How Sleep Helps Us Remember and Forget

Post by Amanda McFarlan

What’s the deal with sleep?

Humans spend approximately one third of their lives sleeping, so it is no surprise that we’re curious about it! Sleep has a wide variety of benefits, like repairing and regenerating tissues in the body, improving cognitive and physical performance, and consolidating memories. On the other hand, a chronic lack of sleep can put us at risk of developing health problems like cardiovascular disease, high blood pressure, diabetes, and depression. So, what happens when we sleep? Every night, when our heads hit the pillow, we enter into the first stage of ‘non-Rapid Eye Movement’ (non-REM) sleep. Non-REM sleep consists of 4 stages, with Stage 1 being the lightest sleep stage and Stage 4 being the deepest. Your body moves through the 4 stages of non-REM sleep and finally through REM sleep in a cycle that takes approximately 90 minutes, and this cycle is repeated throughout the night. Non-REM and REM sleep are characterized by different brain activity patterns, with non-REM sleep creating slow waves in its deepest stages, called ‘slow-wave sleep’, and REM sleep generating activity patterns that resemble wakefulness. The role of non-REM and REM sleep in the transfer and long-term storage of memories, known as memory consolidation, has been studied for many years. Here, we will discuss how sleep helps us remember or forget, as well as what goes wrong when we don’t sleep.

How does sleep help us remember?

Evidence strongly suggests that sleep is integral to memory consolidation. For example, a behavioural study, in which participants performed a visual task, a motor sequence task, and a motor adaptation task, found that participants’ performance was greatly improved if they had a full night’s sleep compared to those that did not sleep. The degree of performance improvement for each type of task was dependent on improved sleep in different stages in the sleep cycle. These findings suggest that non-REM and REM sleep both play an important role in memory consolidation. In line with this, other studies have shown that intensive learning of a new task is followed by increased time spent in REM sleep, resulting in subsequent task improvement, as well as the amplification of slow waves during non-REM sleep. Sleep results in a reactivation of cells in the hippocampus, which subsequently reactivate representations of memory in the cortex, also known as an engram. Over time, after many reactivations, these memories become distributed and consolidated within the cortex. 

Interestingly, research has shown that while we’re sleeping there is increased activity in the same hippocampal place cells (neurons that are activated when moving through specific locations in the environment) that were active throughout the day. This reactivation of hippocampal place cells during REM sleep follows a theta frequency band pattern of firing, hypothesized to be critical for memory consolidation. This hippocampal activity is mediated by neurons that release the neurotransmitter acetylcholine in the hippocampus. Acetylcholine, which plays a major role in altering the strength of synaptic connections, crucial for memory, is known to be elevated during REM sleep. REM sleep has also been associated with the upregulation of the expression of several calcium-dependent genes that are thought to be involved in synaptic plasticity and memory consolidation. 

Compared to REM sleep, the conditions in non-REM sleep are less ideal for promoting synaptic plasticity. For example, acetylcholine and calcium-dependent genes are expressed at low levels or are absent altogether during non-REM sleep. However, researchers have proposed that non-REM sleep might be important for the later stages of memory consolidation, rather than the initial conversion of short-term memories to long-term memories. In support of this, protein synthesis, which is required for long-term but not short-term potentiation (strengthening) of synapses, is increased during non-REM sleep. Therefore, the induction of protein synthesis during non-REM sleep may act to strengthen the synapses that were sufficiently potentiated during wakefulness. 

Although the majority of research on sleep and memory focuses on the role of the hippocampus in memory consolidation, a recent study has provided evidence that the thalamus might also play a role in memory consolidation during sleep. In this study, memory encoding (when memories are initially stored) during a visual task was shown to increase the activity of sensory relay nuclei of the thalamus in mice. Following a night of sleep, the primary visual cortex also showed evidence of a potentiated response to the visual task. Together, these findings suggest that task-related information may be passed from the thalamus to the primary visual cortex, resulting in the formation of a corresponding memory during sleep.

How does sleep help us forget?

Sleep research is centered around how we remember. However, sleep arguably plays just as important a role in the process of forgetting memories. The hippocampus serves as a temporary storage area for newly formed memories until they can be consolidated and integrated into long-term memory storage in the cortex. As a result, the hippocampus must be able to unlearn memories that have already been consolidated or memories that are not pertinent in order to store new memories. Research has shown that in addition to helping with memory consolidation, sleep is also important for unlearning memories. Studies in rats have shown that following sleep, there are widespread reductions in dendritic spines (protrusions on the dendrite that form synapses with nearby neurons) in the cortex as well as a reduction in receptors on glutamatergic neurons that are critical for memory and learning.

Norepinephrine and serotonin are two neurotransmitters in the brain that are associated with the enhancement of synaptic plasticity. During REM sleep, however, norepinephrine and serotonin signaling is suppressed, suggesting that REM sleep may allow for the depotentiation — or weakening — of synapses.  

What happens when we don’t sleep?

We all know how difficult it is to get through the day after a sleepless night. Suddenly, concentrating on what was previously a trivial task can become very challenging. Neuroimaging data has shown that sleep deprived individuals recruit more brain areas while performing the same cognitive task compared to individuals who slept normally. Moreover, brain imaging studies have revealed that hippocampal function is greatly reduced following one night of sleep deprivation, which suggests that losing sleep may actually disrupt our ability to learn new things. Sleep deprivation studies in rats have demonstrated the importance of REM sleep for learning as well as the induction and maintenance of long-term potentiation of synapses during learning. Additionally, REM sleep deprivation was shown to impair learning-dependent neurogenesis (the formation of new neurons) in the hippocampal dentate gyrus, which can impact future learning. The role of REM sleep for learning and memory is particularly relevant for individuals who are treated for depression with antidepressants, since these medications can greatly reduce the amount of time spent in REM sleep and may potentially have consequences on the efficacy of memory consolidation.

How can we get a good night’s sleep?

Given what we know about the role of sleep for learning and memory, it’s important to ensure that we get a good night’s sleep. However, with the challenges of daily life, this is not always an easy feat. First, it is important to establish a regular sleep schedule where you go to sleep and wake up around the same time each day, even when traveling or on the weekends. This habit can reinforce your body’s circadian rhythms, which helps your body to prepare for sleep and wakefulness more efficiently. Second, it is important to avoid using electronic devices before bed, like watching television or using your phone or tablet. The blue light that is emitted by these devices tricks our bodies into thinking it is daylight, and, as a result, our bodies produce lower levels of the hormone melatonin which promotes sleep. Third, use what you know about the science of sleep cycles to your advantage by timing your sleep in 90-minute intervals. For example, by setting your alarm for 7.5 hours of sleep (5 sleep cycles x 90 minutes each) you may actually feel more refreshed than if you slept for 8.5 hours and were awakened during the middle of a deep stage of sleep. Finally, avoiding caffeine and naps late in the afternoon or evening, as well as avoiding large meals or exercise right before bed may help to promote better sleep. 

Now, time to consolidate all of this learning with a good night’s sleep!

Feld, G.B., & Born, J. Sculpting memory during sleep: concurrent consolidation and forgetting. Current opinion in neurobiology, 44, 20–27 (2017). https://doi.org/10.1016/j.conb.2017.02.012

Klinzing, J.G., Niethard, N. & Born, J. Mechanisms of systems memory consolidation during sleep. Nat Neurosci 22, 1598–1610 (2019). https://doi.org/10.1038/s41593-019-0467-3

Poe, G. R., Walsh, C. M., & Bjorness, T. E. Cognitive neuroscience of sleep. Progress in brain research, 185, 1–19 (2010). https://doi.org/10.1016/B978-0-444-53702-7.00001-4

Stickgold, R. Sleep-dependent memory consolidation. Nature 437, 1272–1278 (2005). https://doi.org/10.1038/nature04286

Non-Invasive Electrical Brain Stimulation Reduces Obsessive-Compulsive Behaviours

Post by D. Chloe Chung

What's the science?

Obsessive-compulsive (OC) behaviours are characterized by excessive, unreasonable thoughts and repetitive behaviours. While the exact underlying mechanisms are unclear, OC behaviours may result from excessive habit learning. Habit learning involves the brain’s medial orbitofrontal cortex (OFC) which is connected to the brain’s reward network. This week in Nature Medicine, Grover and colleagues show that non-invasive OFC stimulation, using a high-frequency current to target the high-frequency neural activity associated with reward processing, can modulate OC behaviours.

How did they do it?

In the first experiment, the authors wanted to determine the role of high-frequency, beta-gamma rhythms in reward learning. To do this, they selected a monetary reinforcement learning task that included two trial types – “reward trials” in which the participants earn money (versus not earning any) upon making an optimal choice (choosing the correct image), and “punishment trials” in which the participants lose money (versus not losing any) upon making an incorrect choice (choosing the wrong image). Before the actual task, beta-gamma frequency band activity was measured for 60 participants using electroencephalography (EEG), while the participants learned how to associate visual stimuli with monetary gain and loss. Next, the participants randomly received either control (“passive” sham or “active” alpha frequency of ~10Hz) or personalized beta-gamma neuromodulation (~27Hz on average) and completed the reinforcement learning task for 30 minutes each before, during, and after the neuromodulation (90 minutes total). 

In the second experiment, the authors aimed to evaluate whether chronic beta-gamma neuromodulation of the OFC can impact OC behaviours. To test this, 64 participants first completed a self-assessment of their OC behaviours and then received either control, alpha frequency, or personalized beta-gamma frequency for 5 days (30 minutes per day). The participants self-assessed their OC behaviours right after the last neuromodulation, as well as 1, 2, and 3 months post-neuromodulation. After these two experiments, the authors analyzed the relationship between intrinsic beta-gamma rhythms and a) changes during the reward learning and b) OC behaviours caused by beta-gamma neuromodulation.

What did they find?

In the first experiment, the authors observed that the reward behaviour was altered upon personalized beta-gamma neuromodulation targeting the OFC. Participants made fewer optimal choices during the reward trials of the monetary reinforcement learning task, while no change was observed in either control condition. Importantly, beta-gamma neuromodulation changed behaviours during the reward trials but not during the punishment trials, indicating that beta-gamma frequency specifically modulates reward-related behaviours. These neuromodulation-induced changes in the reward behaviour were found to be reversible, as the participants showed a similar rate of making optimal choices both before and after the neuromodulation. 

In the second experiment, the authors found that the 5-day beta-gamma neuromodulation successfully reduced obsessive-compulsive behaviours for three months (based on self-assessment). Interestingly, participants with more severe OC symptoms displayed a more drastic reduction in their compulsive behaviours after neuromodulation. Lastly, by comparing the two experiments, the authors found that convergent mechanisms exist between both neuromodulation-regulated reward and OC behaviours.

What’s the impact?

This study demonstrates that high-frequency neuromodulation can effectively regulate reward learning. Further, this work supports the link between reward learning and OC behaviours by highlighting shared mechanisms between the two. Findings from this study strongly suggest potential clinical benefits of personalized neuromodulation for obsessive-compulsive disorder (OCD) patients. It will be interesting for future studies to use additional methodologies, such as neuroimaging, to discover how neural processes are altered by beta-gamma neuromodulation.

Grover et al. High-frequency neuromodulation improves obsessive-compulsive behavior. Nature Medicine (2021). Access the original scientific publication here.

The Effect of Nucleus Accumbens Medium Spiny Neuron Subtypes on Stress-Induced Sleep Changes

Post by Lincoln Tracy

What's the science?

Stress is a key contributor to both major depressive disorder and post-traumatic stress disorder. These two conditions have common symptoms, including diminished motivation and sleep dysregulation. Chronic social defeat stress (CSDS) is commonly used to study altered motivation in rodents. Medium spiny neurons within the nucleus accumbens (NAc) release dopamine and contribute to altered motivation in CSDS. Although CSDS can disrupt sleep in mice, the NAc cells’ role in sleep disruption is unknown. This week in Biological Psychiatry, McCullough and colleagues used chemogenetics (the use of chemicals to activate or deactivate certain cells) to selectively manipulate the function of the two dopamine-expressing, medium spiny neuron populations in the NAc to explore the neural mechanisms responsible for the effects of stress on sleep in mice.

How did they do it?

The authors infused viral vectors into the NAc, which would later be activated through clozapine administration in drinking water. Electroencephalography (used to measure brain activity) and electromyography (used to measure muscle activity) wires were attached to the skull and sutured into the trapezius muscle (respectively), while transmitters were implanted into the abdomen of mice to quantify sleep, locomotion, and body temperature. After recovery, mice underwent 10 days of CSDS. Two cohorts of mice were used: one to assess sleep, and the other to assess stress susceptibility. The effects of activating or inhibiting two NAc medium spiny neuron subtypes, D1 and D2 receptor-expressing neurons, were examined over a 10-day period in the former cohort. The latter cohort underwent a battery of behavioral tests: social interaction tests, open field tests, and elevated plus maze tests.   

What did they find?

First, the authors found that chronic inhibition or excitation of medium spiny neurons expressing D1 or D2 receptors in the NAc had unique effects on sleep. Inhibition of medium spiny neurons expressing D1 receptors mimicked the effects of CSDS on rapid eye movement (REM) sleep (i.e., it disrupted sleep) without affecting slow-wave sleep. Activation of the D1-medium spiny neurons had the opposite effect. Conversely, activation of D2-medium spiny neurons increased the time spent in slow-wave sleep. There was no effect of D2-medium spiny neuron activation or inhibition on any of the REM sleep metrics. Taken together, the combined effects of inhibiting D1-medium spiny neurons and activating D2-medium spiny neurons on sleep mirror that of CSDS. They also found that, while activating or inhibiting D1-medium spiny neurons did not reliably alter the daily rhythms in body temperature, activating D2-medium spiny neurons decreased average body temperature. Finally, behavioral testing revealed that D1-medium spiny neuron inhibition increased susceptibility to stress, while D1-medium spiny neuron activation promoted stress resilience, suggesting that they have opposing behavioral effects. 

What's the impact?

McCullough et al. have identified novel information about how stress changes neuronal circuits and leads to numerous diagnostic features of psychiatric illnesses. These findings have translational relevance, as sleep can be defined and measured consistently in both mice and humans. An enhanced understanding of the neural mechanisms underlying the common symptoms of major depressive and post-traumatic stress disorders may improve diagnoses and assist in developing novel treatments that target specific NAc neuronal populations to relieve stress-related illnesses.

McCullough et al. Nucleus accumbens medium spiny neuron subtypes differentially regulate stress-associated alterations in sleep architecture. Biological Psychiatry (2021). Access the original scientific publication here.