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.

Vegetal memory through the lens of transcriptomic changes - recent progress and future practical prospects for exploiting plant transcriptional memory.

Plant memory plays an important role in the efficient and rapid acclimation to a swiftly changing environment. In addition, since plant memory can be inherited, it is also of adaptive and evolutionary importance. The ability of a plant to store, retain, retrieve and delete information on acquired experience is based on cellular, biochemical and molecular networks in the plants. This review offers an up-to-date overview on the formation, types, checkpoints of plant memory based on our current knowledge and focusing on its transcriptional aspects, the transcriptional memory. Roles of long and small non-coding RNAs are summarized in the regulation, formation and the cooperation between the different layers of the plant memory, i.e. in the establishment of epigenetic changes associated with memory formation in plants. The RNA interference mechanisms at the RNA and DNA level and the interplays between them are also presented. Furthermore, this review gives an insight of how exploitation of plant transcriptional memory may provide new opportunities for elaborating promising cost-efficient, and effective strategies to cope with the ever-changing environmental perturbations, caused by climate change. The potentials of plant memory-based methods, such as crop priming, cross acclimatization, memory modification by miRNAs and associative use of plant memory, in the future's agriculture are also discussed.

The impact of doxycycline on human contextual fear memory.

RATIONALE:  Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown. METHODS: Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants. RESULTS: Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group. CONCLUSION: Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.

Effect of the Matrix Metalloproteinase Inhibitor Doxycycline on Human Trace Fear Memory.

Learning to predict threat is of adaptive importance, but aversive memory can also become disadvantageous and burdensome in clinical conditions such as posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a laboratory model of aversive memory and thought to rely on structural synaptic reconfiguration involving matrix metalloproteinase (MMP)9 signaling. It has recently been suggested that the MMP9-inhibiting antibiotic doxycycline, applied before acquisition training in humans, reduces fear memory retention after one week. This previous study used cued delay fear conditioning, in which predictors and outcomes overlap in time. However, temporal separation of predictors and outcomes is common in clinical conditions. Learning the association of temporally separated events requires a partly different neural circuitry, for which the role of MMP9 signaling is not yet known. Here, we investigate the impact of doxycycline on long-interval (15 s) trace fear conditioning in a randomized controlled trial with 101 (50 females) human participants. We find no impact of the drug in our preregistered analyses. Exploratory post hoc analyses of memory retention suggested a serum level-dependent effect of doxycycline on trace fear memory retention. However, effect size to distinguish CS+/CS- in the placebo group turned out to be smaller than in previously used delay fear conditioning protocols, which limits the power of statistical tests. Our results suggest that doxycycline effect on trace fear conditioning in healthy individuals is smaller and less robust than anticipated, potentially limiting its clinical application potential.

Reasoning about Death in Biomedical Decision-Making.

Depending on our mode of reasoning-moral, prudential, instrumental, empirical, dialectical, and so on-we may come to vastly different conclusions on the nature of death and the appropriate orientation toward matters such as euthanasia or procuring organs from brain-dead patients. These differing orientations have resulted in some of the most enduring conflicts in biomedical decision-making with roots in the earliest strands of philosophical discourse. Through continually grappling with questions over matters of death, we continually step closer to clarity, even if certainty on these matters remains necessarily as elusive as death itself.

Rationally Navigating Subjective Preferences in Memory Modification.

Discussion of the ethics of memory modification technologies (MMTs) has often focused on questions about the limits of their permissibility. In the current paper, I focus primarily on a different issue: when (if ever) is it rational to prefer MMTs to alternative interventions? My conclusion is that these conditions are rare. The reason stems from considerations of autonomy. When compared with other interventions, MMTs do a particularly poor job at promoting the autonomy of their users. If this conclusion is true, moreover, it provides a fresh perspective on debates about the permissibility of MMTs. On the one hand, for those who would limit the use of MMTs to a narrow range of circumstances, the conclusion that MMTs are rarely preferable gives them further reason to eye MMTs with suspicion. On the other hand, for those who view MMTs as permissible in a wide range of circumstances, the conclusion may deflate their endorsement.

Memory Modification and Authenticity: A Narrative Approach.

The potential of memory modification techniques (MMTs) has raised concerns and sparked a debate in neuroethics, particularly in the context of identity and authenticity. This paper addresses the question whether and how MMTs influence authenticity. I proceed by drawing two distinctions within the received views on authenticity. From this, I conclude that an analysis of MMTs based on a dual-basis, process view of authenticity is warranted, which implies that the influence of MMTs on authenticity crucially depends on the specifics of how memory modification would eventually work. Therefore, I continue with a systematic analysis of possible properties of MMTs in which I distinguish between the dimensions of memories and the kinds of experiences that can be modified as well as the properties of the process of memory modification. The impact of MMTs on authenticity is analyzed regarding the possible properties of MMTs and based on a narrative approach to authenticity which fulfills the requirements of a dual-basis, process view of authenticity. Lastly, I explore the potential of MMTs to shift the balance between self-discovery and self-creation within authenticity and thereby alter the concept itself as well as the value of authenticity.

The malleability of collective memories: One year after the Tulip Revolution in Kyrgyzstan.

How people view their social groups' history has important implications at both the collective and the individual levels. It has been established that collective memories, the representations of one's groups' history, differ between generations and individuals. Yet, it remains unclear how collective memories change in reaction to dramatic social change. Using temporal collective relative deprivation (TCRD), which reflects how individuals perceive their group's situation in history, we hypothesize that TCRD trajectories change over time and that highly identified individuals will be less likely to change their trajectory. Kyrgyz nationals (N = 166) responded immediately after the Tulip Revolution and one year later to TCRD measurements. Dual group-based trajectory analysis indicates that a third of the sample modified their memories about their group's situation one year after a dramatic social change and that low identification with the group predicted this change. These results support the idea that collective memory is revised at the individual level after dramatic social change.

To remember, or not to remember? Potential impact of memory modification on narrative identity, personal agency, mental health, and well-being.

Memory modification technologies (MMTs)-interventions within the memory affecting its functions and contents in specific ways-raise great therapeutic hopes but also great fears. Ethicists have expressed concerns that developing and using MMTs may endanger the very fabric of who we are-our personal identity. This threat has been mainly considered in relation to two interrelated concerns: truthfulness and narrative self-constitution. In this article, we propose that although this perspective brings up important matters concerning the potential aftermaths of MMT utilization, it fails to tell the whole story. We suggest that capturing more tangible potential consequences of MMT use, namely, its psychological ramifications is crucial both in ethical considerations and in making decisions regarding the permissibility of such interventions. To this end, we first examine what current MMTs are capable of and what are the prospects of emerging MMTs. Subsequently, we outline the relationship between memory and personal identity; specifically, we indicate that concepts of self-defining memories and narrative identity are crucial to considering how MMTs may influence one's psychological functioning. On this basis, we analyze potential consequences of narrative disruption that may be the result of the use of MMTs; more precisely, we consider its potential effects on mental health, well-being, and personal agency, and outline the ethical dilemmas that decision-makers face in this context. We conclude by considering the broader cultural context that may have influence on policymaking regarding permissibility of memory modification interventions.

Personality and Authenticity in Light of the Memory-Modifying Potential of Optogenetics.

There has been a growing interest in research concerning memory modification technologies (MMTs) in recent years. Neuroscientists and psychologists are beginning to explore the prospect of controllable and intentional modification of human memory. One of the technologies with the greatest potential to this end is optogenetics-an invasive neuromodulation technique involving the use of light to control the activity of individual brain cells. It has recently shown the potential to modify specific long-term memories in animal models in ways not yet possible with other MMTs. As the therapeutic potential of optogenetics has already prompted approval of the first human trials, it is especially important and timely to consider the opportunities and dangers this technology may entail. In this article, we focus on possible consequences of optogenetics as an MMT by analyzing fundamental threats potentially associated with memory modifications: the potential disruption of personality and authenticity.

Nucleus reuniens of the thalamus controls fear memory reconsolidation.

The nucleus reuniens has been shown to support the acquisition, consolidation, maintenance, destabilization upon retrieval, and extinction of aversive memories. However, the direct participation of this thalamic subregion in memory reconsolidation is yet to be examined. The present study addressed this question in contextually fear-conditioned rats. Post-reactivation infusion of the GABAA receptor agonist muscimol, the glutamate N2A-containing NMDA receptor antagonist TCN-201, or the protein synthesis inhibitor anisomycin into the NR induced significant impairments in memory reconsolidation. Administering muscimol or TCN-201 and anisomycin locally, or associating locally infused muscimol or TCN-201 with systemically administered clonidine, an α2-receptor adrenergic agonist that attenuates the noradrenergic tonus associated with memory reconsolidation, produced no further reduction in freezing times when compared with the muscimol-vehicle, TCN-201-vehicle, vehicle-anisomycin, and vehicle-clonidine groups. This pattern of results indicates that such treatment combinations produced no additive/synergistic effects on reconsolidation. It is plausible that NR inactivation and antagonism of glutamate N2A-containing NMDA receptors weakened/prevented the subsequent action of anisomycin and clonidine because they disrupted the early stages of signal transduction pathways involved in memory reconsolidation. It is noteworthy that these pharmacological interventions, either alone or combined, induced no contextual memory specificity changes, as assessed in a later test in a novel and unpaired context. Besides, omitting memory reactivation precluded the impairing effects of muscimol, TCN-201, anisomycin, and clonidine on reconsolidation. Together, the present findings demonstrate interacting mechanisms through which the NR can regulate contextual fear memory restabilization.

Parameters of Memory Reconsolidation: Learning Mode Influences Likelihood of Memory Modification.

When previously consolidated hippocampally dependent memory traces are reactivated they enter a vulnerable state in which they can be altered with new information, after which they must be re-consolidated in order to restabilize the trace. The existing body of literature on episodic reconsolidation largely focuses on the when and how of successful memory reactivation. What remains poorly understood is how the nature of newly presented information affects the likelihood of a vulnerable episodic memory being altered. We used our episodic memory reconsolidation paradigm to investigate if the intention to encode impacts what subsequently becomes attributed to an older, reactivated memory. Participants learned two lists of objects separated by 48 h. We integrated a modified item-list directed-forgetting paradigm into the encoding of the second object list by cueing participants to learn some of the objects intentionally (intentional learning), while other objects were presented without a cue (incidental learning). Under conditions of memory reactivation, subjects showed equal rates of memory modification for intentionally- and incidentally-learned objects. However, in the absence of reactivation we observed high misattribution rates of incidentally-learned objects. We consider two interpretations of these data, with contrasting implications for understanding the conditions that influence memory malleability, and suggest further work that should help decide between them.

Taking advantage of fear generalization-associated destabilization to attenuate the underlying memory via reconsolidation intervention.

Upon retrieval, an aversive memory can undergo destabilization and reconsolidation. A traumatic-like memory, however, may be resistant to this process. The present study sought to contribute with a strategy to overcome this potential issue by investigating whether generalized fear retrieval is susceptible to destabilization-reconsolidation that can be pharmacologically modified. We hypothesized that exposure to a context that elicits moderate generalization levels would allow a malleable memory state. We developed a fear conditioning protocol in context A (cxt-A) paired with yohimbine administration to promote significant fear to a non-conditioned context B (cxt-B) in rats, mimicking the enhanced noradrenergic activity reported after traumatic events in humans. Next, we attempted to impair the reconsolidation phase by administering clonidine (CLO) immediately after exposure to cxt-A, cxt-B, or a third context C (cxt-C) neither conditioned nor generalized. CLO administered post-cxt-B exposure for two consecutive days subsequently resulted in decreased freezing levels in cxt-A. CLO after cxt-B only once, after cxt-A or cxt-C in two consecutive days, or independently of cxt-B exposures did not affect fear in a later test. A 6-h-delay in CLO treatment post-cxt-B exposures produced no effects, and nimodipine administered pre-cxt-B exposures precluded the CLO action. We then quantified the Egr1/Zif268 protein expression following cxt-B exposures and CLO treatments. We found that these factors interact to modulate this memory destabilization-reconsolidation mechanism in the basolateral amygdala but not the dorsal CA1 hippocampus. Altogether, memory destabilization can accompany generalized fear expression; thus, we may exploit it to potentiate reconsolidation blockers' action.

Spatial distancing reduces emotional arousal to reactivated memories.

Memories are able to update and adapt with new information about the world after they are reactivated. However, it is unknown whether the labile period following reactivation makes episodic memories more amenable to emotion regulation, an application that holds great clinical promise. Here, we investigated the efficacy of cognitive reappraisal to down regulate negative affect in response to reactivated memories. Healthy young adults (N = 119) rated the emotionality of negative pictures. After a partial reactivation of each picture 2 days later, participants voluntarily engaged in a spatial distancing regulation tactic by imagining the reactivated object extremely far away from them. Compared with no-regulation and no-reactivation controls, self-reported arousal for regulated pictures dropped significantly 2 days after the manipulation, despite no significant difference in memory accuracy or valence. These results open up a new line of work that capitalizes on reactivation-based lability to selectively alter enduring arousal responses to emotional memories.

Decomposing Parietal Memory Reactivation to Predict Consequences of Remembering.

Memory retrieval can strengthen, but also distort memories. Parietal cortex is a candidate region involved in retrieval-induced memory changes as it reflects retrieval success and represents retrieved content. Here, we conducted an fMRI experiment to test whether different forms of parietal reactivation predict distinct consequences of retrieval. Subjects studied associations between words and pictures of faces, scenes, or objects, and then repeatedly retrieved half of the pictures, reporting the vividness of the retrieved pictures ("retrieval practice"). On the following day, subjects completed a recognition memory test for individual pictures. Critically, the test included lures highly similar to studied pictures. Behaviorally, retrieval practice increased both hit and false alarm (FA) rates to similar lures, confirming a causal influence of retrieval on subsequent memory. Using pattern similarity analyses, we measured two different levels of reactivation during retrieval practice: generic "category-level" reactivation and idiosyncratic "item-level" reactivation. Vivid remembering during retrieval practice was associated with stronger category- and item-level reactivation in parietal cortex. However, these measures differentially predicted subsequent recognition memory performance: whereas higher category-level reactivation tended to predict FAs to lures, item-level reactivation predicted correct rejections. These findings indicate that parietal reactivation can be decomposed to tease apart distinct consequences of memory retrieval.

Exploring the role of context on the existing evidence for reconsolidation of episodic memory.

Recent research has provided evidence for memory modifications when a post-reactivation treatment (e.g., drugs, new learning) interferes with the memory re-stabilisation (reconsolidation) process. This finding contradicts the long-standing consolidation theory and has high practical and theoretical implications. With an object-learning paradigm, it was shown that episodic memory is highly susceptible to interfering material presented after its reactivation [Hupbach, A., Gomez, R., Hardt, O., & Nadel, L. (2007). Reconsolidation of episodic memories: A subtle reminder triggers integration of new information. Learning & Memory, 14, 47-53. doi: 10.1101/lm.365707 ]. The reactivation of a learned list (List 1) before a second learned list (List 2) led to intrusion errors from List 2 when trying to recall List 1, but not vice-versa. Their work has been widely cited and their findings have been explained according to reconsolidation theory. For the first time, we systematically explored the role of retrieval context as an alternative explanation for Hupbach's results. Our results showed that the intrusion effect occurs independently of the retrieval context (Experiment 1). Additionally, even when the intrusion rate probability is increased (i.e., List 1 memory test is performed in the List 2 learning context), the groups that did not reactivate the original list did not commit intrusion errors (Experiment 2). In sum, we found that the intrusion effect critically depends on the presence of reactivation, discarding alternative interpretations of the results.

When forgetting preserves memory.

There has been a resurgence of interest in defining the circumstances leading to memory modifications. Studies have shown that reactivating a supposedly stable memory re-introduces a time-limited window of plasticity during which presentation of interfering material can cause long-term memory changes. The present study asks whether such memory changes can be prevented if people are instructed to forget the memory before the new material is encoded. Participants learned a set of objects. After 48 h, they were reminded of this learning episode, and learned another set of objects. Again 48 h later, they recalled the first (Exp. 1) or second set (Exp. 3). As shown previously, a reminder caused intrusions from the second set into recall of the first set. Here I show that the instruction to forget the first set significantly diminished intrusions from the second set, especially when the instruction was given before the new set was encoded in the second session. Experiment 2 suggests that the reduced intrusions were due to list segregation/isolation, rather than temporarily inhibited access to Set 1. Taken together, the study shows that the attempt to forget a memory can immunize it such that the presentation of interfering material has limited effects, and the memory can be recalled unchanged in the future. This is important when veridical memory is essential, such as in eyewitness testimonies.