Disrupted REM Sleep Can Rewire Young Brains

In classic experiments, newborn kittens whose eyes were kept in darkness ended up with permanently impaired connections in a visual center of the brain.

But in a new experiment, newborn kittens similarly deprived of light did not end up with impaired connections when a simple change was made: their REM sleep was interrupted.

This is according to a new Science Advances paper that “adds important new data to our understanding of how the complicated state of REM functions in early life,” University of Mississippi associate professor of psychiatry and human behavior James Shaffery, D.Phil., told Bioscience Technology. Shaffery was not involved in the new study.

“I was surprised how important REM sleep turned out to be,” senior author Marcos Frank, Ph.D., told Bioscience Technology. Frank is a Washington State University neuroscientist. “I thought other stages of sleep would be key, but I was wrong. Happily wrong.”

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The above, with the study’s second finding —that key memories can fail to form in REM-deprived developing brains—indicates that drugs given to children, from antidepressants to stimulants, may need to be intensely analyzed for impact on REM.

REM’s biological function

Since its discovery as “a third state of being sixty-plus years ago, the biological function of the REM sleep state has remained a bit of a mystery,” Shaffery told Bioscience Technology. Shaffery has extensively studied REM.

In the last two decades, understanding has accelerated. “Studies in humans, cats and rats have lent support to the role of the REM sleep state serving important functions in certain forms of memory consolidation and in brain development.”

Early work unexpectedly unearthed the fact that human neonates undergo far more REM sleep than adults. “This observation formed the basis of the Ontogenetic Hypothesis of the function of REM sleep that has generated a considerable amount of supportive research and data,” Shaffery said.

“This most recent contribution from (Frank’s team) demonstrates, for the first time, that REM sleep deprivation, early in the critical period of cortical development, reduces shifts in ocular dominance in primary visual cortex in response to brief monocular deprivation, a well-accepted, physiological measure of cortical plasticity called ocular dominance plasticity (ODP).”

In particular, Frank’s crew placed an eye patch on the eyes of newborn kittens during a phase where it is known that they develop ODP, a kind of permanent vision impairment, when their vision is blocked. Plasticity was impaired when animals were awakened during REM sleep. Similar awakenings in non-REM sleep did not impair plasticity.

Supporting this change in cortical plasticity, Frank also showed for the first time that a neuronal signaling kinase (ERK, extracellular signal-regulated kinase), earlier shown necessary for sleep, receded in young kittens after REM sleep deprivation, confirming an earlier report of a role for ERK in ODP in rodents.

In further support of their own findings, Frank’s group then recorded, using a multiple electrode unit-recording array, the primary visual cortex. They showed that the probability of matching the pattern of neuronal activity in REM sleep during monocular deprivation (via eye patch) was higher during REM sleep after monocular deprivation than before it, Shaffery said.

“The authors conclude that REM sleep promotes cortical plasticity during development,” Shaffery said. “This work not only expands our understanding of the role REM sleep plays in brain development, but it also highlights how little we know about how this state functions in brain maturation and, perhaps, beyond.”

Daytime experiences “relived” in REM

Other groups have found that adults—humans and animals—seem to relive daytime experiences in REM, which cements those memories. This notion that REM sleep “helps consolidate waking experience into brain structure and build circuits, is reinforced by the new findings,” Shaffery said.

Indeed, Frank told Bioscience Technology, his study represents “the first time waking patterns of cortical activity have been detected in REM sleep during early life.”

Different ages used in other studies

The Frank team did note in their study that Shaffery and his collaborator, famed University of Mississippi Division of Sleep Medicine Director Howard Roffwarg, M.D., have come up with different results.

But Shaffery confirmed to Bioscience Technology the fact that those studies “focused upon animals later in the critical period, and showed increased plasticity after REM sleep deprivation during ongoing monocular deprivation, as measured by cell-size changes in the lateral geniculate nucleus.” Those studies found REM sleep deprivation at the later stage of visual cortex development may have “increased cortical synaptic plasticity” and concluded that “REM sleep serves to consolidate plasticity.”

These findings seem the opposite of Frank’s. But as Frank’s study states, Shaffery said: “These apparent differences may be due to the fact REM sleep deprivation and REM sleep, itself, may influence plasticity processes differently at different points during brain development.”

Shaffery noted that, bolstering that idea, another study in young rats, by he and Roffwarg, “showed that a short period of REM sleep deprivation, just at the start of the critical period, leads to decreased expression of several glutamatergic signaling proteins involved in the maturational stabilization of hippocampal synaptic plasticity (long-term potentiation).”

The reductions in synaptic plasticity-related proteins seen in that Shaffery study are consistent with the Frank study’s new finding of reduced phosphorylated ERK signaling proteins. “However, the changes observed by (that Shaffery study) in hippocampal protein expression were present even after several days of presumable recovery (non-REM and REM) sleep.” This was in contrast to Frank’s data, which were collected only one hour after REM sleep deprivation and monocular deprivation, Shaffery noted.

Nothing simple about REM

Shaffery told Bioscience Technology there is nothing simple about REM. “The two bodies of work unveil a complicated picture of the role of REM sleep in brain maturation, one that changes during development, and may have different valences in the service of brain maturation, depending upon time of observation.”

Those data also suggest that “while we are learning important new information about REM sleep in brain maturation, much more work is required to fill in the gaps in our knowledge of how REM sleep contributes to cortical development. Important information that remains to be uncovered is determination of the plasticity mechanisms involved at all points in brain maturation, and how these mechanisms change during their interactions with REM sleep over development. Then we might better appreciate the functional roles of REM sleep in the developing and mature animal.”

Future impact

All this may prompt better choices in treatment of “certain neurodevelopmental psychopathologies such as autism spectrum disorders, major depression and schizophrenia, that are suspected to have roots in disordered sleep in early childhood,” Shaffery said.

Frank told Bioscience Technology he will look at drugs taken by children. Do they affect REM—and thus, the wiring of kid’s brains? “We would like to know more about these biochemical changes, and whether drugs increasingly used to medicate children interfere with these sleep-dependent changes. There is very little basic, pre-clinical research on that. Surprising but true.”

Frank said stimulants and anti-depressants may be “the worst” with regard to disrupting REM.

Said Shaffery: “Most of the commonly used antidepressant drugs cause reductions in REM sleep. I am unaware of the degree to which young children are prescribed antidepressants. Usually depression onset is later in life. On the other hand, one way very young babies are affected by antidepressants is in utero, and thereafter, when the mother is dangerously depressed and cannot suspend antidepressant use during the pregnancy and in the postpartum period.…In adults, REM of course is similarly reduced, but most research points to the lack of adverse effects, with the benefits of managing depression overriding any such side effects.”

Shaffery added that Ritalin type drugs “are certainly `wake enhancers,’ and so the effects on sleep and other behavior would depend in young children upon dosing. Ritalin has a relatively short half-life, and prescribing for ADHD and related issues is usually tailored to avoid interfering with nighttime sleep, with larger doses in the morning and smaller doses later in the day. Of course, the worse cases requiring larger doses and abuse may lead to reductions of REM, but this, to my limited knowledge, is not well documented.”

Shaffery noted, however, that childhood trauma may impact young children—and the adults they will become—more. “By some estimates, around 60 percent of children have experienced an adverse event that, aside from other considerations, potentially negatively affects sleep. When the sleep of children is adversely affected, for the most part, REM is also affected.”