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4 December 2018
Tomoyuki Miyashita, PhD, (Learning and Memory Project) published a paper on ”Long-term memory encoding engram neurons are established by the transcriptional cycling” in Cell Reports.”

Long-term memory encoding engram neurons are established by the transcriptional cycling


Long-term memory (LTM) is formed by repetitive training trials with rest intervals and LTM formation requires transcription factors, including CREB and c-Fos. Miyashita et al. found that MAPK activity is increased during rest intervals to induce transcriptional cycling between c-Fos and CREB in a subset of mushroom body neurons. Significantly, LTM is encoded in these mushroom body neurons, and blocking outputs from these neurons suppress recall of LTM whereas activating these neurons produces memory-associated behaviors.

<Title of the paper>
Long-Term Memory Engram Cells Are Established by c-Fos/CREB Transcriptional Cycling
Cell Reports, Volume 25, Issue 10, 4 December 2018, Pages 2716-2728.e3


Long-term memory (LTM) is known to be encoded in specific neural cells, namely, engram neurons. While engram neurons have been identified by increase in expression of c-Fos(1), it has been unclear how these engram neurons are formed during training.

Drosophila can form olfactory aversive LTM by repetitive training sessions with rest intervals between each session, a training paradigm known as spaced training. Similar to mammals, LTM formation requires de novo gene expression mediated by transcription factor, CREB(2). Phosphorylation of CREB by MAPK is critical for CREB-dependent gene expression, and activity of MAPK(3) is increased during rest intervals of spaced training. In this study, Miyashita et al found that the relationship among MAPK, CREB, and c-Fos in LTM formation is more complex than previously proposed. Repeated and prolonged activation of MAPK produces transcriptional cycling between c-fos and CREB. CREB is phosphorylated by MAPK to induce c-fos expression, while c-Fos is also phosphorylated by MAPK to form the transcription factor AP-1, which promotes expression of CREB. The first c-fos induction step is required to form LTM, while the second CREB induction is required to prolong LTM to last at least 7 days in flies. Furthermore, blocking or activating neurons which had formed c-Fos/CREB cycling inhibits memory recall or induces memory-associated behaviors. These results indicate that memory engram neurons in flies are established by cell-autonomous MAPK-dependent c-Fos/CREB cycling and provide useful procedure to improve memory impairment.

One of the immediate early genes encoding transcription factor. Expression of c-fos is mediated by CREB.
2)CREB (cAMP response element binding protein):
A transcription factor mediating gene expressions required for long-term memory formation.
3)MAPK (mitogen activated protein kinase):
A family of protein kinases that mediate various neuronal function. MAPK family includes ERK (extracellular signal-regulated kinase), JNK (jun kinase), and p38.

Reference figure

Transcription cycle

By repetitive learning at intervals, MAPK is activated in the nerve cells to which repetitive information is input, so that a transcription cycle of CREB and c-fos is formed. In the nerve cells in which the transcription cycle is formed, the amount of CREB increases and it becomes an engram cell in which long-term memory is formed.

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