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Identifying the Molecular Mechanisms of Creating a Memory

Researchers at the RIKEN Center for Brain Science (CBS) have visualized the molecular dynamics in the living mouse brain for the first time, observing fast and slow molecular pathways that support memory function.

Based on a study published in Nature Communications on 24th January 2020, the team of researchers found that there are distinct signalling molecular links to a momentary incident compared to a sustained state that will generate a memory in the brains of mice models.

The processes were found to take place in brain cells called astrocytes, revealing an important way in which these cells support the nervous system. The researchers wanted to observe in real time what happens to astrocytes in mice when given a certain stimulus.

The team artificially stimulated the brain cells with a method called optogenetics, to induce norepinephrine release. Focussing on the noradrenergic neurons originating from the locus coeruleus, norepinephrine release triggered two distinct chains of molecular events. These involved calcium activity and cyclic adenosine monophosphate (cAMP).

Calcium levels in astrocytes were quick to become elevated following norepinephrine release, while cAMP levels had a slower but more sustained increase.

“We think these fast and slow dynamics are significant because calcium elevation in astrocytes promotes synaptic plasticity, or the ability of cells to form new memory connections, while cAMP elevation mobilizes energy metabolism for memory consolidation,” said Hajime Hirase, senior author and team leader at RIKEN CBS.

When the mice were triggered by giving random puffs of air to their face, cAMP levels did not go up while calcium became elevated. However, when the mice were given a foot shock coupled with a sound to create a fear memory. When they heard the sound again, the mice would freeze in anticipation of a shock. This time, cAMP levels were noticeably elevated, while calcium levels also rose but quickly tapered off.

“When mice are in this sustained state of vigilance, a lot of norepinephrine is released, coupled with gradually building cAMP,” explains first author Yuki Oe, a research scientist in Hirase’s group. “This reflects how the astrocytes support the formation of fear memory.” Neither calcium nor cAMP responses were seen in mice that were given norepinephrine-blocking drugs, indicating that norepinephrine release is indeed the trigger for these changes.

The short-term and long-term consequences of norepinephrine release in the brain thus depend on the situation and behaviour. Memory formation, in particular, seems to be supported by increases in cAMP levels, while transient or low vigilance states involve short-term elevated calcium.

“One of the effects of cAMP is to break down glycogen for quick energy in a fight-or-flight situation,” comments Hirase. “This boosting of energy metabolism could help consolidate memories over longer time scales, while rapid calcium boosts could lower the threshold for synaptic plasticity. [APBN]