Sleep Mechanism Identified That Plays Role in Emotional Memory
Sleep researchers from University of California campuses in Riverside and San Diego have identified the sleep mechanism that enables the brain to consolidate emotional memory and found that a popular prescription sleep aid heightens the recollection of and response to negative memories.
Their findings have implications for individuals suffering from insomnia related to posttraumatic stress disorder (PTSD) and other anxiety disorders who are prescribed zolpidem (Ambien) to help them sleep.
The study — “Pharmacologically Increasing Sleep Spindles Enhances Recognition for Negative and High-arousal Memories” — appears in the Journal of Cognitive Neuroscience. It was funded by a National Institutes of Health career award to Sara C. Mednick, assistant professor of psychology at UC Riverside, of $651,999 over five years.
Mednick and UC San Diego psychologists Erik J. Kaestner and John T. Wixted determined that a sleep feature known as sleep spindles — bursts of brain activity that last for a second or less during a specific stage of sleep — are important for emotional memory.
Research Mednick published earlier this year demonstrated the critical role that sleep spindles play in consolidating information from short-term to long-term memory in the hippocampus, located in the cerebral cortex of the brain. Zolpidem enhanced the process, a discovery that could lead to new sleep therapies to improve memory for aging adults and those with dementia, Alzheimer’s and schizophrenia. It was the first study to show that sleep can be manipulated with pharmacology to improve memory.
“We know that sleep spindles are involved in declarative memory — explicit information we recall about the world, such as places, people and events, ” she explained.
But until now, researchers had not considered sleep spindles as playing a role in emotional memory , focusing instead on rapid eye movement (REM) sleep.
Using two commonly prescribed sleep aids — zolpidem and sodium oxybate (Xyrem) — Mednick, Kaestner and Wixted were able to tease apart the effects of sleep spindles and rapid eye movement (REM) sleep on the recall of emotional memories. They determined that sleep spindles, not REM, affect emotional memory.
The researchers gave zolpidem, sodium oxybate (Xyrem) and a placebo to 28 men and women between the ages of 18 and 39 who were normal sleepers, allowing several days between doses to allow the pharmaceuticals to leave their bodies. The participants viewed standardized images known to elicit positive and negative responses for one second before and after taking supervised naps. They recalled more images that had negative or highly arousing content after taking zolpidem, a finding that also suggests that the brain may favor consolidation of negative memories, she said.
“I was surprised by the specificity of the results, that the emotional memory improvement was specifically for the negative and high-arousal memories, and the ramifications of these results for people with anxiety disorders and PTSD,” Mednick said. “These are people who already have heightened memory for negative and high-arousal memories. Sleep drugs might be improving their memories for things they don’t want to remember.”
The study may have even broader implications, the researchers said. Clinical guidelines of the U.S. Department of Veterans Affairs and Department of Defense recommend against the routine use of benzodiazepines to treat PTSD, although their use increased among men and women with PTSD between 2003 and 2010. The effects of benzodiazepines on sleep are similar to those of zolpidem.
The U.S. Air Force uses zolpidem as one of the prescribed “no-go pills” to help flight crews calm down after taking stimulants to stay awake during long missions, the researchers noted in the study.
“In light of the present results, it would be worthwhile to investigate whether the administration of benzodiazepine-like drugs may be increasing the retention of highly arousing and negative memories, which would have a countertherapeutic effect,” they wrote. “Further research on the relationship between hypnotics and emotional mood disorders would seem to be in order.”
Manipulating Memory in the Hippocampus
Protein modification may help control Alzheimer’s and epilepsy, TAU researchers find
In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.
Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain’s activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.
“This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain,” says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer’s. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer’s patient may help increase cognition and combat memory loss.
A maze of memory loss
The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.
In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.
These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.
Correcting neuronal processes
In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer’s patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer’s disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.
Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. “We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing,” he says.
