Progress in Neurobiology

Spatial navigation is a complex cognitive process based on multiple senses that are integrated and processed by a wide network of brain areas. Previous studies have revealed the retrosplenial complex (RSC) to be modulated in a task-related manner during navigation. However, these studies restricted participants movement to stationary setups, which might have impacted heading computations due to the absence of vestibular and proprioceptive inputs. Here, we investigated neural dynamics of RSC in an active spatial navigation task where participants actively ambulated from one location to several other points while the position of a landmark and the starting location were updated. The results revealed theta power in the RSC to be pronounced during heading changes but not during translational movements, indicating that physical rotations induce human RSC theta activity. This finding provides a potential evidence of head-direction computation in RSC in healthy humans during active spatial navigation.

Reactivation of place cells during sharp-wave ripples (SWRs) in the hippocampus is pivotal for memory consolidation, yet differences in SWR dynamics between the hippocampus and its neighboring subiculum remain underexplored. We examined the differential reactivations of task-demand-associated representations during SWR events in the subiculum and CA1 during a visual scene memory task in rats. In the task, the spiking activity of place cell ensembles was reactivated during a SWR event according to task demands. These reactivations were more frequent and were associated with more heterogeneous task-demand types in the subiculum compared with the CA1. Neural manifold analysis showed that the neural states of the reactivated ensemble were more clearly clustered into distinct states during subicular SWRs according to the task-demand-associated variables. These subicular characteristics were driven by multiple subfields of the subicular place field, parcellated by the theta phase precession cycle. In contrast, CA1 exhibited a higher incidence of spatial replay than the subiculum. These findings indicate that the subiculum plays a key role in transmitting task-specific variables from the hippocampus to other brain regions.

In order to investigate the involvement of primary visual cortex (V1) in working memory (WM), parallel, multisite recordings of multiunit activity were obtained from monkey V1 while the animals performed a delayed match-to-sample (DMS) task. During the delay period, V1 population firing rate vectors maintained a lingering trace of the sample stimulus that could be reactivated by intervening impulse stimuli that enhanced neuronal firing. This fading trace of the sample did not require active engagement of the monkeys in the DMS task and likely reflects the intrinsic dynamics of recurrent cortical networks in lower visual areas. This renders an active, attention-dependent involvement of V1 in the maintenance of working memory contents unlikely. By contrast, population responses to the test stimulus depended on the probabilistic contingencies between sample and test stimuli. Responses to tests that matched expectations were reduced which agrees with concepts of predictive coding.

Previous work has proposed two potentials benefits of retrospective attention on working memory (WM): target strengthening and non-target inhibition. It remains unknown which hypothesis contributes to the improved WM performance, yet the neural mechanisms responsible for this attentional benefit are unclear. Here, we recorded electroencephalography (EEG) signals while 33 participants performed a retrospective-cue WM task. Multivariate pattern classification analysis revealed that only representations of target features were enhanced by valid retrospective attention during the retention, supporting the target strengthening hypothesis. Further univariate analysis found that mid-frontal theta inter-trial phase coherence (ITPC) and ERP components were modulated by valid retrospective attention and correlated with individual differences and moment-to-moment fluctuations on behavioral outcomes, suggesting that both trait- and state-level variability in attentional preparatory processes influence goal-directed behavior. Furthermore, task-irrelevant target spatial location could be decoded from EEG signals, indicating that enhanced spatial binding of target representation promotes high WM precision. Importantly, frontoparietal theta-alpha phase-amplitude-coupling was increased by valid retrospective attention and predicted the reduced randomly guessing rates. This long-range connection supported top-down information flow in engagement of frontoparietal networks, which might organize attentional states to integrate target features. Altogether, these results provide neurophysiological bases that retrospective attention improves WM precision through enhancing representation of target and emphasize the critical role of frontoparietal attentional network in the control of WM representations.

1.During goal-directed spatial learning, subjects progressively change their navigation strategies to increase their navigation efficiency, an operation supported by the medial prefrontal cortex (mPFC). However, how the mPFC may integrate relevant information in a wider memory networks involving the hippocampus (HPC) and the posterior parietal cortex (PPC) is poorly understood. We recorded local-field potential and neuronal firing simultaneously from the mPFC, HPC and PPC in mice subjected to spatial memory acquisition in the Barnes maze. During navigation trials, animals demonstrated two consecutive behavioral stages: searching and exploration. Throughout training, mice gradually switched from less efficient (non-spatial) to more efficient (spatial) goal-oriented strategies exclusively during the searching stage. 4-Hz and theta (6-12 Hz) oscillations were detected during spatial navigation in the three recorded areas associated with episodes of immobility and locomotion, respectively. The entrainment of prefrontal gamma oscillations (60-100 Hz) by hippocampal and parietal 4-Hz and theta oscillations, as well as the incidence of prefrontal gamma, was higher when mice implemented spatial strategies during the searching stage. Interestingly, 4-Hz and theta from HPC and PPC also synchronized the spike-timing of prefrontal neurons, which was maximum during spatial strategies in the searching stage. Finally, neurons recorded in the mPFC increased their task stage firing selectivity when they used spatial strategy. Altogether, these results provide evidence for the neural mechanisms underlying the prefrontal large-scale coordination with distributed neural networks during spatial learning.

There is an ongoing debate on the contribution of target enhancement and distractor inhibition processes to selective attention. In a working memory task, we presented to-be-memorized information in a way that posterior hemispheric asymmetries in oscillatory power could be unambiguously linked to lateral target vs. distractor processing. Alpha power asymmetries (8-14 Hz) were insensitive to the number of cued or non-cued items, supporting their relation to spatial attention. Furthermore, we found an increase in alpha power contralateral to non-cued working memory content and an alpha power suppression contralateral to relevant information. These oscillatory patterns relative to the positions of cued and non-cued items were related to the participants ability to control for the impact of irrelevant information on working memory retrieval. Based on these results, we propose that spatially specific modulations of posterior alpha power are related to accessing vs. inhibiting the spatial context of information stored in working memory.

Flexible behaviour requires decision-making that integrates both perceptual and mnemonic-related information. While the dorsal premotor cortex (PMd) is known to support decision-making based on perceptual computations, its contributions to decisions based on mnemonic information for motor planning are underexplored. Here, investigating local field potential (LFP) oscillations in PMd of monkeys performing a transitive inference task required the formation and retrieval of mnemonic representations of an arbitrarily defined rank order among perceptual items. Our results highlight that a dynamic interplay between lower frequencies (Theta, Alpha, Beta) and high-Gamma oscillatory activity of LFP reflects a mechanism for accessing and manipulating memory-related information underlying decision-making. These findings provide evidence that the PMd plays a role in multiplexing both perceptual and mnemonic information, extending its competence beyond the association of perceptual input with motor decisions.

Schema accommodation is the reorganization of a preexisting memory schema to deeply accept new information incongruent with it. Although it is crucial for flexible intelligence, it occurs infrequently, making its neural basis difficult to study. To overcome this, we conducted an fMRI experiment using a newly developed experimental paradigm, the reversal description task. The results suggest that the schema changes that occurred during the task were global reorganizations rather than local adjustments. Moreover, the executive network responsible for deliberate processing played a central role, with the support of widespread amplified activity. Furthermore, reinforcement learning-based control implemented in these neural substrates, in cooperation with the caudate nucleus, emerged as a candidate mechanism for the deliberative schema update. These findings indicate that memory reorganization involves not only automatic but also deliberate processes, in which the desired global structure is explored through the control operation performed by these neural bases. TeaserMemory reorganization is performed through deliberation-related neural computations supported by brain-wide amplified activity.

Sharp wave ripples (SWRs) are synchronous neurophysiological events in the hippocampus (HPC) linked to memory encoding, consolidation, and recall. In freely moving rodents, SWRs typically occur during brief pauses in locomotion when animals halt to explore their surroundings. Whether this is also the case in primates remains unknown. Here, we hypothesize that during spatial navigation in freely moving primates, hippocampal SWRs also occur during pauses in locomotion, but coupled to exploratory gaze shifts that sample visual information to guide navigation. To evaluate this, we wirelessly recorded hippocampal local field potentials (LFPs) in freely moving common marmosets (Callithrix jacchus). Two animals performed a visually guided foraging task in a 3D maze, navigating to reward locations using visual cues while we tracked body, head position, and gaze direction. One animal also performed a memory-guided alternation task navigating to remembered goal locations. Across 24 sessions, we detected 6,772 SWRs; notably 51.86% of events occurred within 5 seconds of the preceding SWR. The sharp wave component averaged 7.96 {+/-} 3.74 Hz in frequency and 143.87 {+/-} 71.87 ms in duration, while the ripple component averaged 163.7 {+/-} 13.47 Hz and 126.07 {+/-} 63.00 ms, respectively. Phase amplitude coupling (PAC) was present with ripple amplitude peaking at specific SW phases. Notably, 94.37% of SWRs occurred when animals were stationary with no significant body or head movement. SWR rates were significantly higher during the memory-guided task (mean: 0.09 {+/-} 0.08 events/s) compared to foraging (mean: 0.02 {+/-} 0.01 events/s). Our findings show that hippocampal SWRs in freely moving marmosets are coupled to pauses in locomotion and gaze exploration, indicating that active vision in primates drives hippocampus mediated memory encoding, consolidation, and recall during navigation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/662661v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1f505fborg.highwire.dtl.DTLVardef@15bcfe0org.highwire.dtl.DTLVardef@acaf1corg.highwire.dtl.DTLVardef@11c9008_HPS_FORMAT_FIGEXP M_FIG C_FIG

Synchronous neuronal ensembles play a pivotal role in the consolidation of long-term memory in the hippocampus. However, their organization during the acquisition of spatial memory remains less clear. In this study, we used neuronal population voltage imaging to investigate the synchronization patterns of CA1 pyramidal neuronal ensembles during the exploration of a new environment, a critical phase for spatial memory acquisition. We found synchronous ensembles comprising approximately 40% of CA1 pyramidal neurons, firing simultaneously in brief windows ([~]25ms) during immobility and locomotion in novel exploration. Notably, these synchronous ensembles were not associated with contralateral ripple oscillations but were instead phase-locked to theta waves recorded in the contralateral CA1 region. Moreover, the subthreshold membrane potentials of neurons exhibited coherent intracellular theta oscillations with a depolarizing peak at the moment of synchrony. Among newly formed place cells, pairs with more robust synchronization during locomotion displayed more distinct place-specific activities. These findings underscore the role of synchronous ensembles in coordinating place cells of different place fields.

Synaptic plasticity is triggered by different patterns of neuronal network activity. Network activity leads to an increase in ambient GABA concentration and tonic activation of GABAA receptors. How tonic GABAA conductance affects synaptic plasticity during temporal and rate-based coding is poorly understood. Here, we show that tonic GABAA conductance differently affects long-term potentiation (LTP) induced by different stimulation patterns. The LTP based on a temporal spike - EPSP order (spike-timing-dependent [st] LTP) was not affected by exogenous GABA application. Backpropagating action potential, which enables Ca2+ entry through N-methyl-D-aspartate receptors (NMDARs) during stLTP induction, was only slightly reduced by the tonic conductance. In contrast, GABA application impeded LTP dependent on spiking rate (theta-burst-induced [tb] LTP) by reducing the EPSP bust response and, hence, NMDAR-mediated Ca2+ entry during tbLTP induction. Our results may explain the changes in different forms of memory under physiological and pathological conditions that affect tonic GABAA conductance.

Spatial working memory (SWM) is a cognitive skill supporting survival-relevant behaviors, such as optimizing foraging behavior by remembering recent routes and visited sites. It is known that SWM decision-making in rodents requires the medial prefrontal cortex (mPFC) and dorsal hippocampus. The decision process in SWM tasks carries a specific electrophysiological signature of a brief, decision-related increase in neuronal communication in the form of an increase in the coherence of neuronal theta oscillations (4-12 Hz) between the mPFC and dorsal hippocampus, a finding we replicated here during spontaneous exploration of a plus maze in freely moving mice. We further evaluated SWM decision-related coherence changes within frequency bands above theta. Decision-related coherence increases occurred in seven frequency bands between 4 and 200 Hz and decision-outcome related differences in coherence modulation occurred within the beta and gamma frequency bands and in higher frequency oscillations up to 130 Hz. With recent evidence that Purkinje cells in the cerebellar lobulus simplex (LS) represent information about the phase and phase differences of gamma oscillations in the mPFC and dorsal hippocampus, we hypothesized that LS might be involved in the modulation of mPFC-hippocampal gamma coherence. We show that optical stimulation of LS significantly impairs SWM performance and decision-related mPFC-dCA1 coherence modulation, providing causal evidence for an involvement of cerebellar LS in SWM decision making at the behavioral and neuronal level. Our findings suggest that the cerebellum might contribute to SWM decision-making by optimizing the decision-related modulation of mPFC-dCA1 coherence.

Sharp-wave ripples (SWRs) are highly synchronous neuronal activity events. They have been predominantly observed in the hippocampus during offline states such as pause in exploration, slow-wave sleep and quiescent wakefulness. SWRs have been linked to memory consolidation, spatial navigation, and spatial decision-making. Recently, SWRs have been reported during visual search, a form of remote spatial exploration, in macaque hippocampus. However, the association between SWRs and multiple forms of awake conscious and goal-directed behavior is unknown. We report that ripple activity occurs in macaque visual areas V1 and V4 during focused spatial attention. The frequency of ripples is modulated by characteristics of the stimuli, by spatial attention directed toward a receptive field, and by the size of the attentional focus. Critically, the monkeys reaction times in detecting behaviorally relevant stimulus changes was affected on trials with SWRs. These results show that ripple activity is not limited to hippocampal activity during offline states, rather they occur in the neocortex during active attentive states and vigilance behaviors.

The hippocampus plays a crucial role in consolidating episodic memories from diverse experiences that encompass spatial, temporal, and novel information. This study analyzed the spike patterns of hippocampal place cells in the CA3 and CA1 areas of rats that sequentially foraged in five rooms, including familiar and novel rooms, followed by a rest period. Across multiple rooms, the generation of place fields by CA1 place cells was coordinated with other place cells. In the subsequent rest period, CA3 place cells that encoded novel environments exhibited stronger and more coordinated reactivation during sharp wave ripples (SWRs) than CA1 place cells. In contrast, CA1 place cells that encoded more recent environments exhibited stronger SWR-associated reactivation, independent of spikes of other cells, with weaker influences from novelty compared to CA3 place cells. These results suggest that post-experience SWR-associated reactivation of CA3 and CA1 neurons primarily processes novelty-related and temporal distance-related aspects of memory, respectively.

Training to improve working memory is associated with changes in prefrontal activation and confers lasting benefits, some of which generalize to untrained tasks, though the issue remains contentious and the neural substrate underlying such transfer are unknown. To assess how neural activity changes induced by training transfer across tasks, we recorded single units, multi-unit activity (MUA) and local field potentials (LFP) with chronic electrode arrays implanted in the prefrontal cortex of two monkeys, as they were trained to perform cognitive tasks. Mastering different tasks was associated with distinct changes in neural activity, which included redistribution of power across frequency bands in the LFP, recruitment of larger numbers of MUA sites, and increase or decrease of mean neural activity across single units. In every training phase, changes induced by the actively learned task transferred to an untrained control task, which remained the same across the training period. The results explicate the neural basis through which training can transfer across cognitive tasks.

Mental exploration enables flexible evaluation of potential future choices, guiding decision-making without requiring direct real-world iterations. Although the hippocampus is known to be active while imagining the future, the precise mechanisms that support mental exploration of future choices remain unclear. In the hippocampus, the theta rhythm (4-12 Hz) is prevalent during movement and supports memory coding during real-world exploration by organizing neuronal activity patterns into short virtual path segments (theta sequences) around the rats location. We observed these theta-related neural activity patterns during movement in a hippocampus-dependent working memory task and also, unexpectedly, theta oscillations and theta-related neural activity during immobility. Compared to standard theta sequences during movement, theta sequences during immobility differed in that they occurred at a shifted theta phase and preferentially represented remote locations, in particular the next choice in the working memory task. Coding for future locations was also observed during awake sharp wave ripple, but these short-lasting events occurred rarely and were biased toward frequently visited locations. Therefore, our findings suggest that recurring bouts of theta oscillations during immobility, which are also observed in primates and humans, support the cognitive demands of mental exploration in the hippocampal network and facilitate ongoing predictions of future choices.

Working memory (WM) is the brains ability to retain information that is not directly available from the sensory systems. WM retention is accompanied by sustained firing rate modulation and changes of the large-scale oscillatory profile. Among other changes, beta-band activity elevates in task-related regions, presumably stabilizing WM retention. Alpha-band activity, in turn, is stronger in task-irrelevant regions, serving to protect WM trace from distracting information. Although a large body of experimental evidence links neural oscillations to WM functions, theoretical understanding of their interrelations is still incomplete. In this study, we used a computational approach to explore a potential role of beta and alpha oscillations in control of WM stability. First, we examined a single bistable module that served as a discrete object representation and was resonant in the beta-band in the active state. We demonstrated that beta-band input produced differentially stronger excitatory effect on the module in the active state compared to the background state, while this difference decreased with the input frequency. We then considered a system of two competing modules, selective for a stimulus and for a distractor, respectively. We simulated a task, in which a stimulus was loaded into the first module, then an identical oscillatory input to both modules was turned on, after which a distractor was presented to the second module. We showed that beta-band input prevented loading of high-amplitude distractors and erasure of the stimulus from WM. On the contrary, alpha-band input promoted loading of low-amplitude distractors and the stimulus erasure. In summary, we demonstrated that stability of WM trace could be controlled by global oscillatory input in a frequency-dependent manner via controlling the level of competition between stimulus-encoding and distractor-encoding circuits. Such control is possible due to difference in the resonant and non-linear properties between the background and the active states.

Visual working memory (VWM) system serves as a cornerstone for high-level cognition. The state-based models of working memory delineated a hierarchy of functional states. Memory representations in the passive state are robustly maintained while the active representations were effectively processed at the same time. The memory representations are dynamically transferred between the two states according to task demands; however, it was still unclear how the state transformation process implemented to achieve a perfect storage-dissociation. To explore the property of transformation process, we adopted a sequential presentation paradigm where two memory arrays were presented sequentially; that effectively directs memory items for retention in the two distinct states. We modulated the temporal context concerned with the state transformation process, presentation time of the second array and retention interval between memory arrays. These results indicated that state transformation reflected a consolidation process of memory representations from the active into the passive state; this transformation process is subject to cognitive control. Moreover, we found that sufficient temporal context facilitated a smooth state transformation, thus minimizing the memory loss. These findings lead to a further understanding for the storage mechanism of working memory representations during the dynamic processing.

Synaptic plasticity is a fundamental mechanism of memory storage in the brain. Among the various rules governing changes in synaptic strength, Spike Timing-Dependent Plasticity (STDP) stands out for its strong physiological relevance in vivo. Ubiquitous across brain regions and neuronal types, STDP is a complex and multifactorial process influenced by factors such as neuromodulation, extracellular calcium levels, and activity patterns. However, one relatively understudied factor is the role of astrocytes, despite their well-established involvement in regulating synaptic transmission and neuronal excitability through gliotransmitter release. While some factors have garnered significant attention, others, like S100{beta}, have remained relatively underexplored despite their potential importance in regulating synaptic plasticity. S100{beta} is a calcium-binding protein, allowing it to influence extracellular Ca{superscript 2} concentration and potentially all Ca2+-dependent plasticity processes. Building on our previous research in the visual cortex, where we examined the regulation of neuronal excitability by S100{beta}, we chose to further investigate the role of astrocytes and S100{beta} in synaptic plasticity at layer 2/3-layer 5 synapses in the visual cortex. We demonstrated that S100{beta} is an important gliotransmitter to consider, capable of regulating long-term potentiation.

Recently, it was discovered that the static magnetic field of an MRI scanner not only causes horizontal vestibular nystagmus in healthy individuals but, in addition, leads to a horizontal bias of spatial orienting and exploration that closely resembles the one observed in stroke patients with spatial neglect (a disorder of spatial attention and exploration). The present study asked whether the behavioral effects of this magnetic vestibular stimulation (MVS) can be inverted and thus be used to reduce the pathological bias of stroke patients with spatial neglect. Indeed, when patients with left-sided spatial neglect entered the scanner with their feet first, i.e., with the magnetic field vector pointing from head to toes, MVS inside the scanner reduced the ipsilesionally biased distribution of overt attention and the corresponding neglect of the left parts of the search-space. Thus, an intervention as simple as lying in a 3T MRI scanner bears the potential to become an integral part of a future strategy for treating spatial neglect.