Inside Neuroscience: Sleep Deprivation Leads to Sex-Specific Effects and Memory Problems
Quality sleep helps with learning, mood, and memory — and poor sleep negatively affects cognition and increases disease risk. Yet more than one-third of U.S. adults sleep less than the seven hours or more needed for optimal health.
Robert Greene
“The natural thing to ask is: Why do we sleep?” said Robert Greene, professor of psychiatry and neuroscience at the University of Texas Southwestern Medical Center and moderator of a Neuroscience 2023 press conference titled, “The Sleep Debt Epidemic: Memory Problems and Sex-Specific Effects.”
Most animals have a circadian rhythm that regulates sleep. Studying the function of sleep in animals provides clues into human sleep and its effect on learning and memory.
Estrogen Regulates Sleep
In women, disrupted sleep is often associated with changes in ovarian hormones. Life stages such as pregnancy and menopause cause disruptions in circadian rhythms. Yet little is known about how hormonal changes disrupt sleep.
Jessica Mong
For decades, researchers focused on neurons’ role in sleep regulation in rodents. “We found that astrocytes are also very responsive to hormones such as estradiol,” said Jessica Mong, professor of pharmacology at the University of Maryland School of Medicine and presenting author.
Estradiol is the primary form of estrogen during reproductive years. Mong’s laboratory activated or inhibited astrocyte function in sleep-promoting brain areas in female rats to show astrocytes are necessary for mediating estradiol’s effects on sleep. Thus, there are sex-specific features to the sleep-wake cycle: estradiol promotes the transition from wakefulness to sleepiness.
As women age, estradiol decreases, leading to delayed and disrupted sleep. As such, women have a 40% higher risk of insomnia, a disorder characterized by trouble falling asleep or staying asleep. Insomnia increases the risk for many negative health effects, including breast cancer, heart disease, and diabetes. Thus, improving women’s sleep is essential for overall health.
“Ultimately, these findings may serve to uncover novel drug targets for the treatment of sleep disorders in women.” Mong said.
Sleep Deprivation Affects Memory and Learning
Although women have a greater risk of insomnia, they also have greater resilience to sleep deprivation at specific points in life, such as during reproductive years. Researchers at Florida State University compared male and female rodent brains to hone in on the mechanisms underlying sex differences in acute sleep deprivation.
The researchers deprived mice of sleep by tapping on their cages and then collected tissue samples at each stage of the mouse estrous cycle, the reproductive cycle in rodents that consists of four phases: proestrus, estrus, metestrus, and diestrus.
They found altered gene expression after sleep deprivation in two areas of the brain involved in memory, the prefrontal cortex and hippocampus. Female mice showed significantly fewer changes in hippocampal gene expression: no gene expression changes in female mice in proestrus — when estradiol levels are highest — and 99 changes in female mice not in proestrus. In male mice, approximately 630 genes associated with memory and cognition changed expression. The prefrontal cortex also showed striking differences in gene expression between males and females after sleep deprivation.
Lisa Lyons
“This suggests that there is a molecular resilience in females after acute sleep deprivation,” said presenting author Lisa C. Lyons, professor of neuroscience at Florida State University. “Females across the lifetime experience many sleep disturbance events — in order to survive, you would expect they would also have some functional resilience to sleep deprivation.”
Separately, researchers at the University of Pennsylvania looked at behavior in male mice to see how chronic short sleep (CSS) affects learning. The researchers gave mice, who are curious creatures, novel objects eight hours a day, three days a week, for two months.
Novel objects cause mice to stay awake because they want to explore the objects. After one month, CSS mice were given a spatial object recognition test where they were placed in an area with two identical objects. The mice were removed for two hours and returned after one of the objects was relocated within the area. The researchers expected mice with good spatial memory to interact with the moved object preferentially. This test was repeated monthly for one year.
Nirinjini Naidoog
Both CSS and control mice performed equally well on this hippocampal-dependent memory test at age 20 weeks. The CSS mice, however, failed to distinguish between the moved and unmoved objects by 28 weeks, whereas the control mice failed to distinguish by 52 weeks. “Memory and learning deficits, while not immediate, occur much earlier with CSS,” explained Nirinjini Naidoo, research professor of sleep medicine at the University of Pennsylvania Perelman School of Medicine and presenting author.
These findings indicate that CSS disrupts proteostasis, a process that ensures protein homeostasis (protein folding, trafficking, and degradation). Proteostasis dysfunction happens in neurodegenerative diseases, which are characterized by misfolded and aggregated proteins. “Sleep is a modifiable risk factor — we think changing sleep behavior could help delay the onset of some of these diseases. Overall, while aging does affect memory, our data indicates that CSS accelerates this cognitive decline.”
Sleep Consolidates Memories
Cephalopods interact, remember, and sleep much like we do — but their brains are very different from ours. A video of a sleeping octopus changing colors made researchers wonder if octopuses dream.
Horst Obenhaus (credit Louise Siskel, MBL)
“One of the most prominent ideas about why we sleep is that we need sleep to form long-term memories,” said presenting author Horst Obenhaus, postdoctoral fellow at Kavli Institute for Systems Neuroscience and Whitman Scientist at Woods Hole Marine Biological Laboratory. Replay, in which the brain re-enacts recent experiences, is thought to underlie memory formation.
Octopus and cuttlefish have tiny organs in their skin called chromatophores that control skin patterning and are under direct neuronal control. When not camouflaging, cuttlefish flash patterns that are unique to social interactions with other cuttlefish.
Obenhaus put two cuttlefish in a tank at a time and filmed their patterns while interacting and sleeping. Using custom machine learning algorithms, he extracted patterns to see if a cuttlefish displayed any patterns during sleep that matched patterns from the social interactions. Several partial or more abstract pattern matches suggest the cuttlefish might replay some of the experiences from the social interactions during sleep.
“The question here is if they co-evolved similar mechanisms [to humans] for consolidating memory during sleep. Learning from a different and complex nervous system architecture might teach us something about our own sleeping brains,” Obenhaus said.
