University of California, San Francisco

Sleep in early life may play crucial role in brain development

University of California, San Francisco researchers are reporting direct evidence that sleep in early life may play a crucial role in brain development.

Their study, the cover story in the April 26 issue of Neuron, indicates that sleep dramatically enhances changes in brain connections during a critical period of visual development in cats, says the lead author of the study, Marcos G. Frank, PhD, a postdoctoral fellow in the laboratory of senior author Michael P. Stryker, PhD.

The capacity for "change," or growth and strengthening, of connections between nerve cells is the basis of development in the brain. The elaboration and refinement of neural circuitry continues to a lesser extent in the adult brain. The process of growth, known as plasticity, is believed to underlie the brain's capacity to control behavior, including learning and memory. Plasticity occurs when neurons are stimulated by events, or information, from the environment.

In their study, the researchers examined the effect of sleep on brain plasticity after cats experienced an environmental challenge. They determined that animals allowed to sleep for six hours after the period of environmental stimulation developed twice the amount of brain change as those cats kept awake during that time. The animals that were allowed to sleep even had slightly more brain change than the animals whose environmental challenge continued during the additional six hours.

The findings provide strong evidence, says Stryker, UCSF professor and chair of the Department of Physiology and a member of the UCSF Keck Center for Integrative Neuroscience, that a function of sleep is to help consolidate the effects of waking experience on cortical plasticity, converting memory into more permanent and/or enhanced forms.

"This is the first direct evidence that sleep modifies the effect of environmental stimuli on the development of new brain connections," says Frank.

While the study focused specifically on the impact of sleep on neuronal remodeling during the critical period for visual development in the cat, the researchers believe the finding has broader implications, not just for plasticity during development in other brain structures, but for plasticity in the adult brain.

If this is shown to be the case, sleep could prove an important part of the strategy for preparing for such challenges as exams. "The fact that sleep provoked slightly more plasticity than double the amount of exposure to experience [when cats remained awake in a lit room] suggests that if you reviewed your notes thoroughly until you were tired and then slept, you'd achieve as much plasticity, or 'learning,' in the brain as if you'd pulled an all-nighter repeating your review of the material," says Stryker.

Significantly, the researchers determined that the amount of plasticity in the brain depended on the amount of sleep known as non-rapid eye movement, a deep, quiet, slumber marked by large, slow brain waves. This is the sleep that a person falls into when he or she first goes to sleep and which accounts for half of sleep in animals of this age. Non-REM sleep alternates with periods of rapid eye movement, or so-called "dream" sleep, a period marked by rapidly changing brain waves and rapid bursts of eye movement.

This discovery offers direction for examining the two major hypotheses for how sleep impacts plasticity. One theory is that patterned neuronal activity following a period of environmental stimulation is replayed during non-REM sleep, strengthening neuronal connection changes. The alternative theory, which could also work in conjunction with the first, is that powerful growth factors, such as neurotrophins, which are known to be necessary for cortical plasticity, are released during non-REM sleep.

"Right now we don't know if these neurotrophins are released during sleep. We do know that other growth factors are released during sleep and we also known that these neurotrophins play a role in learning and making the synapses of the brain stronger and weaker," says co-author Naoum P. Issa, PhD, a postdoctoral fellow in the Stryker lab.

In either case, the new evidence that sleep appears to play a significant role in brain development puts researchers an important step closer to solving a mystery that has persisted for decades. "Every animal sleeps - even flies may have a state like sleep. But despite great progress in our understanding of the regulation and neurobiology of sleep, as well as the consequences of sleep loss on human performance, why the brain needs sleep has remained a mystery," says Frank.

"Speculation has ranged from evolutionary theories - we need sleep to prevent us from wandering out of our caves in the dark or sleep is just a way of keeping us inactive for period of time when goblins or saber tooth tigers are out - to theories having to do with the function of neural networks," says Stryker.

Researchers have known that in early development birds and mammals, including humans, sleep as much as three times the amount as adult birds and mammals. And they have long suspected that neuronal connections are remodeled during sleep. Previous studies in humans have shown that sleep and sleep loss influence learning and memory - two processes thought to depend on neuronal plasticity. And studies have shown that animals and humans deprived of sleep do not perform well on memory tasks. Other studies in rodents, birds and humans have suggested that neuronal activity initiated while awake is reactivated and possibly consolidated during subsequent sleep.

Other studies have shown that sleep and sleep loss modify the expression of several genes and gene products that may be important for synaptic plasticity; that certain forms of long-term potentiation, a neural process associated with the laying down of learning and memory, can be elicited in sleep, suggesting synaptic connections are strengthened during sleep; and that sleep amounts are very high and undergo dramatic modifications during developmental periods of heightened synaptogenesis and synaptic plasticity.

But while these findings together provide strong, suggestive evidence that synaptic circuits are modified during sleep the current study provides the first direct evidence that sleep and sleep loss modify experience-dependent changes in synaptic plasticity.

"The significance of our study is that we examined a system in which we know a great deal about the neural inputs and the outputs - we know how information gets into the visual cortex from the two eyes, how it changes during normal development, and we know a lot about what goes on in the circuitry to cause plasticity in this system, and to cause the loss of response to the eye after monocular deprivation," says Stryker.

"Among other things, now we can begin to examine to what extent the mechanisms inherent in sleep are distinct from those governing cortical plasticity during wakefulness. We should also gain general insights into plasticity."

To tease out the impact of sleep on plasticity during early brain development, the researchers established a model in which they measured in cats the response of neurons of the visual cortex to an environmental challenge -vision blocked in one eye for six hours. The visual deprivation initiates a rapid remodeling of neural circuitry known as ocular dominance plasticity. The researchers then examined the impact of sleep on the long-term effects of those changes by using brain imaging and making electrical recordings from brain cells.

First, in one set of cats they took a measurement of the brain change, or plasticity, immediately following the period of visual deprivation. Then, in the other three sets of cats, they examined the relative effects of sleep or lack of sleep on the initial plasticity. This is where the provocative findings were made, says Frank. The UCSF team determined that animals allowed to sleep for six hours after the period of visual deprivation developed twice the amount of brain change as those cats kept awake in a dark room during those six hours. The animals allowed to sleep also had twice the amount of change as the cats evaluated immediately following the period of visual deprivation. Finally, the cats allowed to sleep even had slightly more brain change than those animals who were kept awake in a light room with continued visual stimulation through one eye and whose brains had therefore had had twice as much time to respond to the light stimulus with just one eye open.

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The study was funded by the National Institutes of Health and the National Research Service Awards.