Frontiers

The Science of Sleep

Biologist Ted Abel discovers a way to reverse cognitive impairment caused by sleep deprivation.
December 2009

The cognitive consequences of not getting enough sleep—such as compromised memory and attention—are well established, both anecdotally and scientifically. However, many of the biological mechanisms by which sleep deprivation affects brain function remain a mystery. A research collaboration led by Edmund J. and Louise W. Kahn Term Professor of Biology Ted Abel has recently identified in mice some of the cellular and molecular effects of sleep deprivation and discovered a way to reverse the resulting cognitive impairment.

The findings, published in the journal Nature, reveal that sleep deprivation alters an intracellular signaling molecule, called cyclic-AMP (cAMP). When we learn, connections between nerve cells, called synapses, change in strength, and cAMP molecular pathways play a critical role in facilitating these changes in neuronal connectivity. Abel and his team discovered that sleep deprivation increases levels of phosphodiesterase 4 (PDE4)—an enzyme that degrades cAMP.

“Having identified the molecule that was impacted by sleep deprivation,” Abel says, “we were able to find a drug that would block the activity of this enzyme, increase levels of cAMP and prevent effects of sleep deprivation.”

"Sleep deprivation seems to specifically impact the hippocampus, a region of the brain that mediates episodic memories. It's also the brain region that is affected by diseases like Alzheimer's, depression and schizophrenia, all of which cause alterations in sleep." – Ted Abel

The researchers tested a specific kind of memory—memory for environments—in mice. In humans this would translate to episodic memory—the memory for events, people, places and things. “What’s interesting,” Abel says, “is that sleep deprivation seems to specifically impact the hippocampus, a region of the brain that mediates episodic memories. It’s also the brain region that is affected by diseases like Alzheimer’s, depression and schizophrenia, all of which cause alterations in sleep.”

Cyclic-AMP has been implicated in some of these disorders, and Abel’s research suggests that the cognitive deficits resulting from these diseases may be due to the changes in sleep they cause. He speculates that addressing patients’ sleep issues could improve some of these deficits.

Because PDE4 has 30 different isoforms (multiple versions of a protein that perform the same function), Abel and his team are now trying to identify and develop drugs that can target the specific isoform increased by a lack of sleep. “We’re trying to find out what it interacts with, where it is in the cell and why it’s sensitive to sleep deprivation,” Abel says. “That will be the key to generating better drugs. Also, a number of pharmaceutical companies are developing compounds to target PDEs because they are implicated in diseases such as chronic obstructive pulmonary disease and psoriasis, so there’s hope that there will be some new drugs to test beyond our search.”

Abel is also conducting further research to explore if there are particular stages of sleep that are more important than others to cognitive activity. “We think there’s a pattern of neuronal firing in the hippocampus during non-REM sleep, called ripples or sharp waves, that may enable memories to be consolidated,” Abel explains.

Although Abel’s findings suggest that some of the effects of sleep deprivation can be reversed, he says the main take-home message of this study is that sleep is a biological necessity.

“A lot of the people I’ve spoken with think that we’ve found a way to get around the need for sleep,” Abel says. “But when you don’t get enough sleep, it’s not just the cognitive effects we’ve focused on that you have to worry about. Sleep deprivation affects your metabolism, your immune system, your whole body.”