Not all declarative memories are created equal: Fast Mapping as a direct route to cortical declarative representations.

Memory formation for newly acquired associations typically depends on hippocampal-neocortical interactions. Through the process of system-consolidation, the mnemonic binding role of the hippocampus is subsequently replaced by cortical hubs, such as the ventromedial prefrontal cortex (vmPFC) or the anterior temporal lobe (ATL). Here, using BOLD-fMRI, we compared retrieval of semantic associations acquired through Fast Mapping (FM), an incidental, exclusion-based learning procedure, to retrieval of similar associations that were intentionally acquired through Explicit Encoding (EE). Despite an identical retrieval task, the encoding histories of the retrieved semantic associations (FM vs. EE) induced distinct neural substrates and disparate related neural dynamics in time. Retrieval of associations acquired through EE engaged the expected hippocampal and vmPFC related networks. Furthermore, retrieval intentionally encoded associations gave rise to a typical overnight increase in engagement of the vmPFC and increased vmPFC-hippocampal-neocortical functional connectivity. On the other hand, retrieval of associations acquired through FM immediately engaged an ATL related network that typically supports well-established semantic knowledge, a network that did not engage the hippocampus and the vmPFC. Moreover, FM learning was associated with minimal overnight changes in the BOLD responses and in the functional connectivity. Our findings indicate that FM may induce a direct, ATL-mediated acquisition and retention of novel arbitrary associations, bypassing the initial hippocampal-cortical representation phase. A direct, ATL-mediated vocabulary acquisition through FM could support the learning and retention of new associations in young children with presumably an immature hippocampal system, and possibly even in amnesic adults with hippocampal lesions.

Neocortical catastrophic interference in healthy and amnesic adults: a paradoxical matter of time.

The human cortex can accommodate overlapping semantic information, such as synonyms, homonyms, or overlapping concepts. However, neuronal models of cortical networks predict Catastrophic Interference in conditions of overlapping information, obliterating old associations and sometimes preventing formation of new ones. It has been proposed that Catastrophic Interference in declarative memory is never observed in biological systems because of hippocampal pattern separation of competing associations. Here, we tested neocortical Catastrophic Interference during acquisition of overlapping associations through Fast Mapping; an incidental, exclusion based learning mechanism, that can support hippocampal-independent learning. Young adults acquired picture-label associations, either through explicit encoding or through Fast Mapping and were tested after 24 h. Overlapping/competing associations were presented either minutes (Early), or 22 h (Delayed) after learning. Catastrophic Interference was evident only following Fast Mapping, and only in the Delayed competition. In a follow-up experiment, Medial Temporal Lobe (MTL) amnesic patients demonstrated retroactive Catastrophic Interference after the Early competition, despite normal memory for noninterfered Fast Mapping associations. Thus, following Fast Mapping, a biological system demonstrated susceptibility to Catastrophic Interference, as predicted by the neuronal-model. Early retroactive Interference, however, can be prevented by MTL integrity.

The ubiquitin-proteasome pathway regulates claudin 5 degradation.

The tight junctions (TJs) form continuous intracellular contacts, which help create selective barriers in epithelial and endothelial cell layers. The structures created by the TJs are very dynamic and can be rapidly remodeled in response to physiological and pathological signals. Claudin 5 is a membranal TJ protein which plays a critical role in determining the permeability of endothelial barriers. We describe the regulation of claudin 5 degradation by the ubiquitin-proteasome system (UPS). Our results indicate that claudin 5 has a relatively short half-life and can be polyubiquitinated on lysine 199. This ubiquitination appears to trigger the proteasome-dependent degradation of claudin 5. Other mechanisms also seem to be involved in the post-translational regulation of claudin 5, including a ubiquitin-independent and probably indirect lysosomal-dependent pathway. These findings provide evidence for the involvement of the UPS in the regulation of claudin 5 levels, and set the stage for further research to determine the involvement of this pathway in the modulation of the properties of TJs and cell-layer barriers.

Facilitation of taste memory acquisition by experiencing previous novel taste is protein-synthesis dependent.

Very little is known about the biological and molecular mechanisms that determine the effect of previous experience on implicit learning tasks. In the present study, we first defined weak and strong taste inputs according to measurements in the behavioral paradigm known as latent inhibition of conditioned taste aversion. We then demonstrated that a strong novel taste input facilitated acquisition of the memory of subsequent weak taste input in inverse correlation with the time interval between the inputs. However, not only was a strong taste input unable to rescue an immediately subsequent strong taste input when the gustatory cortex was under the influence of the protein-synthesis inhibitor, anisomycin, but the effect of the interaction was to reduce the variation among individual taste memories. Taken together, these results demonstrate that taste memory facilitation, induced by previously experiencing a different unimodal taste input, depended on time, novelty, and directionality. Moreover, the results imply that learning is enhanced on the level of acquisition but not of molecular consolidation.

Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity.

Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity. During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and synaptic plasticity. We have tested this hypothesis with genetically engineered mice deficient for either S6K1 or S6K2. We have found that S6K1-deficient mice express an early-onset contextual fear memory deficit within one hour of training, a deficit in conditioned taste aversion (CTA), impaired Morris water maze acquisition, and hypoactive exploratory behavior. In contrast, S6K2-deficient mice exhibit decreased contextual fear memory seven days after training, a reduction in latent inhibition of CTA, and normal spatial learning in the Morris water maze. Surprisingly, neither S6K1- nor S6K2-deficient mice exhibited alterations in protein synthesis-dependent late-phase long-term potentiation (L-LTP). However, removal of S6K1, but not S6K2, compromised early-phase LTP expression. Furthermore, we observed that S6K1-deficient mice have elevated basal levels of Akt phosphorylation, which is further elevated following induction of L-LTP. Taken together, our findings demonstrate that removal of S6K1 leads to a distinct array of behavioral and synaptic plasticity phenotypes that are not mirrored by the removal of S6K2. Our observations suggest that neither gene by itself is required for L-LTP but instead may be required for other types of synaptic plasticity required for cognitive processing.

Aging and spatial cues influence the updating of navigational memories.

Updating navigational memories is important for everyday tasks. It was recently found that older adults are impaired in updating spatial representations in small, bi-dimensional layouts. Because performance in small-scale areas cannot predict navigational behavior, we investigated how aging affects the updating of navigational memories encoded in large, 3-dimensional environments. Moreover, since locations can be encoded relative to the observer (egocentric encoding) or relative to landmarks (allocentric encoding), we tested whether the presumed age-related spatial updating deficit depends on the available spatial cues. By combining whole-body motion tracking with immersive virtual reality, we could dissociate egocentric and allocentric spatial cues and assess navigational memory under ecologically valid conditions (i.e., providing body-based and visual cues). In the task, objects were relocated overnight, and young and older participants had to navigate to the updated locations of the objects. In addition to replicating age-related deficits in allocentric memory, we found age-related impairments in updating navigational memories following egocentric encoding. Finally, older participants depicted stronger representations of the previous navigational context that were correlated with their spatial updating deficits. Given that these effects may stem from inefficient suppression of former navigational memories, our findings propose a mechanism that helps explain the navigational decline in aging.

Spatial updating deficits in human aging are associated with traces of former memory representations.

The ability to update spatial memories is important for everyday situations, such as remembering where we left our keys or parked our car. Although rodent studies have suggested that old age might impair spatial updating, direct evidence for such a deficit in humans is missing. Here, we tested whether spatial updating deficits occur in human aging, whether the learning mode influences spatial updating, and what mnemonic mechanism underlies the presumed deficits. To address these questions, younger and older participants had to indicate the latest location of relocated items, following either incidental or intentional learning. Using eye tracking, we further quantified memory traces of the original and updated locations. We found that older participants were selectively impaired in recalling locations of relocated items. Furthermore, they depicted relatively stronger representations of the original locations, which were correlated with their spatial updating deficits. The findings demonstrate that stronger representations of former spatial contexts can impair spatial updating in aging, a mechanism that can help explain the commonly observed age-related decline in spatial memory.

Behavioral alterations in mice lacking the translation repressor 4E-BP2.

The requirement for de novo protein synthesis during multiple forms of learning, memory and behavior is well-established; however, we are only beginning to uncover the regulatory mechanisms that govern this process. In order to determine how translation initiation is regulated during neuroplasticity we engineered mutant C57Bl/6J mice that lack the translation repressor eukaryotic initiation factor 4E-binding protein 2 (4E-BP2) and have previously demonstrated that 4E-BP2 plays a critical role in hippocampus-dependent synaptic plasticity and memory. Herein, we examined the 4E-BP2 knockout mice in a battery of paradigms to address motor activity and motor skill learning, anxiety and social dominance behaviors, working memory and conditioned taste aversion. We found that the 4E-BP2 knockout mice demonstrated altered activity in the rotating rod test, light/dark exploration test, spontaneous alternation T-maze and conditioned taste aversion test. The information gained from these studies builds a solid foundation for future studies on the specific role of 4E-BP2 in various types of behavior, and for a broader, more detailed examination of the mechanisms of translational control in the brain.

Extinction of conditioned taste aversion depends on functional protein synthesis but not on NMDA receptor activation in the ventromedial prefrontal cortex.

We investigated the role of the ventromedial prefrontal cortex (vmPFC) in extinction of conditioned taste aversion (CTA) by microinfusing a protein synthesis inhibitor or N-methyl-d-asparate (NMDA) receptors antagonist into the vmPFC immediately following a non-reinforced extinction session. We found that the protein synthesis blocker anisomycin, but not the NMDA receptors antagonist D,L-2-amino-5-phosphonovaleric acid, impaired CTA extinction in the vmPFC. Anisomycin microinfusion into vmPFC had no effect on CTA acquisition and by itself did not induce CTA. These findings show the necessary role functional protein synthesis is playing in the vmPFC during the learning of CTA extinction.

Behavioral interference and C/EBPbeta expression in the insular-cortex reveal a prolonged time period for taste memory consolidation.

Memory consolidation is defined as the time window during which the memory trace is susceptible to behavioral, electrical, or pharmacological interventions. Here, we presented rats with two novel tastes at consecutive time intervals. Clear interference was evident when a novel taste formed the second taste input whereby, surprisingly, the time window for interference was found to last more than 10 h. In addition, we detected an increase of C/EBPbeta protein expression in the gustatory cortex 18 h after novel taste learning. This modulation was attenuated by a subsequent novel taste. Our findings reveal temporal constraints and a lingering nature of taste memory consolidation.

Different signal transduction cascades are activated simultaneously in the rat insular cortex and hippocampus following novel taste learning.

Novel taste learning is a robust one-trial incidental learning process, dependent on functional activity of the insular (taste) cortex. In contrast to that of the cortex, the role of the hippocampus in taste learning is controversial. We set out to identify the time courses of the activation of mitogen-associated protein kinase (MAPK), transcription factor cAMP-response element-binding protein (CREB) and Akt/PKB (protein kinase B) in the insular cortex and hippocampus of rats subsequent to novel taste learning. Following taste learning, an early response (20 min) occurred at the same time in the insular cortex and the hippocampus. However, whereas MAPK was activated specifically in the insular cortex, CREB and Akt were phosphorylated in the hippocampus but not in the cortex. In addition, the immediate early gene, CCAAT/enhancer binding protein (C/EBPbeta) was induced in both the hippocampus and the insular cortex 18 h following taste learning. The results demonstrate, for the first time, correlative activation and gene expression in the hippocampus following novel taste learning. Moreover, the results suggest that different signal transduction cascades necessary for taste learning are activated in concert in different brain structures, to enable taste learning and consolidation.