Researchers at RIKEN Center for Brain Science have visualized the dynamic processes involving norepinephrine that influence different types of fear-memory formation in a living mouse model.
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The study found that a sustained state of vigilance caused a different type of memory to form than a temporary startle did - differences that were influenced by changes in calcium signaling and the signaling molecule cAMP.
Norepinephrine or noradrenaline is both a hormone released into the blood from the adrenal medulla and a neurotransmitter produced by nerve cells in the brain. It works together with adrenaline to prepare the body for action, by increasing heart rate, blood pressure, and blood sugar levels (as an energy source).
Studies have previously demonstrated that norepinephrine release is important for the modification of synapses – connections between nerve cells that are involved in the formation and consolidation of memories. Changes in synaptic strength are thought to influence learning and memory mechanisms.
Norepinephrine is mainly produced in neurons located in a brain region called the locus coeruleus. Within these neurons, norepinephrine is transported to synaptic vesicles that carry it along axons of the noradrenergic bundle to its site of release.
Emotional arousal triggers activation of the locus coeruleus and the subsequent release of norepinephrine, which induces both pre- and post-synaptic adrenergic receptors at central synapses.
Astrocytes are important mediators of the synaptic changes and researchers at RIKEN’s Hajime Hirase Laboratory for Neuron-Glia Circuitry wanted to observe in real-time what happens in these cells during the learning process.
What did the study involve?
Focusing on noradrenergic neurons originating in the locus coeruleus, the team used a light-based technique known as optogenetics to artificially stimulate brain cells, inducing the release of norepinephrine.
As reported in the journal Nature Communications, this triggered two distinct chains of molecular events, one involving calcium activity and one involving cAMP.
Calcium levels in astrocytes rapidly increased, while the increase in cAMP levels was slower but more sustained.
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."
To test these molecular responses when mice were triggered naturally, the researchers applied random air puffs to the animals’ faces to momentarily startle them. While this produced no change in cAMP, calcium levels quickly increased, as they did in the previous test.
Next, the animals were given a foot shock that was accompanied by a sound to induce the formation of fear memory. When the researchers played the sound again, the mice froze. In this situation, the researchers found that cAMP levels were significantly elevated, while calcium levels rose, but quickly tapered off.
What did the authors learn from the study?
When mice are in this sustained state of vigilance, a lot of norepinephrine is released, coupled with gradually building camp. This reflects how astrocytes support the formation of fear memory."
Furthermore, when mice were administered a norepinephrine blocker, no changes in either calcium or cAMP were observed, indicating that norepinephrine release is indeed the trigger of these changes.
The study suggests that short- and long-term effects of norepinephrine release in the brain depend on the situation and behavior. It seems that memory formation is supported by increased cAMP levels, whereas transient or low vigilance states are supported by short-term elevations in calcium.
"One of the effects of cAMP is to break down glycogen for quick energy in a fight-or-flight situation," explains 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."