Labile State Research Articles

S33. Angiotensin Type 1 Receptor (AT1R) Inhibition Disrupts Reconsolidation of Conditioned Auditory Fear

Recent studies demonstrate that consolidated memories temporarily return to a labile state following retrieval. This window of reconsolidation presents a potential therapeutic target for treatment of psychiatric disorders such as PTSD. The renin-angiotensin system contributes to memory consolidation processes in rodent models of Pavlovian conditioning; however, its role in reconsolidation of auditory fear conditioning has not been investigated.

Sleep accelerates re-stabilization of human declarative memories.

Consolidated memories can return to a labile state upon presentation of a reminder, followed by a period of re-stabilization known as reconsolidation. This period can take several hours, and if an amnesic agent (e.g. new learning) is administered inside the time window of reconsolidation (when the memory is still labile) the memory is impaired, whereas the memory remains unaffected if the amnesic agent is administered outside this time window. Sleep plays a fundamental role in the consolidation and integration of new memories, and recently sleep has also been implicated in memory reconsolidation. Here, we studied the role of sleep in accelerating the reconsolidation time window. On day 1, participants learned a list of syllable-pairs (List 1). On day 2, they received a reminder, followed by interference learning (List 2) administered either after 90 min of wakefulness, after 90 min of sleep, or after 10 h of wakefulness. On day 3, participants had to recall List 1 first, followed by List 2, and we assessed the Retrieval-Induced-Forgetting Effect (RIF) on List 2 as a measure of List 1 memory stability. We found that the 90 min sleep group showed an intact RIF effect similar to the 10 h wake group, reflecting stable List 1 memory after 90 min of sleep and after 10 h of wakefulness. However, the RIF effect was absent after 90 min of wakefulness, suggesting that the List 1 memory was still labile at that time. Moreover, the RIF effect in the 90 min sleep group was associated with power density in the slow oscillation frequency band (0.5-1 Hz) during SWS and S2. These findings suggest that 90 min of sleep accelerate memory re-stabilization after reminder presentation, shortening the reconsolidation time window and protecting the memory against subsequent interference. This rapid memory re-stabilization may depend on slow oscillation activity during NREM sleep.

The effects of stress and glucocorticoids on vocalizations: a test in North American red squirrels

AbstractAcoustic signaling is an important means by which animals communicate both stable and labile characteristics. Although it is widely appreciated that vocalizations can convey information on labile state, such as fear and aggression, fewer studies have experimentally examined the acoustic expression of stress state. The transmission of such public information about physiological state could have broad implications, potentially influencing the behavior and life-history traits of neighbors. North American red squirrels (Tamiasciurus hudsonicus) produce vocalizations known as rattles that advertise territorial ownership. We examined the influence of changes in physiological stress state on rattle acoustic structure through the application of a stressor (trapping and handling the squirrels) and by provisioning squirrels with exogenous glucocorticoids (GCs). We characterized the acoustic structure of rattles emitted by these squirrels by measuring rattle duration, mean frequency, and entropy. We found evidence that rattles do indeed exhibit a “stress signature.” When squirrels were trapped and handled, they produced rattles that were longer in duration with a higher frequency and increased entropy. However, squirrels that were administered exogenous GCs had similar rattle duration, frequency, and entropy as squirrels that were fed control treatments and unfed squirrels. Our results indicate that short-term stress does affect the acoustic structure of vocalizations, but elevated circulating GC levels do not mediate such changes.

Interfering with emotional processing resources upon associative threat memory reactivation does not affect memory retention

Ample evidence suggests that memories enter a labile state upon retrieval, requiring reconsolidation processes in order to be retained. During this period of instability, various interventions can be applied to modify problematic memories. A novel behavioral intervention was designed, aimed at disrupting amygdala-based cognitive processing following the retrieval of a conditioned threat memory, in order to prevent its reconsolidation. We fear-conditioned participants on day 1, and reactivated their memory on day 2. Following reactivation, the reactivation plus emotional working memory task (R + EWMT) group completed an EWMT, while the reactivation only (RO) group served as a no-task control. On day 3, all participants were tested for memory retention, followed by a test for sensitivity to reinstatement. We observed successful acquisition and reactivation in fear-potentiated startle responding, skin conductance responding and US expectancies in both groups. Differential fear responding was fully preserved in the R + EWMT group relative to the RO group at the beginning of retention testing, and both groups were comparably sensitive to reinstatement. Thus, we failed to obtain any evidence that the execution of an EWMT after threat memory reactivation impairs reconsolidation. Further research is indicated to clarify whether threat memory reconsolidation can be disrupted by taxing relevant WM resources.

The art therapy relational neuroscience and memory reconsolidation four drawing protocol

Novel and rewarding experiences can reconsolidate people's memories and recalibrate their reactions to past events. Memory reconsolidation (MR) is a positive process whereby as autobiographical memories are recalled, they return to a labile state, and can be either reinforced or updated before reconsolidation. Thus, updating fear-based memories with non-fearful information may lead to permanent reduction in automatic responses and lasting changes to distressing memories. During recall, both implicit and explicit memories may be updated. The arts therapies offer rewarding and creative access to nonverbal autobiographical memories, as well as mitigate habitual reactions. When informed by the neuroscience of MR, art therapy relational neuroscience (ATR-N) practices support therapeutic MR dynamics. In support of these theoretical claims, the relevant literature is reviewed and then illustrated by a MR-ATR-N trauma-based protocol.

Roll with the fear: environment and state dependence of pill bug (Armadillidium vulgare) personalities

Most studies on animal personality evaluate individual mean behaviour to describe individual behavioural strategy, while often neglecting behavioural variability on the within-individual level. However, within-individual behavioural plasticity (variation induced by environment) and within-individual residual variation (regulatory behavioural precision) are recognized as biologically valid components of individual behaviour, but the evolutionary ecology of these components is still less understood. Here, we tested whether behaviour of common pill bugs (Armadillidium vulgare) differs on the among- and within-individual level and whether it is affected by various individual specific state-related traits (sex, size and Wolbachia infection). To this aim, we assayed risk-taking in familiar vs. unfamiliar environments 30 times along 38 days and applied double modelling statistical technique to handle the complex hierarchical structure for both individual-specific trait means and variances. We found that there are significant among-individual differences not only in mean risk-taking behaviour but also in environment- and time-induced behavioural plasticity and residual variation. Wolbachia-infected individuals took less risk than healthy conspecifics; in addition, individuals became more risk-averse with time. Residual variation decreased with time, and individuals expressed higher residual variation in the unfamiliar environment. Further, sensitization was stronger in females and in larger individuals in general. Our results suggest that among-individual variation, behavioural plasticity and residual variation are all (i) biologically relevant components of an individual’s behavioural strategy and (ii) responsive to changes in environment or labile state variables. We propose pill bugs as promising models for personality research due to the relative ease of getting repeated behavioural measurements.

Post-retrieval oxytocin facilitates next day extinction of threat memory in humans.

Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown. This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants. In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40IU) or placebo after memory retrieval, or an intranasal dose of OT (40IU) without retrieval. On day 3, the participantswere tested for extinction and reinstatement. On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups. The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory.

The Possible Role of Neurobeachin in Extinction of Contextual Fear Memory

Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.

Positive emotional induction interferes with the reconsolidation of negative autobiographical memories, in women only.

After reactivation, a previously consolidated memory can enter into a labile state followed by a re-stabilization process defined as reconsolidation. The aim of this study was to explore whether an existing negative autobiographical memory can be modified by using a non-invasive interference (audiovisual positive preparation) after reactivation and to determine if this effect could be dependent on the reconsolidation process. We found that the presentation of a positive inductor after a negative autobiographical memory reactivation may lead to a change in the emotional information of the original trace and that such effect can be mediated by the reconsolidation process. The modification of the memory has been shown in women only. These results suggest that a positive audiovisual induction may play a potential role in psychotherapeutic techniques for the modification of dysfunctional autobiographical memories.

The mitigating effect of repeated memory reactivations on forgetting

Memory reactivation is a process whereby cueing or recalling a long-term memory makes it enter a new active and labile state. Substantial evidence suggests that during this state the memory can be updated (e.g., adding information) and can become more vulnerable to disruption (e.g., brain insult). Memory reactivations can also prevent memory decay or forgetting. However, it is unclear whether cueing recall of a feature or component of the memory can benefit retention similarly to promoting recall of the entire memory. We examined this possibility by having participants view a series of neutral images and then randomly assigning them to one of four reactivation groups: control (no reactivation), distractor (reactivation of experimental procedures), component (image category reactivation), and descriptive (effortful description of the images). The experiment also included three retention intervals: 1 h, 9 days, and 28 days. Importantly, the participants received three reactivations equally spaced within their respective retention interval. At the end of the interval, all the participants were given an in-lab free-recall test in which they were asked to write down each image they remembered with as many details as possible. The data revealed that both the participants in the descriptive reactivation and component reactivation groups remembered significantly more than the participants in the control groups, with the effect being most pronounced in the 28-day retention interval condition. These findings suggest that memory reactivation, even component reactivation of a memory, makes memories more resistant to decay.

β-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation

Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that β-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a β-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of β-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that β-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability.

Octahedral Co(III) salen complexes: the role of peripheral ligand electronics on axial ligand release upon reduction

A series of octahedral CoIII salen complexes (where salen represents a N2O2 bis-Schiff-base bis-phenolate framework) were prepared with axial imidazole ligating groups. When using 1-methylimidazole (1-MeIm) axial ligands, the CoIII/CoII reduction potential could be altered by 220 mV via variation of the electron-donating ability of the para-ring substituents (R = H (1), OMe (2), tBu (3), Br (4), NO2 (5), and CF3 (6)). In addition, the irreversibility of the reduction process suggested substantial geometrical changes and axial ligand exchange upon reduction to the more labile CoII oxidation state. Installing an imidazole-coumarin conjugate as the axial ligands resulted in fluorescence quenching when bound to the CoIII centre (R = H (7), OMe (8), and CF3 (9)). The redox properties and fluorescence increase upon ligand release for 7–9 were studied under reducing conditions and in the presence of excess competing ligand (1-MeIm). It was determined that the Lewis acidity of the CoIII centre was the dominant factor in controlling axial ligand exchange for this series of complexes.

The surprising subtleties of changing fear memory: a challenge for translational science.

Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. The (re)discovery in neuroscience that after reactivation consolidated fear memories may return to a transient labile state, requiring a process of restabilization in order to persist, offers a window of opportunity for modifying fear memories with amnestic agents. This process, known as memory reconsolidation, opens avenues for developing a revolutionary treatment for emotional memory disorders. The reconsolidation intervention challenges the dominant pharmacological and psychological models of treatment: it is only effective when the amnestic drug is given in conjunction with memory reactivation during a specific time window, and a modification of cognitive processes is a boundary condition for changing fear. Notwithstanding the dramatic effects of targeting memory reconsolidation in the laboratory (i.e. proof of principle), the greatest hurdle to overcome is that the success of the manipulation depends on subtle differences in the reactivation procedure. These experimental parameters cannot be easily controlled in clinical practice. In harnessing the clinical potential of memory reconsolidation, a heuristic for bi-directionally translating behavioural neuroscience and clinical science is proposed.This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

Nanomorphology Effects in Semiconductors with Native Ferromagnetism: Hierarchical Europium (II) Oxide Tubes Prepared via a Topotactic Nanostructure Transition.

Semiconductors with native ferromagnetism barely exist and defined nanostructures are almost unknown. This lack impedes the exploration of a new class of materials characterized by a direct combination of effects on the electronic system caused by quantum confinement effects with magnetism. A good example is EuO for which currently no reliable routes for nanoparticle synthesis can be established. Bottom-up approaches applicable to other oxides fail because of the labile oxidation state +II. Instead of targeting a direct synthesis, the two steps-"structure control" and "chemical transformation"-are separated. The generation of a transitional, hybrid nanophase is followed by its conversion into EuO under full conservation of all morphological features. Hierarchical EuO materials are now accessible in the shape of oriented nanodisks stacked to tubular particles. Magnetically, the coupling of either vortex or onion states has been found. An unexpected temperature dependence is governed by thermally activated transitions between these states.

Re-stepping into the same river: competition problem rather than a reconsolidation failure in an established motor skill

Animal models suggest that consolidated memories return to their labile state when reactivated and need to be restabilized through reconsolidation processes to persist. Consistent with this notion, post-reactivation pharmacological protein synthesis blockage results in mnemonic failure in hippocampus-dependent memories. It has been proposed that, in humans, post-reactivation experience with a competitive task can also interfere with memory restabilization. However, several studies failed to induce performance deficit implementing this approach. Moreover, even upon effective post-reactivation interference, hindered performance may rapidly recover, raising the possibility of a retrieval rather than a storage deficit. Here, to address these issues in procedural memory domain, we used new learning to interfere with restabilization of motor memory acquired through training on a sequence of finger movements. Only immediate post-reactivation interference was associated with the loss of post-training delayed gains in performance, a hallmark of motor sequence memory consolidation. We also demonstrate that such performance deficit more likely indicates a genuine memory impairment rather than a retrieval failure. However, the reconsolidation view on a reactivation-induced plasticity is not supported. Instead, our results are in line with the integration model according to which new knowledge acquired during the interfering experience, is integrated through its consolidation creating memory competition.

Breaking boundaries: optimizing reconsolidation-based interventions for strong and old memories.

Recent research has demonstrated that consolidated memories can enter a temporary labile state after reactivation, requiring restabilization in order to persist. This process, known as reconsolidation, potentially allows for the modification and disruption of memory. Much interest in reconsolidation stems from the possibility that maladaptive memory traces—a core feature of several psychiatric conditions—could be tackled by disrupting their reconsolidation. However, research has indicated a range of supposed boundary conditions on the induction of reconsolidation. Stronger memories, often resulting from exposure to stressful conditions, or older memories, appear to be relatively resistant to undergoing reconsolidation. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Yet, boundary conditions have been derived from limited experimental evidence, are not unique to reconsolidation-based interventions, and do not seem to be absolute. In this paper, we review a range of experimental studies that have aimed to disrupt old memories, or memories that were strengthened by stress manipulations, through reconsolidation. Such research highlights several techniques that could be used to optimize reconsolidation-based approaches and overcome putative boundary conditions. We supplement this review of experimental literature with a case study of a reconsolidation-based treatment of a strong and decades-old phobia for mice, further suggesting that age and strength of memory may not be insurmountable barriers. Translating findings from basic science, to human experiments, to clinical applications and back again, can potentially unlock powerful new treatments for the many people who suffer daily from anxiety disorders.

Intervention strength does not differentially affect memory reconsolidation of strong memories

Recently, it has become clear that retrieval (i.e., reactivation) of consolidated memories may return these memories into a labile state before they are restored into long-term memory (‘reconsolidation’). Using behavioral manipulations, reactivated memories can be disrupted via the mechanism of novel learning. In the present study, we investigated whether changing a strong memory during reconsolidation depends on the strength of novel learning. To test this, participants (N=144) in six groups acquired a relatively strong memory on Day 1 by viewing and recalling a series of pictures three times. On Day 8, these pictures were reactivated in three groups, and they were not reactivated in the other three groups. Then, participants viewed and recalled new pictures once (weak new learning) or three times (strong new learning), or they did not learn any new pictures. On Day 9, participants performed a recognition test in which their memory for Day 1 pictures was assessed. Two main results are noted. First, the groups that reactivated pictures from Day 1 and received weak or strong new learning did not differ in memory performance. Second, these two groups consistently performed similar to groups that controlled for new learning without reactivation. Because these results contradict what was expected based on the reconsolidation hypothesis, we discuss possible explanations and implications.

Transient acidosis while retrieving a fear-related memory enhances its lability.

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.

Photo‐Chromium: Sensitizer for Visible‐Light‐Induced Oxidative C−H Bond Functionalization—Electron or Energy Transfer?

AbstractThe chromium(III) sensitizer [Cr(ddpd)2]3+ (ddpd=N,N′‐dimethyl‐N,N′‐dipyridine‐2‐ylpyridine‐2,6‐diamine), based on an earth‐abundant metal centre, possesses a unique excited‐state potential‐energy landscape. The very large energy gap between the redox‐active and substitutionally labile 4T2 state and the long‐lived low‐energy 2E spin‐flip state enables a selective, efficient sensitization of triplet dioxygen to give singlet dioxygen. Ultrafast intersystem crossing after the Franck Condon point from the 4T2 to the 2E excited state within 3.5 ps precludes intermolecular electron‐transfer pathways from the ultrashort‐lived excited 4T2 state. This specific excited‐state reactivity enables a selective visible‐light‐induced C−H bond activation of tertiary amines with 1O2 and subsequent trapping with cyanide to yield α‐aminonitriles in good to excellent yields.

Direct Observation of Coordinatively Unsaturated Sites on the Surface of a Fluoride-Doped Alumina Catalyst

Coordinatively unsaturated sites (CUS) present a key feature of alumina based catalysts as they are believed to act as Lewis-acid sites in heterogeneously catalyzed reactions. In the present study, the direct observation of active species on a fluoride-doped aluminum oxide catalyst is demonstrated. This new fluoride-doped aluminum oxide exhibits strong Lewis-acid sites and superior catalytic activity as compared to γ-Al2O3. To emphasize the labile state of Lewis-acid sites, two distinctive states of the catalysts surface are addressed using 1H–27Al cross-polarization (CP) MAS NMR. On the one hand, the highly dehydrated and active state after calcination at 700 °C and on the other hand the rehydrated and catalytically inactive surface (produced by contact to air) are probed. These experiments revealed the presence of significant amounts of coordinatively unsaturated sites in the form of 4- and 5-fold coordinated Al-sites on the highly dehydrated surface. In contrast to this, the rehydrated sample exhibited...