In one recent study, the c-fos promoter was combined with elements of the Tet regulatory system in transgenic mice to allow the introduction of a lacZ marker into neurons activated with fear conditioning[ ]. The marker provided a long-lasting record of brain activity during learning that could be compared to activity during recall.
A partial reactivation of the neurons that were active during learning and the strength of the recalled memory were correlated with the degree of circuit reactivation. This important new approach provides an opportunity to introduce any genetically encoded effector molecule into neurons based on their recent activity thereby providing the potential to study circuits based on the specific memory they encode. We now understand — in considerable molecular detail — the mechanisms underlying long-term learning-related synaptic plasticity, and the importance that such plastic changes play in memory storage, across a broad range of species and forms of memory.
In fact, one of the most striking features that has emerged through the application of molecular biology to neural science is the ability to see how unified all of the biological sciences have become. However, although it is now clear that long-term synaptic plasticity is a key step in memory storage, it is important to note that a simple enhancement in the efficacy of a synapse is not sufficient to store a complex memory.
Rather, changes in synaptic function must occur within the context of an ensemble of neurons to produce a specific alteration in information flow through a neural circuit. With the recent development of powerful genetic tools, it may soon be possible to meet the daunting challenge of visualizing and manipulating such changes in neural circuitry[ ]. It also will be interesting to see to what degree computational models will contribute to our further understanding of synaptic plasticity. The influential cascade model of synaptically stored memory by Stefano Fusi, Patrick Drew, and Larry Abbott[ ] emphasizes that switch-like mechanisms are good for acquiring and storing memory but bad for retaining it.
Retention, they argue, requires a cascade of states, each more stable than its precursor. As their hypothesis predicted, a progressive stabilization of changes in the synapse has been found to take place during the transition from short-term to intermediate-term to long-term memory storage Jin et al. A major reason why computational neuroscience is rising and becoming more powerful and more interesting, as evident in the cascade model, is that these models lend themselves to experimental testing.
In the future, however, computational models will need to broaden their focus to include the role of modulatory transmitters, the molecular components of synapses and their anatomical substrates. Finally, we need to understand how memory is recalled. This is a deep problem whose analysis is just beginning. Mayford has made an important start of this problem and found that the same cells activated in the amygdala during the acquisition of learned fear are reactivated during retrieval of those memories.
In fact, the number of reactivated neurons correlated positively with the behavioral expression of learned fear, indicating that associative memory has a stable neural correlate[ ]. But one of the characteristics of declarative memory is the requirement for conscious attention for recall. How does this attention mechanism come into play? Do modulatory transmitters such as dopamine and acetylcholine have a role in the retrieval process?
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Proc Natl Acad Sci. Download references. Correspondence to Eric R Kandel. This article is published under license to BioMed Central Ltd. Reprints and Permissions. Search all BMC articles Search. Background: Simple systems in the study of implicit learning and memory By , we had already learned from the pioneering work of Brenda Milner that certain forms of memory were stored in the hippocampus and the medial temporal lobe. Emergence of a molecular biology of memory-related synaptic plasticity The delineation of cAMP and PKA in short-term memory storage Cell biological studies of the synaptic connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia revealed a biochemical mechanism for the short-term increase in transmitter release produced by sensitization[ 24 ] and later for classical conditioning Hawkins et al.
Classical conditioning involves both pre- and postsynaptic mechanisms of plasticity In , Hawkins, Abrams, Carew and Kandel[ 25 ] succeeded in establishing differential classical conditioning of the gill-withdrawal reflex and in beginning its cellular analysis. A molecular biology of learning-related long-term synaptic plasticity Beginning in , the insights and methods of molecular biology were being brought to bear on the nervous system, making it possible to see commonalities in the molecular mechanisms of short-term memory among different animals and to begin to explore how short-term memory is converted to long-term memory.
Activation of nuclear transcription factors Long-term memory is represented at the cellular level by activity-dependent modulation of both the function and the structure of specific synaptic connections that, in turn, depends on the activation of specific patterns of gene expression[ 15 ]. Chromatin alteration and epigenetic changes in gene expression with memory storage Studies by Guan et al.
Synaptic capture Retrograde signaling from the synapse to the nucleus One of the features that fundamentally distinguishes the storage of long-term memory from short-term cellular changes is the requirement for the activation of gene expression. Molecular mechanisms of synaptic capture Studies of synaptic capture at the synapses between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia have demonstrated that to achieve synapse-specific LTF more than the production of CRE-driven gene products in the nucleus is necessary.
Emergence of a genetics of learning-related synaptic plasticity for explicit memory Unlike implicit memory, the conscious remembrance of things past requires a complex system involving the medial temporal lobe and the hippocampus.
Overall view We now understand — in considerable molecular detail — the mechanisms underlying long-term learning-related synaptic plasticity, and the importance that such plastic changes play in memory storage, across a broad range of species and forms of memory. Since those breakthrough studies were done, there have been several others to probe the theory of memory reconsolidation.
Subjects in these studies, along with humans , have included crabs , chicks , honeybees , medaka fish , lymnaea , and various rodents. Some studies have supported this theory, while others have failed to demonstrate disruption of consolidated memory after retrieval. It is important to note that negative results may be examples of conditions where memories are not susceptible to a permanent disruption, thus a determining factor of reconsolidation.
However the need for standardized methods was underscored as in some learning tasks such as fear conditioning , certain forms of memory reactivation could actually represent new extinction learning rather than activation of an old memory trace. Under this possibility, traditional disruptions of reconsolidation might actually maintain the original memory trace but preventing the consolidation of extinction learning. Reconsolidation experiments are more difficult to run than typical consolidation experiments as disruption of a previously consolidated memory must be shown to be specific to the reactivation of the original memory trace.
Furthermore, it is important to demonstrate that the vulnerability of reactivation occurs in a limited time frame, which can be assessed by delaying infusion till six hours after reactivation. It is also useful to show that the behavioral measure used to assess disruption of memory is not just due to task impairment caused by the procedure, which can be demonstrated by testing control groups in absence of the original learning.
Finally, it is important to rule out alternative explanations, such as extinction learning by lengthening the reactivation phase. Questions arose if reconsolidation was a unique process or merely another phase of consolidation. Both consolidation and reconsolidation can be disrupted by pharmacological agents e. However, recent amygdala research suggests that BDNF is required for consolidation but not reconsolidation whereas the transcription factor and immediate early gene Zif is required for reconsolidation but not consolidation.
In the decade between and , at least five groups argued the notion that memory reconsolidation can be used to treat psychological problems.
Long-term potentiation and long-term depression: a clinical perspective
From Wikipedia, the free encyclopedia. Main article: Long-term potentiation. See also: Sleep and memory.
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