Visualizing How Astrocytes Support Memory Function

A sustained state of vigilance will generate a different type of memory than a momentary startle—differences that are linked to distinct signaling molecules. In a study published today in Nature Communications, RIKEN CBS researchers have visualized these dynamics in the living mouse brain for the first time. They observed fast and slow molecular pathways in astrocytes that support memory function.

The team focused on noradrenergic neurons originating in a part of the brain called the locus coeruleus. Using a method called optogenetics, they artificially stimulated these cells to induce norepinephrine release, launching two distinct chains of molecular events in astrocytes. Following norepinephrine release, calcium levels were quick to become elevated, 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,” says senior author Hajime Hirase.

To see how these fast and slow molecular responses are triggered naturally, mice were given random air puffs to the face to evoke a brief startle response. In this situation, cAMP levels did not go up at all, while calcium became elevated as previously observed. In a second experiment, 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,” says first author Yuki Oe. “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 behavior. 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,” Hirase explains. “This boosting of energy metabolism could help consolidate memories over longer time scales, while rapid calcium boosts could lower the threshold for synaptic plasticity.”

Image: Specific gene expression allows light to trigger norepinephrine release in the locus coeruleus (yellow). In red, the ventral tegmental area without gene expression. Image courtesy of RIKEN.