Hippocampal-Medial Prefrontal Event Segmentation and Integration Contribute to Episodic Memory Formation.

How do we encode our continuous life experiences for later retrieval? Theories of event segmentation and integration suggest that the hippocampus binds separately represented events into an ordered narrative. Using a functional Magnetic Resonance Imaging (fMRI) movie watching-recall dataset, we quantified two types of neural similarities (i.e., "activation pattern" similarity and within-region voxel-based "connectivity pattern" similarity) between separate events during movie watching and related them to subsequent retrieval of events as well as retrieval of sequential order. We demonstrated that compared with forgotten events, successfully remembered events were associated with distinct "activation patterns" in the hippocampus and medial prefrontal cortex. In contrast, similar "connectivity pattern" between events were associated with memory formation and were also relevant for retaining events in the correct order. We applied the same approaches to an independent movie watching fMRI dataset as validation and highlighted again the role of hippocampal activation pattern and connectivity pattern in memory formation. We propose that distinct activation patterns represent neural segmentation of events, while similar connectivity patterns encode context information and, therefore, integrate events into a narrative. Our results provide novel evidence for the role of hippocampal-medial prefrontal event segmentation and integration in episodic memory formation of real-life experience.

Learning and Representation of Hierarchical Concepts in Hippocampus and Prefrontal Cortex.

A key aspect of conceptual knowledge is that it can be flexibly applied at different levels of abstraction, implying a hierarchical organization. It is yet unclear how this hierarchical structure is acquired and represented in the brain. Here we investigate the computations underlying the acquisition and representation of the hierarchical structure of conceptual knowledge in the hippocampal-prefrontal system of 32 human participants (22 females). We assessed the hierarchical nature of learning during a novel tree-like categorization task via computational model comparisons. The winning model allowed to extract and quantify estimates for accumulation and updating of hierarchical compared with single-feature-based concepts from behavior. We find that mPFC tracks accumulation of hierarchical conceptual knowledge over time, and mPFC and hippocampus both support trial-to-trial updating. As a function of those learning parameters, mPFC and hippocampus further show connectivity changes to rostro-lateral PFC, which ultimately represented the hierarchical structure of the concept in the final stages of learning. Our results suggest that mPFC and hippocampus support the integration of accumulated evidence and instantaneous updates into hierarchical concept representations in rostro-lateral PFC.SIGNIFICANCE STATEMENT A hallmark of human cognition is the flexible use of conceptual knowledge at different levels of abstraction, ranging from a coarse category level to a fine-grained subcategory level. While previous work probed the representational geometry of long-term category knowledge, it is unclear how this hierarchical structure inherent to conceptual knowledge is acquired and represented. By combining a novel hierarchical concept learning task with computational modeling of categorization behavior and concurrent fMRI, we differentiate the roles of key concept learning regions in hippocampus and PFC in learning computations and the representation of a hierarchical category structure.

Reassigning the Pressure-Induced Phase Transitions of Methylammonium Lead Bromide Perovskite.

The high-pressure crystal structure evolution of CH3NH3PbBr3 (MAPbBr3) perovskite has been investigated by single-crystal X-ray diffraction and synchrotron-based powder X-ray diffraction. Single-crystal X-ray diffraction reveals that the crystal structure of MAPbBr3 undergoes two phase transitions following the space-group sequence: Pm3̅m → Im3̅ → Pmn21, unveiling the occurrence of a nonpolar/polar transition (Im3̅ → Pmn21). The transitions take place at around 0.8 and 1.8 GPa, respectively. This result contradicts the previously reported phase transition sequence: Pm3̅m → Im3̅ →Pnma. In this work, the crystal structures of each of the three phases are determined from single-crystal X-ray diffraction analysis, which is later supported by Rietveld refinement of powder X-ray diffraction patterns. The pressure dependence of the crystal lattice parameters and unit-cell volumes are determined from the two aforementioned techniques, as well as the bulk moduli for each phase. The bandgap behavior of MAPbBr3 has been studied up to around 4 GPa, by means of single-crystal optical absorption experiments. The evolution of the bandgap has been well explained using the pressure dependence of the Pb-Br bond distance and Pb-Br-Pb angles as determined from single-crystal X-ray diffraction experiments.

Mild early-life stress exaggerates the impact of acute stress on corticolimbic resting-state functional connectivity.

Abundant evidence shows that early-life stress (ELS) predisposes for the development of stress-related psychopathology when exposed to stressors later in life, but the underlying mechanisms remain unclear. To study predisposing effects of mild ELS on stress sensitivity, we examined in a healthy human population the impact of a history of ELS on acute stress-related changes in corticolimbic circuits involved in emotional processing (i.e., amygdala, hippocampus and ventromedial prefrontal cortex [vmPFC]). Healthy young male participants (n = 120) underwent resting-state functional magnetic resonance imaging (fMRI) in two separate sessions (stress induction vs. control). The Childhood Trauma Questionnaire (CTQ) was administered to index self-reported ELS, and stress induction was verified using salivary cortisol, blood pressure, heart rate and subjective affect. Our findings show that self-reported ELS was negatively associated with baseline cortisol, but not with the acute stress-induced cortisol response. Critically, individuals with more self-reported ELS exhibited an exaggerated reduction of functional connectivity in corticolimbic circuits under acute stress. A mediation analysis showed that the association between ELS and stress-induced changes in amygdala-hippocampal connectivity became stronger when controlling for basal cortisol. Our findings show, in a healthy sample, that the effects of mild ELS on functioning of corticolimbic circuits only become apparent when exposed to an acute stressor and may be buffered by adaptations in hypothalamic-pituitary-adrenal axis function. Overall, our findings might reveal a potential mechanism whereby even mild ELS might confer vulnerability to exposure to stressors later in adulthood.

Locus coeruleus and dopaminergic consolidation of everyday memory.

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH+) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH+ neurons project more profusely than ventral tegmental area TH+ neurons to the hippocampus, optogenetic activation of locus coeruleus TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.

The association between serotonin transporter availability and the neural correlates of fear bradycardia.

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which-similarly to the human population-mediated the 5-HTT genotype's effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.

The Hippocampus Maps Concept Space, Not Feature Space.

The hippocampal formation encodes maps of space and a key question in neuroscience is whether its spatial coding principles also provide a universal metric for the organization of nonspatial, conceptual information. Previous work demonstrated directional coding during navigation through a continuous stimulus feature space as well as mapping of distances in a feature space that was relevant for concept learning. Here we provide the first unambiguous evidence for a hippocampal representation of the actual concept space, by showing that the hippocampal distance signal selectively reflects the mapping of specifically conceptually relevant rather than of all feature dimensions. During fMRI scanning of 32 human participants (21 females), we presented everyday objects, which had beforehand been associated with specific values on three continuous feature dimensions. Crucially, only two dimensions were relevant to prior concept learning. We find that hippocampal responses to the objects reflect their relative distances in a space defined along conceptually relevant dimensions compared with distances in a space defined along all feature dimensions. These findings suggest that the hippocampus supports knowledge acquisition by dynamically encoding information in a space spanned along dimensions that are relevant in relation to define concepts.SIGNIFICANCE STATEMENT How are neural representations of conceptual knowledge organized, such that humans are able to infer never experienced relations or categorize new exemplars? Map-like representations as supported by the hippocampal formation to encode physical space during navigation have been suggested as a suitable format. Here we provide the first evidence for a hippocampal representation of a conceptual space compared with a general feature-based space.

Dynamic Transitions between Neural States Are Associated with Flexible Task Switching during a Memory Task.

Flexible behavior requires switching between different task conditions. It is known that such task switching is associated with costs in terms of slowed RT, reduced accuracy, or both. The neural correlates of task switching have usually been studied by requiring participants to switch between distinct task conditions that recruit different brain networks. Here, we investigated the transition of neural states underlying switching between two opposite memory-related processes (i.e., memory retrieval and memory suppression) in a memory task. We investigated 26 healthy participants who performed a think/no-think task while being in the fMRI scanner. Behaviorally, we show that it was more difficult for participants to suppress unwanted memories when a no-think was preceded by a think trial instead of another no-think trial. Neurally, we demonstrate that think-no-think switches were associated with an increase in control-related and a decrease in memory-related brain activity. Neural representations of task condition, assessed by decoding accuracy, were lower immediately after task switching compared with the nonswitch transitions, suggesting a switch-induced delay in the neural transition toward the required task condition. This suggestion is corroborated by an association between condition-specific representational strength and condition-specific performance in switch trials. Taken together, we provided neural evidence from the time-resolved decoding approach to support the notion that carryover of the previous task set activation is associated with the switching cost, leading to less successful memory suppression.

Differences in executive abilities rather than associative processes contribute to memory development.

Children's learning capabilities change while growing up. One framework that describes the cognitive and neural development of children's growing learning abilities is the two-component model. It distinguishes processes that integrate separate features into a coherent memory representation (associative component) and executive abilities, such as elaboration, evaluation, and monitoring, that support memory processing (strategic component). In an fMRI study using an object-location association paradigm, we investigated how the two components influence memory performance across development. We tested children (10-12 years, n = 31), late adolescents (18 years, n = 29), and adults (25+ years, n = 30). For studying the associative component, we also probed how the utilisation of prior knowledge (schemas) facilitates memory across age groups. Children had overall lower retrieval performance, while adolescents and adults did not differ from each other. All groups benefitted from schemas, but this effect did not differ between groups. Performance differences between groups were associated with deactivation of the dorsal medial prefrontal cortex (dmPFC), which in turn was linked to executive functioning. These patterns were stronger in adolescents and adults and seemed absent in children. Thus, the children's executive system, the strategic component, is not as mature and thus cannot facilitate memory performance in the same way as in adolescents/adults. In contrast, we did not find age-related differences in the associative component; with activity in the angular gyrus predicting memory performance systematically across groups. Overall, our results suggest that differences of executive rather than associative abilities explain memory differences between children, adolescents, and adults.

Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes.

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

Transcranial Magnetic Stimulation of the Medial Prefrontal Cortex Decreases Emotional Memory Schemas.

Mood-congruent memory bias is a critical characteristic of depression, but the underlying neural mechanism is largely unknown. Negative memory schemas might enhance encoding and consolidation of negative experiences, thereby contributing to the genesis and perpetuation of depressive pathology. To investigate this relationship, we aimed to perturb medial prefrontal cortex (mPFC) processing, using neuronavigated transcranial magnetic stimulation (TMS) targeting the mPFC. Forty healthy volunteers first underwent a negative mood induction to activate negative schema processing after which they received either active inhibitory (N = 20) or control (N = 20) stimulation to the mPFC. Then, all participants performed the encoding of an emotional false memory task. Recall and recognition performance was tested the following morning. Polysomnographic data were recorded continuously during the night before and after encoding. We observed a significantly lower false recognition of negative critical lures following mPFC inhibition, but no differences in veridical memory. These findings were supported by reaction time data, showing a relative slower response to negative compared with positive critical lures. The current findings support previous causal evidence for a role of the mPFC in schema memory processing and further suggest a role of the mPFC in memory bias.

Probing the neural dynamics of mnemonic representations after the initial consolidation.

Memories are not stored as static engrams, but as dynamic representations affected by processes occurring after initial encoding. Previous studies revealed changes in activity and mnemonic representations in visual processing areas, parietal lobe, and hippocampus underlying repeated retrieval and suppression. However, these neural changes are usually induced by memory modulation immediately after memory formation. Here, we investigated 27 healthy participants with a two-day functional Magnetic Resonance Imaging study design to probe how established memories are dynamically modulated by retrieval and suppression 24 h after learning. Behaviorally, we demonstrated that established memories can still be strengthened by repeated retrieval. By contrast, repeated suppression had a modest negative effect, and suppression-induced forgetting was associated with individual suppression efficacy. Neurally, we demonstrated item-specific pattern reinstatements in visual processing areas, parietal lobe, and hippocampus. Then, we showed that repeated retrieval reduced activity amplitude in the ventral visual cortex and hippocampus, but enhanced the distinctiveness of activity patterns in the ventral visual cortex and parietal lobe. Critically, reduced activity was associated with enhanced representation of idiosyncratic memory traces in the ventral visual cortex and precuneus. In contrast, repeated memory suppression was associated with reduced lateral prefrontal activity, but relative intact mnemonic representations. Our results replicated most of the neural changes induced by memory retrieval and suppression immediately after learning and extended those findings to established memories after initial consolidation. Active retrieval seems to promote episode-unique mnemonic representations in the neocortex after initial encoding but also consolidation.

The role of hippocampal spatial representations in contextualization and generalization of fear.

Using contextual information to predict aversive events is a critical ability that protects from generalizing fear responses to safe contexts. Animal models have demonstrated the importance of spatial context representations within the hippocampal formation in contextualization of fear learning. The ventromedial prefrontal cortex (vmPFC) is known to play an important role in safety learning, possibly also through the incorporation of context information. However, if contextual representations are related to context-dependent expression of fear memory in humans remains unclear. Twenty-one healthy participants underwent functional MRI combined with a cue-context conditioning paradigm within a self-navigated virtual reality environment. The environment included two buildings (Threat and Safe context), which had distinct features outside but were identical inside. Within each context, participants saw two cues (CS+, CS-). The CS+ was consistently (100% reinforcement rate) paired with an electric shock in the Threat context, but never in the Safe context. The CS- was never paired with a shock. We found robust differential skin conductance responses (SCRs; CS+ â€‹> â€‹CS-) in the Threat context, but also within the Safe context, indicating fear generalization. Within the Safe context, vmPFC responses to the CS+ were larger than those in the Threat context. We furthermore found environment-specific representations for the two contexts in the training paradigm (i.e., before conditioning took place) in the hippocampus to be related to fear expression and generalization. Namely, participants with a weak context representation (z-score < 1.65) showed stronger fear generalization compared to participants with a strong context representation (z-score > 1.65). Thus, a weak neural representation strength of spatial context may explain overgeneralization of memory to safe contexts. In addition, our findings demonstrate that context-dependent regulation of fear expression engages ventromedial prefrontal pathways suggesting this involves a similar mechanism that is known to be involved in retrieval of extinction memory.

A mechanistic model for individualised treatment of anxiety disorders based on predictive neural biomarkers.

Increased amygdala responsiveness is the hallmark of fear and a characteristic across patients with anxiety disorders. The amygdala is embedded in a complex regulatory circuit. Multiple different mechanisms may elevate amygdala responsiveness and lead to the occurrence of an anxiety disorder. While top-down control by the prefrontal cortex (PFC) downregulates amygdala responses, the locus coeruleus (LC) drives up amygdala activation via noradrenergic projections. This indicates that the same fearful phenotype may result from different neural mechanisms. We propose a mechanistic model that defines three different neural biomarkers causing amygdala hyper-responsiveness in patients with anxiety disorders: (a) inherent amygdala hypersensitivity, (b) low prefrontal control and (c) high LC drive. First-line treatment for anxiety disorders is exposure-based cognitive behavioural therapy, which strengthens PFC recruitment during emotion regulation and thus targets low-prefrontal control. A treatment response rate around 50% (Loerinc et al., 2015, Clinical Psychological Reviews, 42, 72-82) might indicate heterogeneity of underlying neurobiological mechanisms among patients, presumably leading to high variation in treatment benefit. Transforming insights from cognitive neuroscience into applicable clinical heuristics to categorise patients based on their underlying biomarker may support individualised treatment selection in psychiatry. We review literature on the three anxiety-related mechanisms and present a mechanistic model that may serve as a rational for pathology-based diagnostic and biomarker-guided treatment selection in psychiatry.

The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical.

While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations-context preexposure or interference during memory retrieval-differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure.

Functional network interactions at rest underlie individual differences in memory ability.

Intrinsic network interactions may underlie individual differences in the ability to remember. The default mode network (DMN) comprises subnetworks implicated in memory, and interactions between the DMN and frontoparietal network (FPN) were shown to support mnemonic processing. However, it is unclear if such interactions during resting-state predict episodic memory ability. We investigated whether intrinsic network interactions within and between the DMN and FPN are related to individual differences in memory performance. Resting-state activity was measured using functional MRI in healthy young adults followed by a memory test for object-location associations that were studied 3 d earlier. We identified two subnetworks within the DMN, the main-DMN and the medial temporal lobe, retrosplenial cortex (MTL_RSC)-DMN. Further, we found regions forming the FPN. Memory performance was associated with lower connectivity within the MTL_RSC-DMN, and stronger connectivity between the main-DMN and FPN. Exploratory whole-brain analysis revealed stronger MTL connectivity with the left posterior parietal cortex that was related to better memory performance. Furthermore, we found increased task-evoked activation during successful retrieval within the main-DMN and FPN, but not within the MTL_RSC-DMN. In sum, lower intrinsic connectivity within the MTL_RSC-DMN, combined with stronger connectivity between the main-DMN and FPN, explain individual differences in memory ability.

Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation.

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (η p2 = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (η p2 = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

Intersubject similarity of personality is associated with intersubject similarity of brain connectivity patterns.

Personality is a central high-level psychological concept that defines individual human beings and has been associated with a variety of real-world outcomes (e.g., mental health and academic performance). Using 2 h, high resolution, functional magnetic resonance imaging (fMRI) resting state data of 984 (primary dataset N = 801, hold-out dataset N = 183) participants from the Human Connectome Project (HCP), we investigated the relationship between personality (five-factor model, FFM) and intrinsic whole-brain functional connectome. We found a pattern of functional brain connectivity ("global personality network") related to personality traits. Consistent with the heritability of personality traits, the connectivity strength of this global personality network is also heritable (more similar between monozygotic twin pairs compared to the dizygotic twin pairs). Validated by both the repeated family-based 10-fold cross-validation and hold-out dataset, our intersubject network similarity analysis allowed us to identify participants' pairs with similar personality profiles. Across all the identified pairs of participants, we found a positive correlation between the network similarity and personality similarity, supporting our "similar brain, similar personality" hypothesis. Furthermore, the global personality network can be used to predict the individual subject's responses in the personality questionnaire on an item level. In sum, based on individual brain connectivity pattern, we could predict different facets of personality, and this prediction is not based on localized regions, but rather relies on the individual connectivity pattern in large-scale brain networks.

Thalamo-cortical coupling during encoding and consolidation is linked to durable memory formation.

Memory formation transforms experiences into durable engrams. The stabilization critically depends on processes during and after learning, and involves hippocampal-medial prefrontal interactions that appear to be mediated by the nucleus reuniens of the thalamus in rodents, which corresponds to the human medioventral thalamus. How this region contributes to durable memory formation in humans is, however, unclear. Furthermore, the anterior-, lateral dorsal-, and mediodorsal nuclei appear to promote mnemonic function as well. We hypothesized that durable memory formation is associated with increases in thalamo-cortical interactions during encoding and consolidation. Thirty-three human subjects underwent fMRI while studying picture-location associations. To assess consolidation, resting-state brain activity was measured after study and was compared to a pre-study baseline. Memory was tested on the same day and 48 h later. While "weak" memories could only be remembered at the immediate test, "durable" memories persisted also after the delay. We found increased coupling of the medioventral-, adjacent anterior-, lateral dorsal-, and mediodorsal thalamus with the hippocampus and surrounding medial temporal lobe, as well as with anterior and posterior midline regions related to durable memory encoding. The medioventral and lateral dorsal thalamus showed increased connectivity with posterior medial and parietal cortex from baseline to post-encoding rest, positively scaling with the proportion of durable memories formed across subjects. Additionally, the lateral dorsal thalamus revealed consolidation-related coupling with the inferior temporal, retrosplenial, and medial prefrontal cortex. We suggest that thalamo-cortical cross-talk strengthens mnemonic representations at initial encoding, and that cortical coupling of specific thalamic subregions supports consolidation thereafter.

Stress leads to aberrant hippocampal involvement when processing schema-related information.

Prior knowledge, represented as a mental schema, has critical impact on how we organize, interpret, and process incoming information. Recent findings indicate that the use of an existing schema is coordinated by the medial prefrontal cortex (mPFC), communicating with parietal areas. The hippocampus, however, is crucial for encoding schema-unrelated information but not for schema-related information. A recent study indicated that stress mediators may affect schema-related memory, but the underlying neural mechanisms are currently unknown. Here, we thus tested the impact of acute stress on neural processing of schema-related information. We exposed healthy participants to a stress or control manipulation before they processed, in the MRI scanner, words related or unrelated to a preexisting schema activated by a specific cue. Participants' memory for the presented material was tested 3-5 d after encoding. Overall, the processing of schema-related information activated the mPFC, the precuneus, and the angular gyrus. Stress resulted in aberrant hippocampal activity and connectivity while participants processed schema-related information. This aberrant engagement of the hippocampus was linked to altered subsequent memory. These findings suggest that stress may interfere with the efficient use of prior knowledge during encoding and may have important practical implications, in particular for educational settings.