Basis Of Long-term Memory Research Articles

The Molecular Basis of Destabilization of Synapses as a Factor of Structural Plasticity

Within the framework of ideas about structural plasticity as the basis of long-term memory it has been proven that destabilization of the molecular complex that supports the existing state of the synapse is necessary to begin the consolidation process. This complex consists of proteins of the extracellular matrix, including cell adhesion molecules and transsynaptic proteins, as well as skeletal, scaffold, and anchoring proteins that form the basis for integration and maintenance of signaling and regulatory proteins. We review the experimental data on the importance of destabilization of synapses for efficient maintenance of long-term potentiation (LTP). We demonstrate that induction of structural modifications depends on the composition of NMDA receptors, which are closely related to destabilization of proteins of the cytoskeleton. It is suggested that the interaction of CAMKII and the intracellular domain of NMDA2B receptors is necessary for destabilization and activation of synaptogenesis not only in early ontogeny but also in adult animals, whereas its substitution for the NMDA2A subunit promotes stabilization of synapses. The key role of proteolysis in long-term plasticity and destabilization of synapses is discussed.

Transcription control pathways decode patterned synaptic inputs into diverse mRNA expression profiles.

Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic-activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression.

Common chromosomal fragile sites (CFS) may be involved in normal and traumatic cognitive stress memory consolidation and altered nervous system immunity

Previous reports of specific patterns of increased fragility at common chromosomal fragile sites (CFS) found in association with certain neurobehavioural disorders did not attract attention at the time due to a shift towards molecular approaches to delineate neuropsychiatric disorder candidate genes. Links with miRNA, altered methylation and the origin of copy number variation indicate that CFS region characteristics may be part of chromatinomic mechanisms that are increasingly linked with neuroplasticity and memory. Current reports of large-scale double-stranded DNA breaks in differentiating neurons and evidence of ongoing DNA demethylation of specific gene promoters in adult hippocampus may shed new light on the dynamic epigenetic changes that are increasingly appreciated as contributing to long-term memory consolidation. The expression of immune recombination activating genes in key stress-induced memory regions suggests the adoption by the brain of this ancient pattern recognition and memory system to establish a structural basis for long-term memory through controlled chromosomal breakage at highly specific genomic regions. It is furthermore considered that these mechanisms for management of epigenetic information related to stress memory could be linked, in some instances, with the transfer of the somatically acquired information to the germline. Here, rearranged sequences can be subjected to further selection and possible eventual retrotranscription to become part of the more stable coding machinery if proven to be crucial for survival and reproduction. While linkage of cognitive memory with stress and fear circuitry and memory establishment through structural DNA modification is proposed as a normal process, inappropriate activation of immune-like genomic rearrangement processes through traumatic stress memory may have the potential to lead to undesirable activation of neuro-inflammatory processes. These theories could have a significant impact on the interpretation of risks posed by heredity and the environment and the search for neuropsychiatric candidate genes.

The evidence for hippocampal long-term potentiation as a basis of memory for simple tasks

Long-term potentiation (LTP) is the enhancement of postsynaptic responses for hours, days or weeks following the brief repetitive afferent stimulation of presynaptic afferents. It has been proposed many times over the last 30 years to be the basis of long-term memory. Several recent findings finally supported this hypothesis: a) memory formation of one-trial avoidance learning depends on a series of molecular steps in the CA1 region of the hippocampus almost identical to those of LTP in the same region; b)hippocampal LTP in this region accompanies memory formation of that task and of another similar task. However, CA1 LTP and the accompanying memory processes can be dissociated, and in addition plastic events in several other brain regions(amygdala, entorhinal cortex, parietal cortex) are also necessary for memory formation of the one-trial task, and perhaps of many others.

Genes and Circuits for Olfactory-Associated Long-Term Memory in Drosophila

One of the formidable challenges in modern neuroscience is to identify the physical basis of long-term memory (LTM) storage—the engram. Cellular and molecular experiments have suggested that the engram for a particular behavioral task is encoded as changes in synaptic structure and function, yet distributed in an unknown fashion across an ill-defined neural circuit or network. Accumulating genetic and circuitry information has provided some clues toward resolving this engram puzzle. This review will focus on recent discoveries of genes and circuits involved in the formation of olfactory-associated LTM in Drosophila.

Long term maintenance of synaptic plasticity via CPEB mediated local translation control at synapses

The persistent change in synaptic efficacy, which is a basis of long term memory and learning, depends on synthesis of new proteins. The phenomenon of late long-term potentiation (L-LTP), the persistent activity dependent enhancement of synaptic efficacies, is protein synthesis dependent. The main objective of this work is to explore a possible link between activity dependent temporal and spatial regulation of gene expression and life long stability of some memories despite the rapid turnover of their molecular substrates. This work is motivated by the following three experimental observations. 1. L-LTP requires new protein synthesis but not new mRNAs [1,2]. 2. Some local mRNAs encode proteins which regulate the synaptic functions e.g., αCaMKII-mRNA encodes the αCaMKII, which has crucial role in activity induced L-LTP [3-5]. 3. Almost all the components of translational machinery are constitutively localized in dendrites [6-8]. Here, we propose a hypothesis that a molecular loop between a kinase and a translation regulation factor acts as a bistable switch to stabilize activity induced synaptic plasticity over long periods of time. We implement one possible instantiation of such a loop; an αCaMKII-CPEB molecular pair. Our proposed model of translation regulation is based on αCaMKII induced phosphorylation of CPEB at synapses which can trigger the cytoplasmic polyadenylation initiated translation of αCaMKII-mRNA at synapses in CPE dependent manner. We show that αCaMKII-CPEB loop can operate as a bistable switch. Our results imply that L-LTP should produce a significant change in the total amount of αCaMKII at potentiated synapses, but that the fraction of phosphorylated αCaMKII only moderately changes. By carrying out bifurcation analysis we identify the key parameters that determine whether the system is in a bistable region, this could indicate the key parameters that should be measured experimentally. We also demonstrate that a partial block of αCaMKII translation in the induction phase of L-LTP can block L-LTP, but a partial block of translation in the maintenance phase might not block L-LTP. Our results provide a possible explanation for why the application of protein synthesis inhibitors at the induction and maintenance phases of L-LTP can have a very different outcome. This proposed molecular switch, based on translation initiated by phosphorylation, provides the mechanistic basis both for persistency and input specificity during L-LTP.

Mathematical modeling of short-term memory

A study of the proposed mathematical model of the mechanism of operative memory indicates that formation of circulating excitations is accounted for by short-term trace effects of synaptic transmission, well known in neurophysiology (posttetanic potentiation, temporary facilitation, and path formation). These results give added support to the recirculation theory, which maintains that fixation and storage of incoming information occurs via a stream of nervous impulses circulating in closed chains. The circulation of a stream, in turn, leads to stable morphological or chemical alterations in the structure of the synaptic apparatus, which constitutes the basis of long-term memory.