Some stressful experiences—such as childhood abuse—are so overwhelming and traumatic that the memories hide in the brain.
Those hidden memories may protect us from the emotional pain of recalling an event. But eventually they can lead to debilitating problems, such as anxiety, depression, post-traumatic stress disorder, or dissociative disorders.
A process known as state-dependent learning is thought to help us form memories that are inaccessible to normal consciousness. So, memories formed in a particular mood, arousal, or drug-induced state can best be retrieved when the brain is back in that state.
In a new study with mice, scientists discovered for the first time the mechanism by which state-dependent learning renders fear-related memories consciously inaccessible.
Brain’s Yin and Yang
“The findings show there are multiple pathways to storage of fear-inducing memories, and we identified an important one for fear-related memories,” said principal investigator Jelena Radulovic, professor of bipolar disease at Northwestern University Feinberg School of Medicine.
“This could eventually lead to new treatments for patients with psychiatric disorders for whom conscious access to their traumatic memories is needed if they are to recover.”
It’s difficult for therapists to help these patients, Radulovic said, because patients themselves can’t remember the traumatic experiences that are the root cause of their symptoms.
Two amino acids, glutamate and GABA, are the yin and yang of the brain, directing its emotional tides and controlling whether nerve cells are excited or inhibited (calm). Under normal conditions the system is balanced.
But when we are hyper-aroused and vigilant, glutamate surges. Glutamate is also the primary chemical that helps store memories in our neuronal networks in a way that they are easy to remember. GABA, on the other hand, calms us and helps us sleep, blocking the action of the excitable glutamate. The most commonly used tranquilizing drug, benzodiazepine, activates GABA receptors in our brains.
Tuning the Brain
There are two kinds of GABA receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.
The other kind, extra-synaptic GABA receptors, are independent agents and ignore the peppy glutamate. Instead, their job is internally focused, adjusting brain waves and mental states according to the levels of internal chemicals, such as GABA, sex hormones and micro RNAs.
Extra-synaptic GABA receptors change the brain’s state to make us aroused, sleepy, alert, sedated, inebriated, or even psychotic. However, scientists discovered another critical role; these receptors also help encode memories of a fear-inducing event and then store them away, hidden from consciousness.
“The brain functions in different states, much like a radio operates at AM and FM frequency bands,” Radulovic said. “It’s as if the brain is normally tuned to FM stations to access memories, but needs to be tuned to AM stations to access subconscious memories. If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again, essentially tuning the brain into the AM stations.”
For the new study, published in the journal Nature Neuroscience, researchers infused the hippocampus of mice with gaboxadol, a drug that stimulates extra-synaptic GABA receptors. “It’s like we got them a little inebriated, just enough to change their brain state,” Radulovic said.
Then the mice were put in a box and given a brief, mild electric shock. When the mice were returned to the same box the next day, they moved about freely and weren’t afraid, indicating they didn’t recall the earlier shock in the space. However, when scientists put the mice back on the drug and returned them to the box, they froze, fearfully anticipating another shock.
“This establishes when the mice were returned to the same brain state created by the drug, they remembered the stressful experience of the shock,” Radulovic said.
The experiment showed when the extra-synaptic GABA receptors were activated with the drug, they changed the way the stressful event was encoded. In the drug-induced state, the brain used completely different molecular pathways and neuronal circuits to store the memory.
“It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories,” said lead author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic’s lab.
This different system is regulated by a small microRNA, miR-33, and may be the brain’s protective mechanism when an experience is overwhelmingly stressful.
The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.
The National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and a Ken and Ruth Davee Award for Innovative Investigations in Mood Disorders funded the work.