Sleep: memory's careful custodian

Anyone who’s had a poor night’s rest can attest that lack of sleep impairs cognition, especially memory. But researchers don’t really know why, and unknowns like these complicate the scientific understanding of memory-related conditions like Alzheimer’s disease (AD) and other types of dementia, which affect more than 5 million Americans, according to the Alzheimer’s Association.

Yale researchers are using neurological imaging and such monitoring tools as functional magnetic resonance imaging (fMRI), electrophysiology, and electroencephalography (EEG) to explore different aspects of memory and the various ways sleep influences memory development, storage, and degeneration. Their findings could eventually improve how doctors identify, diagnose, treat, and even potentially prevent an array of neurological conditions, including AD.

Most research shows that sleep plays a critical role in the formation and storage of long-term memories. And different types of memories seem to be processed in different brain regions during certain stages of sleep, especially such phases of deep sleep as rapid eye movement (REM) and slow-wave sleep (SWS).

George Dragoi, MD, PhD, assistant professor of psychiatry and of neuroscience at Yale School of Medicine, studies how episodic memories—memories of specific events or experiences—form and develop. Episodic memories complement semantic memories based on facts and general information. They primarily involve parts of the hippocampus and neocortex, and require two separate phases: encoding and consolidation.

During encoding, the brain samples stimuli from the outside world and rapidly encodes them within sequences inside networks of neurons in the hippocampus. Dragoi said that when activated, these connected neurons fire one after another, fleshing out the details of the memory. The amygdala seems to attach emotional significance to these memories or details as appropriate at some point along the way.

In consolidation, a process that researchers think occurs during sleep, particularly SWS, encoded sequences are integrated by chemical connections into new and existing neuronal knowledge networks, and filed for long-term storage in the neocortex. That means that sleep is essential for episodic memory formation, and likely for most types of memory formation. “Encoding is certainly required but not sufficient for [episodic] memory formation,” Dragoi explained. “If encoded information is not consolidated after exposure to new experiences, you simply won’t remember it.”

But why is sleep so essential to consolidation? Possibly because sleep seems to offer optimal conditions for consolidation, providing periods of reduced external stimulation and increased levels of neurotransmitters that promote communication between the hippocampus and the neocortex.

Sleep may also give the brain time to make space for new memories by removing or reducing the strength of neural links tied to memories that are no longer useful. During human development, a process called pruning culls excess neuronal links. “Like in a tree you cut the branches or remove connections in the brain long term,” Dragoi explained. “In adults, the structure of the connections is already built and the strength of these connections can be reduced or increased over time.”

Based on his work and that of others, Dragoi thinks that sleep may aid this mental tidying-up process, scaling back increased neuronal activity from exposure to specific stimuli and maintaining homeostatic balance in the brain. He adds that some studies also show that the brain seems to produce the templates for proteins according to a kind of internal clock, but that these templates aren’t translated into actual proteins without sleep. “This seems to further link the need for sleep with healthy synaptic function and protein production,” he concluded, a finding that could have wide-ranging therapeutic applications.

The question of how memories are lost remains a major focus of memory and sleep research. Using techniques like MRI and EEG, Helene Benveniste, MD, PhD, professor of anesthesiology, and her colleagues have found that sleep may allow the brain critical time and conditions to remove waste metabolites. The accumulation of certain metabolites in the brain, in particular beta-amyloid and abnormal tau proteins, seems to increase the risk of cognitive disorders like AD.

Benveniste said researchers once thought the primary purpose of sleep is to allow rest and memory processing. “Now I think we’re understanding another purpose of sleep may also be to give the brain time to clean itself,” she said.

In 2013 Benveniste helped to initially describe the glymphatic system, a waste-removal pathway in the brain that acts like the lymphatic system but relies largely on astroglial brain cells. In a nutshell, the glymphatic system allows cerebrospinal fluid to flow into the spaces around arteries before passing through aquaporin-4 (AQP4) water channels into brain tissues, where it mixes with fluids and metabolic waste around cells, and then moves out of brain tissues into the space surrounding veins for clearance through the lymphatic or circulatory system.

Benveniste and others have found evidence that healthy glymphatic function may reduce the effects of risk factors implicated in cognitive conditions like AD by facilitating metabolic waste clearance in the brain. A study she worked on in 2018 concluded that even one night of sleep deprivation increases beta-amyloid burden in the right hippocampus of adults.

Some studies, including several Benveniste co-authored, also show that many people with AD, or cognitive impairment from vascular dementia or small-vessel disease, experience glymphatic dysfunction. The system also seems to be most efficient during sleep, in particular slow-wave sleep (SWS). “By far the biggest differences we’ve seen in glymphatic transport rates are when people go from being awake to asleep,” Benveniste explained, adding that medications which manipulate arousal states like anesthetics also seem to heavily influence glymphatic function.

Factors that influence circulation also appear to affect glymphatic function, including pulse rate, breathing rate, and some metabolic conditions. Benveniste and others have also found that glymphatic efficiency improves when rats and other subjects sleep lying on their sides or backs. She noted these positions are the preferred sleeping posture in many animals, including humans.

“This is something I find very interesting clinically,” Benveniste said. “People in the ICU that have trouble swallowing or protecting their airways or have brain trauma are often kept seated with the head raised—even while sleeping. Sometimes we even interrupt sleep frequently for checking up on them.” With a better understanding of sleep and glymphatic function, Benveniste explained, practices like these may be revised.

As sleep’s effects on memory become clearer, researchers are studying how sleep interventions affect elements of cognition, especially memory difficulties. Hilary Blumberg, MD, the John and Hope Furth Professor of Psychiatric Neuroscience and the director of Yale’s Mood Disorders Research Program, is the principal investigator of a study exploring how behavioral techniques to improve sleep influence cognitive and emotional aging in women. She is collaborating in this research with Carolyn M. Mazure, PhD, the Norma Weinberg Spungen and Joan Lebson Bilder Professor in Women’s Health Research and director of Women’s Health Research at Yale, in a study funded by Women’s Health Access Matters.

Women experience higher rates of sleep disturbances than men, especially as they age—something Blumberg helped link to the fact that women’s frontotemporal brain circuitry seems to be more sensitive to the negative effects of stress than men’s. Frontotemporal brain circuitry involves parts of the amygdala and hippocampus, the brain regions most responsible for cognitive and emotional functioning.

Blumberg said that a focus of her study is teaching people strategies they can use throughout their lives to regularize sleep and other daily activity patterns, which may improve emotional regulation, stress resilience, and cognitive functioning. Focusing on women aged 50 years and over, the study employs a modified version of social rhythm therapy called SLEEP-SMART (Sleep Self-Monitoring And Regulation Therapy), with sessions that review daily activities and interactions and then modifies them to increase regularity. This review involves tracking such details as the person someone first comes into contact with each day; mealtimes; and all other daily activities that influence biological rhythms. It also involves using simple self-regulating activities like getting exposure to sunshine before anything else; scheduling important daytime activities; and of course, turning off technological devices before bed.

Study subjects participate in MRI scans before and after the 12-week intervention, which along with other data will identify changes in emotional regulation, cognition, and brain circuitry. These data will allow the team to assess the impact of SLEEP-SMART interventions on cognitive and emotional health, as well as blood and brain biomarkers considered risk factors for AD and related dementias (ADRD).

Researchers have a lot of work to do before they reveal the full intricacies of memory and the extent to which sleep shapes this defining neurological process. Dragoi and his team are currently following up on their 2019 work, which used electrophysiology to uncover three developmental stages that allow rodent brains to form neuronal sequences used in memory formation. The team hopes to understand what controls shifts between these stages, which could improve the scientific understanding of conditions in which memory is altered, or when internally generated representations like memories dominate the cognitive state, as in autism or schizophrenia.

Blumberg and her team have seen preliminary evidence that regularizing sleep patterns can improve the functioning of the brain circuitry that regulates emotion. She hopes to expand this work, writing that “teaching healthier, more regular sleep and daily activity patterns is something that could be disseminated globally and have a wide impact in improving emotional and cognitive health.”

Benveniste said that researchers will likely need a better understanding of the relationships among glymphatic function, memory, and sleep before therapeutically manipulating these processes. She added that researchers specifically need to know whether slow-wave sleep really boosts waste clearance in the brain. “If this is the case,” she explained, “this is where the focus should be going forward.”