Sequential Reactivation Research Articles

Replay-triggered brain-wide activation in humans

The consolidation of discrete experiences into a coherent narrative shapes the cognitive map, providing structured mental representations of our experiences. In this process, past memories are reactivated and replayed in sequence, fostering hippocampal-cortical dialogue. However, brain-wide engagement coinciding with sequential reactivation (or replay) of memories remains largely unexplored. In this study, employing simultaneous EEG-fMRI, we capture both the spatial and temporal dynamics of memory replay. We find that during mental simulation, past memories are replayed in fast sequences as detected via EEG. These transient replay events are associated with heightened fMRI activity in the hippocampus and medial prefrontal cortex. Replay occurrence strengthens functional connectivity between the hippocampus and the default mode network, a set of brain regions key to representing the cognitive map. On the other hand, when subjects are at rest following learning, memory reactivation of task-related items is stronger than that of pre-learning rest, and is also associated with heightened hippocampal activation and augmented hippocampal connectivity to the entorhinal cortex. Together, our findings highlight a distributed, brain-wide engagement associated with transient memory reactivation and its sequential replay.

Neurofeedback training can modulate task-relevant memory replay rate in rats.

Hippocampal replay - the time-compressed, sequential reactivation of ensembles of neurons related to past experience - is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.

Neurofeedback training can modulate task-relevant memory replay rate in rats

Hippocampal replay – the time-compressed, sequential reactivation of ensembles of neurons related to past experience – is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.

Disruption of awake sharp-wave ripples does not affect memorization of locations in repeated-acquisition spatial memory tasks.

Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through space. However, it is unclear if awake replay impacts immediate future behavior, gradually creates and stabilizes long-term memories over a long period of time (hours and longer), or enables the temporary memorization of relevant events at an intermediate time scale (seconds to minutes). In this study, we aimed to address the uncertainty around the timeframe of impact of awake replay by collecting causal evidence from behaving rats. We detected and disrupted sharp wave ripples (SWRs) - signatures of putative replay events - using electrical stimulation of the ventral hippocampal commissure in rats that were trained on three different spatial memory tasks. In each task, rats were required to memorize a new set of locations in each trial or each daily session. Interestingly, the rats performed equally well with or without SWR disruptions. These data suggest that awake SWRs - and potentially replay - does not affect the immediate behavior nor the temporary memorization of relevant events at a short timescale that are required to successfully perform the spatial tasks. Based on these results, we hypothesize that the impact of awake replay on memory and behavior is long-term and cumulative over time.

Distinct replay signatures for prospective decision-making and memory preservation

Theories of neural replay propose that it supports a range of functions, most prominently planning and memory consolidation. Here, we test the hypothesis that distinct signatures of replay in the same task are related to model-based decision-making ("planning") and memory preservation. We designed a reward learning task wherein participants utilized structure knowledge for model-based evaluation, while at the same time had to maintain knowledge of two independent and randomly alternating task environments. Using magnetoencephalography and multivariate analysis, we first identified temporally compressed sequential reactivation, or replay, both prior to choice and following reward feedback. Before choice, prospective replay strength was enhanced for the current task-relevant environment when a model-based planning strategy was beneficial. Following reward receipt, and consistent with a memory preservation role, replay for the alternative distal task environment was enhanced as a function of decreasing recency of experience with that environment. Critically, these planning and memory preservation relationships were selective to pre-choice and post-feedback periods, respectively. Our results provide support for key theoretical proposals regarding the functional role of replay and demonstrate that the relative strength of planning and memory-related signals are modulated by ongoing computational and task demands.

Compositional Sequence Generation in the Entorhinal-Hippocampal System.

Neurons in the medial entorhinal cortex exhibit multiple, periodically organized, firing fields which collectively appear to form an internal representation of space. Neuroimaging data suggest that this grid coding is also present in other cortical areas such as the prefrontal cortex, indicating that it may be a general principle of neural functionality in the brain. In a recent analysis through the lens of dynamical systems theory, we showed how grid coding can lead to the generation of a diversity of empirically observed sequential reactivations of hippocampal place cells corresponding to traversals of cognitive maps. Here, we extend this sequence generation model by describing how the synthesis of multiple dynamical systems can support compositional cognitive computations. To empirically validate the model, we simulate two experiments demonstrating compositionality in space or in time during sequence generation. Finally, we describe several neural network architectures supporting various types of compositionality based on grid coding and highlight connections to recent work in machine learning leveraging analogous techniques.

Catalytic Synergies in Bimetallic RuPt Single–Atom Catalysts via Speciation Control

AbstractBimetallic single–atom catalysts (b–SACs) have recently gained prominence by virtue of the unique catalytic cooperative interactions they can exhibit, intertwining electronic and geometric effects. To date, research efforts have exclusively focused on direct mechanisms such as electron density transfer or sequential reactivity. Herein, the first study on indirect, coordination–induced catalytic synergies in carbon‐supported RuPt SACs is conducted. To this end, a holistic approach is developed, combining i) precision synthesis, ii) advanced characterization, iii) exploration of single–site adsorption properties via the hydrogen evolution reaction, and iv) modeling through density functional theory. Despite the lack of both intermetallic coordination in the first or second shell and charge redistribution effects, the RuPt SACs exhibit a H2 formation rate enhanced up to 15–fold compared with their monometallic counterparts. To unfold the origin of the intermetallic cooperativity, modifications of the structural and catalytic properties induced by the integration of a second metal species are investigated. Thus, Pt atoms are found to selectively occupy the most energeticallyfavorable cavities in the support, prompting Ru atoms to assume a distinct, more active, configuration. This contribution unveils a novel principle of bimetallic cooperativity, demonstrating the key role of integrative experimental and computational analyses in studying b–SACs.

Experience-driven rate modulation is reinstated during hippocampal replay.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter - based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

Sequential reactivation of differently oriented weak planes of the basement under uniform state of stress: A possible mechanism of evolution of Tatapani–Ramkola basin, central India

Sequential reactivation of differently oriented weak planes of the basement under uniform state of stress: A possible mechanism of evolution of Tatapani–Ramkola basin, central India

Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice

The ability to remember conspecifics is critical for adaptive cognitive functioning and social communication, and impairments of this ability are hallmarks of autism spectrum disorders (ASDs). Although hippocampal ventral CA1 (vCA1) neurons are known to store social memories, how their activities are coordinated remains unclear. Here we show that vCA1 social memory neurons, characterized by enhanced activity in response to memorized individuals, were preferentially reactivated during sharp-wave ripples (SPW-Rs). Spike sequences of these social replays reflected the temporal orders of neuronal activities within theta cycles during social experiences. In ASD model Shank3 knockout mice, the proportion of social memory neurons was reduced, and neuronal ensemble spike sequences during SPW-Rs were disrupted, which correlated with impaired discriminatory social behavior. These results suggest that SPW-R-mediated sequential reactivation of neuronal ensembles is a canonical mechanism for coordinating hippocampus-dependent social memories and its disruption underlie the pathophysiology of social memory defects associated with ASD.

On-surface homocoupling reactivity of a chiral bifunctional bromoindanone molecule on Cu(111)

Sequential reactivity is creating various kinds of macromolecular compounds with distinct prochirality using an on-surface synthesis approach.

The role of inheritance in forming rifts and rifted margins and building collisional orogens: a Biscay-Pyrenean perspective

A long-standing challenge in tectonics is to evaluate the role of inheritance and define the initial conditions of a geodynamic system, which are prerequisites to understand and model its evolution with some accuracy. Here we revisit the concept of “inheritance” by distinguishing “interface shape inheritance”, which includes the transient thermal state and gravitational potential energy, and “persisting inheritance”, which encompasses long-lasting structural and compositional inheritance. This new approach allows us to investigate, at each stage of a Wilson Cycle, the interplay between inheritance (innate/“genetic code”) and the physical processes at play (extension/compression, magmatism etc.). The aim of this paper is to provide a conceptual framework that integrates the role of inheritance in the study of rifts, rifted margins and collisional orogens based on the work done in the OROGEN project, which focuses on the Biscay-Pyrenean system. The Biscay-Pyrenean rift system resulted from a multistage rift evolution that developed over a complex lithosphere pre-structured by the Variscan orogenic cycle. There is a general agreement that the Pyrenean-Cantabrian orogen resulted from the reactivation of an increasingly mature rift system along-strike, ranging from mature rifted margins in the west to an immature and segmented hyperextended rift in the east. However, different models have been proposed to explain the preceding rifting and its influence on the subsequent reactivation. Results from the OROGEN project highlight the sequential reactivation of rift-inherited decoupling horizons and identify the specific role of exhumed mantle, hyperextended and necking domains during compressional reactivation. They also highlight the contrasting fate of rift segment centresversussegment boundaries during convergence, explaining the non-cylindricity of internal parts of collisional orogens. Results from the OROGEN project also suggest that the role of inheritance is more important during the initial stages of collision, which may explain the higher complexity of internal parts of orogenic systems with respect to their external parts. In contrast, when the system involved in the orogeny is more mature, the orogenic evolution is mostly controlled by first-order physical processes as described in the Coulomb Wedge theory, for instance. This may account for the simpler and more continuous architecture of external parts of collisional orogens and may also explain why most numerical models can reproduce mature orogenic architectures with a better accuracy compared to those of initial collisional stages. The new concepts developed from the OROGEN research are now ready to be tested at other orogenic systems that result from the reactivation of rifted margins, such as the Alps, the Colombian cordilleras and the Caribbean, Taiwan, Oman, Zagros or Timor.

Influence of corticosteroid therapy on viral reactivation in drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction characteristically associated with sequential reactivation of herpesviruses, such as human herpesvirus 6 (HHV‐6), Epstein‐Barr virus (EBV), and cytomegalovirus (CMV). Since systemic corticosteroids are thought to result in viral reactivation due to their immunosuppressive effects, we clarified the influence of systemic corticosteroid therapy on viral reactivation in DIHS/DRESS. Viral DNA in peripheral whole blood and serum sIL‐2R level were measured during the disease course in twenty DIHS/DRESS patients. Six of seven patients treated without corticosteroids experienced HHV‐6 viremia associated with elevated serum sIL‐2R levels. In contrast, high‐dose corticosteroids started within 1 week after onset tended to inhibit the occurrence of HHV‐6 reactivation with remarkable suppression of serum sIL‐2R level. Low‐dose corticosteroids or late‐start high‐dose corticosteroids did not suppress occurrence of HHV‐6 viremia and the increase of sIL‐2R levels. HHV‐6 load in the blood was clearly correlated with the serum sIL‐2R level. On the other hand, increased CMV load were found in patients treated with corticosteroids regardless of the start time. The frequency of detection of EBV DNA in peripheral blood was similarly observed in all groups. In conclusion, high‐dose corticosteroids started within 1 week tended to suppress HHV‐6 reactivation through suppression of T cell activation. However, CMV proliferation was promoted by corticosteroids regardless of the start time. These observations suggested that careful consideration should be given to the dose and timing of administration of systemic corticosteroids in the treatment of DIHS/DRESS.

Development of a Tethered Palladium–BODIPY Dual Catalyst for Enhanced Photo- and Thermally Activated Catalysis, and for Promoting Sequential Reactivity

In recent years there has been a growing interest in merging different types of catalysis to create new multistep catalytic processes. However, the majority of reported dual catalysis strategies use a mixture of individual catalysts, with limited reports of dual catalysis reactions where the different catalysts are combined in a single compound. This work reports the synthesis of a tethered palladium-BODIPY dual catalyst to enable increased synergistic interactions between the catalytic centres. Detailed analysis, including single crystal X-ray crystallography, absorption, fluorescence, and phosphorescence measurements, and kinetic analyses to determine singlet oxygen quantum yields, confirm that chemical tethering results in a significant increase in the photocatalytic potential of the palladium-BODIPY dual catalyst, relative to the parent BODIPY chromophore. Interestingly, the palladium-BODIPY complex also exhibited rare long-lived room temperature phosphorescence. Catalytic applications of the palladium-BODIPY dual catalyst indicate that chemical tethering increases the reactivity of the catalytic centres for both photocatalytic oxidation of thioanisole and palladium catalysed Suzuki–Miyaura cross coupling, highlighting that enhancements in both photo and thermally activated catalysis can be achieved on chemical tethering. In addition, the dual catalytic potential of the palladium-BODIPY catalyst was demonstrated using a representative sequential photocatalytic oxidation–cross coupling reaction.

Pan-African structural evolution of Paleoproterozoic basement gneiss and Cu-Co mineralized shear zones in the Domes Region of the Lufilian Belt, Mwombezhi Dome, Zambia

In the Domes Region of the Lufillian Belt, world-class stratiform Cu (±Co, ±Ni, ±U, ±Pb, ±Zn) deposits are closely associated with tectonized pre-existing basement unconformities, viz. the pre-Katanga-basement décollement (KD). In the KD footwall on the Mwombezhi Dome, the Lumwana Mine exploits mineralization within <60 m thick, laterally-extensive shear zones beneath kilometer-scale thrust sheets of Paleoproterozoic gneiss and schist. New field data and structural analysis highlight preferential strain localization, kinematics and sequential reactivation of multiple shear zone generations (D1-3) under high- to medium-grade, metamorphic conditions and clockwise P-T-t path during the Lufillian Orogeny (ca. 550-500). Regional, progressive, top-to-the-NNE fore-thrusting is assigned to D1, while D2 represents localized, opposite, top-to-the-SSW kinematics attributed to under-thrusting by dome-scale fore-thrusted basement slivers. Subsequent D3 shear zones transposed D1-2 structures and represent overall top-to-the-NNE extensional detachment and NNE-SSW-elongation along a maximum principal extension axis (L3) which defines kilometer-scale shear- or asymmetrical-boudins of competent gneiss in the KD footwall. A pre-existing NNE-SSW prolate dome asymmetry (L1-2) dictates a downlimb-directed sense of shear on the short axes of D3 asymmetrical boudins (WNW-ESE). D3 shear zones are preferentially localized along relict pre-Katanga anisotropy and D1-2 mylonitic horizons, while Cu–Co bearing ore shoots are associated with passive fold hinges in these asymmetrical boudin necks.

Replay of activity in the human brain

Neuroscience Electrophysiological recordings in rats and mice have shown that specific hippocampal neuronal activity patterns are sequentially reactivated during rest periods or sleep. Does the human hippocampus also replay activity sequences, even in a nonspatial task, such as, for example, decision-making? Schuck and Niv studied functional magnetic resonance imaging signals in subjects after they had learned a decision-making task. While people rested, the replay of activity patterns in the hippocampus reflected the order of previous task-state sequences. Thus, sequential hippocampal reactivation might participate in decision-making in humans. Science , this issue p. [eaaw5181][1] [1]: /lookup/doi/10.1126/science.aaw5181

Role of rift structural inheritance in orogeny highlighted by the Western Pyrenees case-study

It is commonly accepted that many orogens form by contractional reactivation of earlier continental rifts or rifted margins. Therefore, to better understand orogenesis, it is important to also understand how rift domains and their associated structures are incorporated into orogens.We investigate the role of rift structural inheritance during orogeny using the Western Pyrenees as a case-study. To achieve our aim, we use a kinematic forward lithosphere deformation model (RIFTER) to produce flexural isostatically compensated as well as balanced cross-sections showing the structural and stratigraphic development of both the rift and orogenic stages of the Western Pyrenees. The cross-section produced extends from the Northern to the Southern Foreland Basins and crosses the Mauléon-Arzacq Basin.Our modelling results show how rift-domains and their faults are sequentially reactivated and incorporated into the present-day Western Pyrenees architecture. Based on the results from our case-study, we identify a sequence of tectonic stages separated by critical events that record the transition between different tectonic styles by which lithosphere is deformed. The pre-orogenic extensional stage is characterized by a hyper-extended rift system that eventually led to exhumed mantle. This constitutes the pre-orogenic template. The subsequent contractional tectonics consists of two stages: (i) the inversion of the hyper-extended rift system reactivating extensional structures and (ii) the crustal shortening of the southern proximal rift domain.Results of the Western Pyrenees case-study may be used to understand the development of other Alpine-type collisional systems involving the sequential reactivation and inversion of former hyper-extended rift systems.

Phosphorylated mTORC1 represses autophagic-related mRNA translation in neurons exposed to ischemia-reperfusion injury.

The sequential reactivation of mechanistic target of rapamycin (mTOR) inhibited autophagic flux in neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R), which was characterized by reduction of autophagosome formation and restriction of autolysosome degradation. However, its detailed molecular mechanism was still unknown. In this study, we further explore the existing form of mTOR and its suppression on the transcriptional levels of related mRNA from neurons exposed to ischemia-reperfusion injury. The OGD/R or middle cerebral artery occlusion/reperfusion (MCAO/R)-treated neurons was used to simulate ischemia/reperfusion injury . Autophagy flux was monitored by means of microtubule-associated protein 1 light chain 3 (LC3) and p62. The reactivation of mTOR was determined by phosphorylation of ribosomal protein S6 kinase 1 (S6K1). Then the inhibitors of mTOR were used to confirm its existence form. Finally, the mRNA transcription levels were analyzed to observe the negative regulation of mTOR. The sequential phosphorylation of mTOR contributed to the neuronal autophagy flux blocking. mTOR was re-phosphorylated and existed as mTOR complex 1 (mTORC1), which was supported by phosphorylation of S6K1 at Thr 389 in neurons. In addition, the phosphorylation of S6K1 was decreased roughly by applying mTORC1 inhibitors, rapamycin and torin 1. However, the administration of mTORC1/2 inhibitor PP242 could recover the phosphorylation of S6K1, which suggested that mTORC2 was involved in the regulation of mTORC1 activity. In paralleling with reactivation of mTORC1, related mRNA transcription was repressed in neurons under ischemia-reperfusion exposure in vivo and in vitro. The mRNA expression levels of LC3, Stx17, Vamp8, Snap29, Lamp2a, and Lamp2b were decreased in neurons after reperfusion, comparing with ischemia-treated neurons. The reactivated mTORC1 could suppress the transcription levels of related mRNA, such as LC3, Stx17, Vamp8, Snap29, Lamp2a, and Lamp2b. The research will expand the horizons that mTOR would negatively regulate autophagy at transcription and post-translation levels in neurons suffering ischemia-reperfusion injury.

Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine-tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS. To investigate whether the shift from Treg to Th17 could specifically occur during the course of DiHS/DRESS and to elucidate which subsets of monocytes could be involved in the shift. We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of DiHS/DRESS and SJS/TEN, and long after their clinical resolutions. We next examined whether pMOs and cMOs could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by invitro cocultures. Selective depletion of pMOs occurring at the acute stage of DiHS/DRESS was associated with the relative increase in the frequencies of cMOs producing IL-10 and it did drive Treg expansions. After clinical resolution, pMOs producing IL-6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. The gradual shift from Treg to Th17 cell development observed during the clinical course of DiHS/DRESS is mediated by the predominance of cMOs at the acute stage and alternatively recruited pMOs at the resolution stage, respectively.

Molecular Manipulations of a Utility Nitrogen-Heterocyclic Carbene by Sodium Magnesiate Complexes and Transmetallation Chemistry with Gold Complexes.

Expanding the scope and applications of anionic N-heterocyclic carbenes (NHCs), a novel series of magnesium NHC complexes is reported using a mixed sodium-magnesium approach. Sequential reactivity of classical imidazol- 2-ylidene carbene IPr with NaR and MgR2 (R=CH2 SiMe3 ) affords [(THF)3 Na(μ-IPr- )MgR2 (THF)] (2) [IPr- =:C{[N(2,6-iPr2 C6 H3 )]2 CHC] containing an anionic NHC ligand, whereas surprisingly sodium magnesiate [NaMgR3 ] fails to deprotonate IPr affording instead the redistribution coordination adduct [IPr2 Na2 MgR4 ] (1). Compound 2 undergoes selective C2-methylation when treated with MeOTf furnishing novel abnormal NHC complex [{aIPrMe MgR2 }2 ] (3). Dissolving 3 in THF led to the dissociation of this complex into MgR2 and aIPrMe with the latter isomerizing to the olefinic NHC IPr=CH2 . The ability of 2 and 3 to transfer their anionic and abnormal NHC ligands, respectively to AuI metal fragments has been investigated allowing the isolation and structural characterization of [RAu(μ-IPr- )MgR(THF)2 ] (4) and [aIPrMe AuR] (5) respectively. In both cases transfer of an alkyl R group is observed. However while 3 can also transfer its abnormal NHC ligand to give 5, in 4 the anionic NHC still remains coordinated to Mg via its C4 position, whereas the {AuR} fragment occupies the C2 position previously filled by a donor-solvated {Na(THF)3 }+ cation.