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The participation of the hippocampal formation in consolidation and reconsolidation of contextual fear memories has been widely recognized and known to be dependent on the activation of the cAMP response element (CRE) binding protein (CREB) pathway. Recent findings have challenged the prevailing view that over time contextual fear memories migrate to neocortical circuits and no longer require the hippocampus for retrieval of remote fearful memories. It has also recently been found that this brain structure is important for the maintenance and recall of remote fear memories associated with aversive events, a common trait in stress-related disorders such as generalized anxiety disorder (GAD), major depression, and post-traumatic stress disorder. In view of these findings, here we examined the putative role of CREB in the hippocampus of an animal model of GAD during the retrieval of remote contextual fear memories. Specifically, we evaluated CREB phosphorylation in the hippocampus of male Carioca High- and Low-conditioned Freezing rats (CHF and CLF, respectively) upon re-exposure of animals to contextual cues associated to footshocks weeks after fear conditioning. Age-matched male rats from a randomized crossbreeding population served as controls (CTL). Adrenal catecholamine levels were also measured as a biological marker of stress response. Seven weeks after contextual fear conditioning, half of the sample of CHF (n = 9), CLF (n = 10) and CTL (n = 10) rats were randomly assigned to return to the same context chamber where footshocks were previously administrated (Context condition), while the remaining animals were individually placed in standard housing cages (Control condition). Western blot results indicated that pCREB levels were significantly increased in the hippocampus of CHF rats for both Context and Control conditions when compared to the other experimental groups. CHF rats in the Context condition also exhibited significant more freezing than that observed for both CLF and CTL rats. Lastly, CHF animals in the Context condition displayed significantly higher adrenal catecholamine levels than those in the Control condition, whereas no differences in catecholamine levels were observed between Context and Control conditions for CLF and CTL rats. These findings are discussed from a perspective in which the hippocampus plays a role in the maintenance and recall of remote contextual fear memories via the CREB pathway. [ABSTRACT FROM AUTHOR]

Highlights • Medial prefrontal (mPFC) inactivation impairs both spatial and object memories. • Effects of dorsal hippocampal inactivation (DH) on memory depend on DREADD type. • Episodic memory consolidation requires concurrent activation of the DH and mPFC. Abstract The dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) are brain regions essential for processing and storing episodic memory. In rodents, the DH has a well-established role in supporting the consolidation of episodic-like memory in tasks such as object recognition and object placement. However, the role of the mPFC in the consolidation of episodic-like memory tasks remains controversial. Therefore, the present study examined involvement of the DH and mPFC, alone and in combination, in object and spatial recognition memory consolidation in ovariectomized female mice. To this end, we utilized two types of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH alone, the mPFC alone, or both brain regions concurrently immediately after object training to assess the role of each region in the consolidation of object recognition and spatial memories. Our results using single and multiplexed DREADDS suggest that excitatory activity in the DH and mPFC, alone or in combination, is required for the successful consolidation of object recognition and spatial memories. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate memory consolidation in female mice. [ABSTRACT FROM AUTHOR]

Single neuron activity in the corvid nidopallium caudolaterale (NCL), the supposed avian functional analog of the prefrontal cortex, represents associations of auditory with visual stimuli. This is of high adaptive value for songbirds that need to rely on audio-visual associations to communicate, find a mate or escape predators. However, it remains unclear whether NCL neurons can represent cross-modal associations in a modality invariant, abstract fashion. To dissociate between modality-dependent and modality-invariant NCL activity, we trained two crows to match auditory sample cues with visual test stimuli, and vice versa, across a temporal memory delay. During sample presentation, NCL activity selectively encoded associations in a modality invariant fashion. During the delay, we observed subject specific, population-level coding biases in NCL activity. Despite of these biases, task relevant information could be decoded equally well from either subject’s neuronal delay activity. Decoding success was facilitated by many mixed selectivity neurons, which mediated high dimensional representations of task variables on the NCL population level. These results parallel findings from the mammalian PFC, suggesting common mechanisms responsible for the adaptability of multimodal association areas across taxa. [ABSTRACT FROM AUTHOR]

Taste information is processed in different brain structures in the mammalian brain, including the gustatory cortex (GC), which resides within the insular cortex. N-methyl- d -aspartate receptor (NMDAR) activity in the GC is necessary for the acquisition of conditioned taste aversion (CTA) but not positive novel taste learning. Previous studies have shown that taste memory consolidation requires intact protein synthesis in the GC. In addition, the direct involvement of translation initiation and elongation factors was documented in the GC during taste learning. However, protein expression is defined by protein synthesis, degradation, and localization. Protein degradation is critical for the consolidation and reconsolidation of other forms of learning, such as fear learning and addiction behavior, but its role in cortical-dependent learning is not clear. Here, we show for the first time that proteasome activity is specifically increased in the GC 4 h following experiencing of a novel taste. This increase in proteasome activity was abolished by local administration to the GC of the NMDA antagonist, APV, as well as a CaMKII inhibitor, at the time of acquisition. In addition, local application of lactacystin, a proteasome inhibitor, resulted in impaired CTA, but not novel taste learning. These results suggest that NMDAR-dependent proteasome activity in the GC participates in the association process between novel taste experience and negative visceral sensation. [ABSTRACT FROM AUTHOR]

We examined the performance of healthy young ( n = 57) and older adults ( n = 43) genotyped as apolipoprotein E-ε4 (APOE-ε4) carriers or APOE-ε4 non-carriers on a delayed match-to-sample task involving varying degrees of spatial interference hypothesized to assess spatial pattern separation. Older adult ε4 carriers were further divided into “impaired” and “unimpaired” groups based on their performance on a standardized test of verbal memory. We found that performance on the spatial pattern separation test increased as a function of decreased spatial interference across all groups. The older ε4 carriers in the impaired group performed significantly worse ( p < .05) than unimpaired ε4 carriers, ε4 non-carriers, and young adults. The data suggest that spatial pattern separation may be less efficient in a subset of healthy older adults with subtle memory decline who are carriers of the ε4 allele. However, pattern separation performance may be comparable to that of young adults in a subset of older adult ε4 carriers and more broadly among non-carriers. Our findings offer additional evidence that pattern separation may vary in older adults, and they provide novel insight into pattern separation efficiency in ε4-positive older adults. [ABSTRACT FROM AUTHOR]

Pattern separation (PS) has been defined as a process of reducing overlap between similar input patterns to minimize interference amongst stored representations. The present article describes this putative PS process from the “representational–hierarchical” perspective (R–H), which uses a hierarchical continuum instead of a cognitive modular processing framework to describe the organization of the ventral visual perirhinal–hippocampal processing stream. Instead of trying to map psychological constructs onto anatomical modules in the brain, the R-H model suggests that the function of brain regions depends upon what representations they contain. We begin by discussing a main principle of the R–H framework, the resolution of “ambiguity” of lower level representations via the formation of unique conjunctive representations in higher level areas, and how this process is remarkably similar to definitions of PS. Work from several species and experimental approaches suggest that this principle of resolution of ambiguity via conjunctive representations has considerable explanatory power, leads to wide possibilities for experimentation, and also supports some perhaps surprising conclusions. [ABSTRACT FROM AUTHOR]

Memories for context become less specific with time resulting in animals generalizing fear from training contexts to novel contexts. Though much attention has been given to the neural structures that underlie the long-term consolidation of a context fear memory, very little is known about the mechanisms responsible for the increase in fear generalization that occurs as the memory ages. Here, we examine the neural pattern of activation underlying the expression of a generalized context fear memory in male C57BL/6J mice. Animals were context fear conditioned and tested for fear in either the training context or a novel context at recent and remote time points. Animals were sacrificed and fluorescent in situ hybridization was performed to assay neural activation. Our results demonstrate activity of the prelimbic, infralimbic, and anterior cingulate (ACC) cortices as well as the ventral hippocampus (vHPC) underlie expression of a generalized fear memory. To verify the involvement of the ACC and vHPC in the expression of a generalized fear memory, animals were context fear conditioned and infused with 4% lidocaine into the ACC, dHPC, or vHPC prior to retrieval to temporarily inactivate these structures. The results demonstrate that activity of the ACC and vHPC is required for the expression of a generalized fear memory, as inactivation of these regions returned the memory to a contextually precise form. Current theories of time-dependent generalization of contextual memories do not predict involvement of the vHPC. Our data suggest a novel role of this region in generalized memory, which should be incorporated into current theories of time-dependent memory generalization. We also show that the dorsal hippocampus plays a prolonged role in contextually precise memories. Our findings suggest a possible interaction between the ACC and vHPC controls the expression of fear generalization. [ABSTRACT FROM AUTHOR]

In healthy young subjects, the brain derived neurotropic factor ( BDNF ) val 66 met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF -genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val 66 met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results. [ABSTRACT FROM AUTHOR]

Variance in spatial abilities are thought to be determined by in utero levels of testosterone and oestrogen, measurable in adults by the length ratio of the 2nd and 4th digit (2D:4D). We confirmed the relationship between 2D:4D and spatial performance using rats in two different tasks (paired-associate task and watermaze) and replicated this in humans. We further clarified anatomical and functional brain correlates of the association between 2D:4D and spatial performance in humans. [ABSTRACT FROM AUTHOR]

Experience-dependent formation of synaptic input clusters can occur in juvenile brains. Whether this also occurs in adults is largely unknown. We previously reconstructed the normal and learned circuits of prism-adapted barn owls and found that changes in clustering of axo-dendritic contacts (putative synapses) predicted functional circuit strength. Here we asked whether comparable changes occurred in normal and prism-removed adults. Across all anatomical zones, no systematic differences in the primary metrics for within-branch or between-branch clustering were observed: 95–99% of contacts resided within clusters (<10–20 μm from nearest neighbor) regardless of circuit strength. Bouton volumes, a proxy measure of synaptic strength, were on average larger in the functionally strong zones, indicating that changes in synaptic efficacy contributed to the differences in circuit strength. Bootstrap analysis showed that the distribution of inter-contact distances strongly deviated from random not in the functionally strong zones but in those that had been strong during the sensitive period (60–250 d), indicating that clusters formed early in life were preserved regardless of current value. While cluster formation in juveniles appeared to require the production of new synapses, cluster formation in adults did not. In total, these results support a model in which high cluster dynamics in juveniles sculpt a potential connectivity map that is refined in adulthood. We propose that preservation of clusters in functionally weak adult circuits provides a storage mechanism for disused but potentially useful pathways. [ABSTRACT FROM AUTHOR]

Highlights: [•] We test how the neural circuit for trace fear extinction differs from that of delay. [•] Glutamate receptor blockade in the amygdala impairs delay but not trace extinction [•] pERK is increased in the RSC and not the amygdala for trace extinction. [•] Intra-RSC blockade of NMDA receptors impairs trace but not delay extinction. [•] The RSC, instead of the amygdala, is required for complex trace fear extinction. [Copyright &y& Elsevier]

Highlights: [•] Stress fosters amygdala–hippocampus connectivity in B6 mice. [•] Stress fosters amygdala-dorsolateral striatum connectivity in D2 mice. [•] Hippocampus mediates consolidation of stress memory in B6 but not in D2 mice. [•] Dorsolateral striatum mediates consolidation of stress memory only in D2 mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] Converging evidence points to essential roles of the cingulate and entorhinal cortices in consolidated memory. [•] Anatomical connectivity patterns between cingulate and entorhinal cortices are consistent with a role in long-term memory. [•] Observations related to neural coding and plasticity suggest that plastic changes in these areas are memory-specific. [•] We offer several experimental predictions consistent with the hypothesis that connections between cingulate and entorhinal cortex hold initially hippocampal-dependent memories in the long-term. [Copyright &y& Elsevier]

Abstract: While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training–testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time. [Copyright &y& Elsevier]

Abstract: Adult neurogenesis occurs in two discrete regions of the adult mammalian brain, the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) along the lateral ventricles. Signaling mechanisms regulating adult neurogenesis in the SGZ are currently an active area of investigation. Adult-born neurons in the DG functionally integrate into the hippocampal circuitry and form functional synapses, suggesting a role for these neurons in hippocampus-dependent memory formation. Although results from earlier behavioral studies addressing this issue were inconsistent, recent advances in conditional gene targeting technology, viral injection and optogenetic approaches have provided convincing evidence supporting a role for adult-born neurons in the more challenging forms of hippocampus-dependent learning and memory. Here, we briefly summarize these recent studies with a focus on extra signal-regulated kinase (ERK) 5, a MAP kinase whose expression in the adult brain is restricted to the neurogenic regions including the SGZ and SVZ. We review evidence identifying ERK5 as a novel endogenous signaling pathway that regulates the pro-neural transcription factor Neurogenin 2, is activated by neurotrophins and is critical for adult neurogenesis. We discuss studies demonstrating that specific deletion of ERK5 in the adult neurogenic regions impairs several forms of hippocampus-dependent memory formation in mice. These include contextual fear memory extinction, the establishment and maintenance of remote contextual fear memory, and several other challenging forms of hippocampus-dependent memory formation including 48h memory for novel object recognition, contextual fear memory established by a weak foot shock, pattern separation, and reversal of spatial learning and memory. We also briefly discuss current evidence that increasing adult neurogenesis, by small molecules or genetic manipulation, improves memory formation and long-term memory. [Copyright &y& Elsevier]

• Ipsi or contralateral inactivations of the retrosplenial cortex and target brain regions. • Many cortical-thalamic paths seem to be important for object memory consolidation. • Medial entorhinal cortex is required for object recognition memory consolidation. • Anterior thalamic nuclei is involved in object recognition memory consolidation. Recognition memory can rely on three components: "what", "where" and "when". Recently we demonstrated that the anterior retrosplenial cortex (aRSC), like the perirhinal cortex (PRH) and unlike the hippocampus (HP), is required for consolidation of the "what" component. Here, we aimed at studying which brain structures interact with the aRSC to process object recognition (OR) memory in rats. We studied the interaction of six brain structures that are connected to the aRSC during OR memory processing: PRH, medial prefrontal cortex (mPFC), anteromedial thalamic nuclei (AM), medial entorhinal cortex (MEC), anterior cingulate cortex (ACC) and the dorsal HP (dHP). We previously described the role of the PRH and dHP, so we first studied the participation of the mPFC, AM, MEC and ACC in OR memory consolidation by bilateral microinfusions of the GABA A receptor agonist muscimol. We observed an impairment in OR long-term memory (LTM) when inactivating the mPFC, the AM and the MEC, but not the ACC. Then, we studied the functional connections by unilateral inactivation of the aRSC and each one of the six structures in the same (ipsilateral) or the opposite (contralateral) hemisphere. Our results showed an amnesic LTM effect in rats with ipsilateral inactivations of aRSC-PRH, aRSC-mPFC, aRSC-AM, or aRSC-MEC. On the other hand, we observed memory impairment when aRSC-ACC were inactivated in opposite hemispheres, and no effect when the aRSC-dHP connection was inactivated. Thus, our ipsilateral inactivation findings reveal that the aRSC and, at least one brain region required in OR LTM processing are essential to consolidate OR memory. In conclusion, our results show that several cortico-cortical and cortico-thalamic pathways are important for OR memory consolidation. [ABSTRACT FROM AUTHOR]

• Probabilistic learning and episodic memory tasks were examined in dyslexia. • Immediate feedback on choices harmed learning in the dyslexia group. • A temporal gap between choices and feedback enabled intact learning in dyslexia. • Episodic knowledge of feedback events was preserved in the dyslexia group. • Shifting the load from procedural to declarative memory can improve learning in dyslexia. A theoretical framework suggests that developmental dyslexia is characterized by abnormalities in brain structures underlying the procedural learning and memory systems while the declarative learning and memory systems are presumed to remain intact or even enhanced (Procedural Deficit Hypothesis). This notion has been supported by a substantial body of research, which focused on each system independently. However, less attention has been paid to interactions between these memory systems which may provide insights as to learning situations and conditions in which learning in dyslexia can be improved. The current study was undertaken to examine these important but unresolved issues. To this end, probabilistic reinforcement learning and episodic memory tasks were examined in participants with dyslexia and neurotypicals simultaneously within a single task. Feedback timing presentation was manipulated, building on prior research indicating that delaying feedback timing shifts striatal-based probabilistic learning, to become more hippocampal-dependent. It was hypothesized that if the procedural learning and memory systems are impaired in dyslexia, performance will be impaired under conditions that encourage procedural memory engagement (immediate feedback trials) but not under conditions that promote declarative memory processing (long delayed feedback trials). It was also predicted that the ability to incidentally acquire episodic information would be preserved in dyslexia. The results supported these predictions. Participants with dyslexia were impaired in probabilistic learning of cue-outcome associations compared to neurotypicals in an immediate feedback condition, but not when feedback on choices was presented after a long delay. Furthermore, participants with dyslexia demonstrated similar performance to neurotypicals in a task requiring incidental episodic memory formation. These findings attest to a dissociation between procedural-based and declarative-based learning in developmental dyslexia within a single task, a finding that adds discriminative validity to the Procedural Deficit Hypothesis. Just as important, the present findings suggest that training conditions designed to shift the load from midbrain/striatal systems to declarative memory mechanisms have the potential to compensate for impaired learning in developmental dyslexia. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we used a model of individual differences in fear responses in rats selected according to their low and high freezing response in the contextual fear test and termed these animals “low- and high anxiety” rats, respectively. We studied differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in the brain structures of low (LR) and high (HR) anxiety rats subjected to extinction trials and re-learning of a conditioned fear response. We found different patterns of spontaneous (western blotting) and fear-stimulated expression of alpha-2 subunits and gephyrin (western blotting and immunocytochemistry) in brain structures of HR and LR animals. Increased basal concentrations of alpha-2 subunits in the amygdala were observed in HR rats (compared to unconditioned control group). The density of alpha-2 subunits in the amygdala negatively correlated with freezing response duration in the aversive context on re-learning in the same group of animals. This finding supports data on the role of GABA-A receptor alpha-2 subunits in the amygdala in modulation of anxiety-like behaviour. Western blotting revealed that exposure of HR animals to fear-conditioned context upon re-test of the conditioned fear test elevated the concentration of alpha-2 subunits in the amygdala and prefrontal cortex. In addition, immunocytochemistry showed that conditioned fear increased the number of cells co-expressing alpha-2 subunits and gephyrin in the basolateral amygdala and dentate gyrus of the hippocampus in the HR group. Together, these findings suggest that animals that are more vulnerable to stress differ in the intracellular mechanisms that control GABA-A receptor trafficking in limbic structures (hippocampus and amygdala), which are involved in the control of emotional behaviour. These data indicate a possible mechanism for the variable effects of benzodiazepines among patients with anxiety disorders. The obtained data may also help to better explain the neurobiological mechanisms that operate in clinical situations where anxious patients subjected to exposure therapy are exposed to an aversive, contextual and conditioning stimulus. [Copyright &y& Elsevier]