. Approximately 24h later, participants received a reminder of the word list followed by exposure to the social evaluative cold pressor task (reactivation/stress group, nexp1=20; nexp2=18) or control task (reactivation/no-stress group, nexp1=23; nexp2=18). An additional control group was solely exposed to the stress task, without memory reactivation (no-reactivation/stress group, nexp1=23; nexp2=21). The next day, memory performance was tested using a free recall and a recognition task. In the first experiment we showed that participants in the reactivation/stress group recalled more words than participants in the reactivation/no-stress and no-reactivation/stress group, irrespective of valence of the word stimuli. Furthermore, participants in the reactivation/stress group made more false recognition errors. In the second experiment we replicated our observations on the free recall task for a new set of word stimuli, but we did not find any differences in false recognition. The current findings indicate that post-reactivation stress can improve declarative memory performance by modulating the process of reconsolidation. This finding contributes to our understanding why some memories are more persistent than others.