Abstract
Memories are stored within neuronal ensembles in the brain. Modern genetic techniques can be used to not only visualize specific neuronal ensembles that encode memories (e.g., fear, craving) but also to selectively manipulate those neurons. These techniques are now being expanded for the study of various types of memory. In this review, we will summarize the genetic methods used to visualize and manipulate neurons involved in the representation of memory engrams. The methods will help clarify how memory is encoded, stored and processed in the brain. Furthermore, these approaches may contribute to our understanding of the pathological mechanisms associated with human memory disorders and, ultimately, may aid the development of therapeutic strategies to ameliorate these diseases.
Highlights
One of the major aims of modern memory research is to locate the physical substrate of memory in the brain
At the beginning of the 20th century, Richard Semon introduced the word, ‘engram’, to describe the memory trace, ‘Its result, namely, the enduring though primarily latent modification in the irritable substance produced by stimulus, I have called an Engram, . . ..’ [1]
Using the same c-fos-LacZ rat, Bossert et al found neural ensembles that mediated a context-induced relapse to heroin addiction in the ventral medial prefrontal cortex [45]. These results suggest that the c-fos promoter can be used to genetically tag the neuronal ensemble involved in memory encoding
Summary
One of the major aims of modern memory research is to locate the physical substrate of memory ( referred to as ‘memory trace’ or ‘neural substrates of memory’) in the brain. Reijimers et al [34] visualized c-fos positive neurons using a transgenic mouse line expressing βgalactosidase (LacZ) under the control of a c-fos promoter via a self-activating tTA-TetO system to examine the memory trace of tone fear memory in the amygdala (Figure 3). It will be interesting to examine whether CREB overexpression can induce memory encoding in the hippocampus or other brain regions [26] Optogenetics Another powerful tool that has recently emerged in the field of memory research is the use of light-activated proteins to control neuronal activity. Inhibition of activity 30 minutes before the test abolished the above effect (i.e., reduction in freezing), which is in agreement with other reports that utilize the other methods (e.g., physical, pharmacological, and genetic lesions) [9,12,13] These results showed that the hippocampus is still engaged after memory consolidation, and highlight the higher temporal resolution of optogenetic approaches over other more conventional approaches.
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