The brain stores information over time through memory. Making memories involves three distinct but overlapping steps: acquisition (getting information), consolidation (storing information), and retrieval (recalling information at a later time).
Sleep deprivation interferes with memory processes, but the exact mechanisms remain unknown. To better understand the impacts of sleep deprivation on memory, these researchers conducted experiments to prompt memory retrieval in sleep-deprived mice.
The results show that sleep deprivation interferes with memory consolidation, making it more difficult to retrieve information later. Impaired memory consolidation can be reversed in mice by stimulating neurons and by using medications. Future research will continue to improve our understanding of memory in both mice and humans.
How many of you get enough sleep each night? The American Academy of Sleep Medicine recommends that children ages 6-12 years get 9-12 hours of sleep per night and adolescents ages 13-18 years get 8-10 hours of sleep per night. When the Centers for Disease Control and Prevention (CDC) analyzed student responses about sleep in 2015, they found that 6 out of 10 middle school students and 7 out of 10 high school students did not get enough sleep.
With so many obligations and distractions—like homework, family commitments, and social media, just to name a few—a restful night of sleep can be hard to come by. Yet sleep is critically important. That is why we spend about one third of our lives asleep. Research shows that students who consistently lack sleep are at higher risk of health and behavioral issues including
diabetes,
obesity,
attention problems, poor mental health, and injuries.
“Before you pull an all-nighter, you should know that lack of sleep also impairs memory,” explained Dr. Pim Heckman, Assistant Professor at the Faculty of Psychology and
Neuroscience
at Maastricht University in the Netherlands. “If you stay up all night studying just before a test, you might be able to cram all the information you need in your brain to pass, but it is unlikely you will be able to retain much of what you learned afterwards for, say, the final exam.”
Making Memories
To understand why this happens, let us explore what neuroscientists know about the brain and memory. The brain is part of the
nervous system,
which also includes the
spinal cord
and
nerves.
Memory refers to the storage of information in the brain over time. At the broadest level, memory can be broken down into two categories: conscious and unconscious. Conscious memory is the remembering of concrete information. For example, Washington D.C. is the capital of the United States. Unconscious memory refers to actions like riding a bike that you do remember but not in a way that it is associated with a concrete piece of information. This research is focused on conscious memory.
The main area of the brain associated with conscious memory is called the
hippocampus.
The name “hippocampus” comes from the Greek and Latin word for “seahorse.” The brain structure was named for its similar appearance to the sea creature.
The hippocampus is divided into subregions that are involved in different aspects of memory. Memory formation begins in the subregion called the dentate gyrus (DG), where information enters the hippocampus.
Neurons in the DG are activated when you learn something new. The cluster of DG neurons related to a specific learning experience is known as an
engram.
In other words, an engram is a group of neurons that together store one memory. Neurons in the engram produce different proteins in the process of memory formation.
One protein critical to initial memory formation and other memory processes is cyclic adenosine monophosphate or cAMP, a cell signaling molecule. Good sleep promotes memory by increasing the levels of cAMP available for memory processes. Once cAMP has completed its function in memory formation, it is degraded by the enzyme, phosphodiesterase 4 (PDE4). Sleep deprivation impairs memory by increasing levels of PDE4, thus decreasing the levels of cAMP available for memory processes.
The process of making memories is divided into three different actions: acquisition (getting information), consolidation (storing information), and retrieval (recalling information at a later time).
Researchers
hypothesize that acquisition, consolidation, and retrieval occur through distinct, overlapping mechanisms that are regulated through shared pathways, such as cAMP signaling.
Here is another way to think about memory: throughout the day we learn all kinds of information (acquisition), which is temporarily stored in the hippocampus in what is called short-term memory. While you sleep, most of your short-term memory gets cleared in preparation for the day ahead, while some information (the important experiences) is transferred from short-term to long-term storage (a process called consolidation). This stored information can be used at a later time (retrieval).
Figure 6. The process of making memories involves acquisition (short term memory (STM)/working memory (WM)), consolidation to intermediate memory (IM) and long-term memory (LTM), and retrieval. Information reaches the senses (sensory store) before attention to the information leads to its acquisition. Time periods refer to the average time information is retained.
[Source: Dr. Heckman, based on
Kelly et al 2020,
Fig 1]
“If you think of your brain as a laptop,” explained Dr. Heckman, “your short-term memory is like your temporary storage file, and every night those files get cleared, except for the most important ones that get backed up onto the hard drive.” When you remember something, you filter through the files stored on the hard drive until you find the one you are looking for. Even if you cannot remember something right away, it is possible it will come back later. For example, when you suddenly lose your train of thought, go do something else, and in the process of doing something else the original thought comes back to you. Or you hear a song that you definitely recognize but cannot remember the lyrics or the title or the singer—and then pieces of it come back to you later on.
Investigating the Connection Between Sleep and Memory
We know that lack of sleep interferes with memory. However, the particular memory processes affected—consolidation or retrieval or a mixture of both—remain unknown. Do memories formed under sleep-deprived conditions never get consolidated? Or are some parts consolidated insufficiently so the memory retrieval process is impaired?
Dr. Heckman and colleagues designed experiments to distinguish between impairments in memory consolidation and memory retrieval. They conducted these experiments using healthy mice, taking advantage of mice’s innate curiosity and eagerness to explore new environments.
The researchers used an object-location memory (OLM) task to test the effects of sleep impairment on mouse memory. In this task, the mice were placed in an environment with two objects and allowed to explore for ten minutes. This is the learning or acquisition phase.
Figure 7. Video of mouse performing the object-location memory task.
[Source: Dr. Heckman]
The next day, the mice were placed back in the same environment, but one of the objects had changed location. If the mice remembered the environment from the day before, they would gravitate towards the object that had changed location. If not, they would behave just as before. In this way, the researchers used the OLM task to test the memories of the mice under fully rested and sleep-deprived conditions.
To show the test was effective, the researchers performed this test on control mice. The mice were shown the OLM task, given a full nights’s sleep, and then shown the same environment with one object moved. As expected, the mice were much more interested in the newly located object, indicating that they remembered the environment. The researchers conducted a similar process with sleep-deprived mice that were not allowed to sleep for the first six hours of their sleep cycle. The researchers made sure the sleepy mice stayed awake by gently touching the cage any time the mice wanted to doze off. Under sleep-deprived conditions, the mice were exposed to the same environment with one object moved, but based on their behavior they clearly did not remember it.
Next, the researchers wanted to know whether they were able to stimulate the mice to remember the environment. New developments in neuroscientific research allowed them to do this. Dr. Heckman and colleagues used a combined optogenetics and labeling approach. Optogenetics is a technique that uses light to activate neurons. This activation is made more specific by a labeling approach that captures only a single engram, the neurons involved in a specific memory. Used together, these techniques allowed the researchers to stimulate precisely the neurons of the DG engram that encoded the memory of the new environment in the acquisition phase of the experiment.
After the mice experienced sleep deprivation overnight, the researchers stimulated the neurons in the mice that had encoded the memory from the previous day and exposed them to the OLM task again. Without any intervention, the mice did not recognize the environment. However, with the intervention of the DG engram stimulation five minutes prior to exposure, the mice were able to retrieve their memories and recognize the new location of the object. The researchers tested this intervention again after five days and eight days of sleep-deprived training and found that DG engram stimulation continued to prompt memory retrieval in the mice.
These outcomes shed light on the researchers’ question about whether sleep loss leads to a storage (consolidation) or retrieval problem. The results provide evidence that some information was stored in the neurons of the engram. This means that sleep loss after learning does not lead to a storage problem (where nothing is stored), but to a retrieval problem.
To better understand the specificity of DG stimulation necessary for memory retrieval, the researchers conducted a similar set of experiments. This time, though, they used optogenetic simulation on random DG neurons outside of the engram. This approach did not lead to memory retrieval. These findings confirmed that only stimulation of the DG neurons in the engram encoding a specific memory would result in memory retrieval.
“We were so excited that we were able to retrieve these memories that are otherwise lost to sleep deprivation,” commented Dr. Heckman. “But this has little application to memory retrieval in humans.” In order to make these results more relevant to humans, the researchers turned to the medication roflumilast.
Roflumilast inhibits the enzyme PDE4 and is approved by the U.S. Food and Drug Administration for asthma treatment. This is because, like the brain, the lungs contain cAMP and PDE4. In the lungs, cAMP and PDE4 are related to inflammation, so roflumilast is used as an anti-inflammatory treatment. In the brain, inhibition of PDE4 by roflumilast increases the amount of cAMP available for memory processes. It is currently being studied in
clinical trials
for use in patients with
Alzheimer’s disease.
The researchers conducted similar trials with sleep-deprived mice, this time using the intervention of roflumilast 30 minutes before the second day of their trial to stimulate the memory engram instead of using optogenetics. They noticed similar effects on memory retrieval using either DG engram stimulation or roflumilast. However, the memory retrieval induced by these interventions did not last long.
To make the retrieval last longer, the researchers used both interventions at the same time. Using both DG engram stimulation and roflumilast, the researchers showed that they could successfully promote memory retrieval for up to two days in sleep-deprived mice.
Together, these studies demonstrate that sleep deprivation disrupts the function of neurons in the hippocampus by interfering with cAMP signaling. Furthermore, treatments like roflumilast, which increase cAMP in the hippocampus, can be successfully used to prevent and treat memory problems after sleep loss in mice.
Directions for Future Research
“This is a really important step in our understanding of how sleep deprivation affects memory,” Dr. Heckman concluded. The fundamental question of whether impaired memory due to sleep deprivation is a problem of memory consolidation or retrieval has been answered. The memories are consolidated to some extent during the night, but not enough to be properly retrieved.
There are two main directions for future research. First, the researchers want to understand the mechanisms behind their results. They know that stimulating neurons of the DG engram and giving roflumilast can prompt memory retrieval, but they do not yet know exactly how. In addition, the researchers hypothesize that the two interventions function differently and seem to work in a complementary fashion to extend the duration of memory recall. Second, the researchers are actively working to develop experiments to test avenues to prompt memory retrieval in humans.
Dr. Pim Heckman is Assistant Professor of Psychology and Neuroscience at Maastricht University in the Netherlands. His research focuses on the neurobiology of memory and memory impairment with the goal of improving the lives of people with memory problems. When not in the laboratory, Dr. Heckman enjoys cycling and is involved in multiple community service projects such as bringing science education to high school students and planning activities for students with disabilities.
For More Information:
Bolsius, Y. et al. 2023. “Recovering object-location memories after sleep deprivation-induced amnesia.” Current Biology, 33: 298-308. http://dx.doi.org/10.1016/j.cub.2022.12.006
