Repeated Labilization-Reconsolidation Processes Strengthen Declarative Memory in Humans

The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative

Synaptic tagging and capture in the living rat

In isolated hippocampal slices, decaying long-term potentiation can be stabilized and converted to late long-term potentiation lasting many hours, by prior or subsequent strong high-frequency tetanization of an independent input to a common population of neurons—a phenomenon known as ‘synaptic tagging and capture’. Here we show that the same phenomenon occurs in the intact rat. Late long-term potentiation can be induced in CA1 during the inhibition of protein synthesis if an independent input is strongly tetanized beforehand. Conversely, declining early long-term potentiation induced by weak tetanization can be converted into lasting late long-term potentiation by subsequent strong tetanization of a separate input. These findings indicate that synaptic tagging and capture is not limited to in vitro preparations; the past and future activity of neurons has a critical role in determining the persistence of synaptic changes in the living animal, thus providing a bridge between cellular studies of protein synthesis-dependent synaptic potentiation and behavioural studies of memory persistence

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine

Clustered Gene Expression Changes Flank Targeted Gene Loci in Knockout Mice

Gene expression profiling using microarrays is a powerful technology widely used to study regulatory networks. Profiling of mRNA levels in mutant organisms has the potential to identify genes regulated by the mutated protein.Using tissues from multiple lines of knockout mice we have examined genome-wide changes in gene expression. We report that a significant proportion of changed genes were found near the targeted gene.The apparent clustering of these genes was explained by the presence of flanking DNA from the parental ES cell. We provide recommendations for the analysis and reporting of microarray data from knockout mice

Nuclear Translocation of Jacob in Hippocampal Neurons after Stimuli Inducing Long-Term Potentiation but Not Long-Term Depression

Background: In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons. Jacob is another messenger that couples NMDA-receptor-activity to nuclear gene expression. We therefore aimed to study whether Jacob accumulates in the nucleus in physiological relevant models of activity-dependent synaptic plasticity. Methodology/Principal Findings: We have analyzed the dynamics of Jacob’s nuclear import following induction of NMDA-receptor dependent LTP or LTD at Schaffer collateral-CA1 synapses in rat hippocampal slices. Using time-lapse imaging of neurons expressing a Jacob-Green-Fluorescent-Protein we found that Jacob rapidly translocates from dendrites to the nucleus already during the tetanization period of LTP, but not after induction of LTD. Immunocytochemical stainings confirmed the nuclear accumulation of endogenous Jacob in comparison to apical dendrites after induction of LTP but not LTD. Complementary findings were obtained after induction of NMDA-receptor dependent chemical LTP and LTD i

Computing, Design, Art: Reflections on an Innovative Moment in History

The paper is concerned with the role of art and design in the history and philosophy of computing. It offers insights arising from research into a period in the 1960s and 70s, particularly in the UK, when computing became more available to artists and designers, focusing on John Lansdown (1929-1999) and Bruce Archer (1922-2005) in London. Models of computing interacted with conceptualisations of art, design and related creative activities in important ways

Role of C/EBPβ Transcription Factor in Adult Hippocampal Neurogenesis

[Background]: The dentate gyrus of the hippocampus is one of the regions in which neurogenesis takes place in the adult brain. We have previously demonstrated that CCAAT/enhancer binding protein β (C/EBPβ) is expressed in the granular layer of the dentate gyrus of the adult mouse hippocampus. Taking into account the important role of C/EBPβ in the consolidation of long term memory, the fact that newborn neurons in the hippocampus contribute to learning and memory processes, and the role of this transcription factor, previously demonstrated by our group, in regulating neuronal differentiation, we speculated that this transcription factor could regulate stem/progenitor cells in this region of the brain. [Methodologu/Principal Findings]: Here, we show, using C/EBPβ knockout mice, that C/EBPβ expression is observed in the subset of newborn cells that proliferate in the hippocampus of the adult brain. Mice lacking C/EBPβ present reduced survival of newborn cells in the hippocampus, a decrease in the number of these cells that differentiate into neurons and a diminished number of cells that are proliferating in the subgranular zone of the dentate gyrus. These results were further confirmed in vitro. Neurosphere cultures from adult mice deficient in C/EBPβ present less proliferation and neuronal differentiation than neurospheres derived from wild type mice. [Conclusions/Significance]: In summary, using in vivo and in vitro strategies, we have identified C/EBPβ as a key player in the proliferation and survival of the new neurons produced in the adult mouse hippocampus. Our results support a novel role of C/EBPβ in the processes of adult hippocampal neurogenesis, providing new insights into the mechanisms that control neurogenesis in this region of the brain.This work was supported by a postdoctoral fellowship of the Consejo Superior de Investigaciones Cientificas (M.C.-C.) Grant Sponsor: Ministerio de Investigación y Ciencia; Grant numbers: SAF2007-62811 and SAF2010-16365. CIBERNED is funded by the Instituto de Salud Carlos III.Peer reviewe