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Penn Study Shows Why Sleep is Needed to Form Memories

First-of-its-kind study shows how brain connections strengthen during sleep

If you ever argued with your mother when she told you to get some sleep after studying for an exam instead of pulling an all-nighter, you owe her an apology, because it turns out she's right. And now, scientists are beginning to understand why.

In research published this week in Neuron, Marcos Frank, PhD, Assistant Professor of Neuroscience, at the University of Pennsylvania School of Medicine, postdoctoral researcher Sara Aton, PhD, and colleagues describe for the first time how cellular changes in the sleeping brain promote the formation of memories.

"This is the first real direct insight into how the brain, on a cellular level, changes the strength of its connections during sleep," Frank says.

The findings, says Frank, reveal that the brain during sleep is fundamentally different from the brain during wakefulness.

"We find that the biochemical changes are simply not happening in the neurons of animals that are awake," Frank says. "And when the animal goes to sleep it's like you’ve thrown a switch, and all of a sudden, everything is turned on that's necessary for making synaptic changes that form the basis of memory formation. It's very striking."

The team used an experimental model of cortical plasticity – the rearrangement of neural connections in response to life experiences. "That's fundamentally what we think the machinery of memory is, the actual making and breaking of connections between neurons,” Frank explains

In this case, the experience Frank and his team used was visual stimulation. Animals that were young enough to still be establishing neural networks in response to visual cues were deprived of stimulation through one eye by covering that eye with a patch. The team then compared the electrophysiological and molecular changes that resulted with control animals whose eyes were not covered. Some animals were studied immediately following the visual block, while others were allowed to sleep first.

From earlier work, Frank's team already knew that sleep induced a stronger reorganization of the visual cortex in animals that had an eye patch versus those that were not allowed to sleep. Now they know why.

A molecular explanation is emerging. The key cellular player in this process is a molecule called N-methyl D-aspartate receptor (NMDAR), which acts like a combination listening post and gate-keeper. It both receives extracellular signals in the form of glutamate and regulates the flow of calcium ions into cells.

Essentially, once the brain is triggered to reorganize its neural networks in wakefulness (by visual deprivation, for instance), intra- and intercellular communication pathways engage, setting a series of enzymes into action within the reorganizing neurons during sleep.

To start the process, NMDAR is primed to open its ion channel after the neuron has been excited. The ion channel then opens when glutamate binds to the receptor, allowing calcium into the cell. In turn, calcium, an intracellular signaling molecule, turns other downstream enzymes on and off.

Some neural connections are strengthened as a result of this process, and the result is a reorganized visual cortex. And, this only happens during sleep.

“To our amazement, we found that these enzymes never really turned on until the animal had a chance to sleep," Frank explains, "As soon as the animal had a chance to sleep, we saw all the machinery of memory start to engage." Equally important was the demonstration that inhibition of these enzymes in the sleeping brain completely prevented the normal reorganization of the cortex.

Frank stresses that this study did not examine recalling memories. For example, these animals were not being asked to remember the location of their food bowl. "It's a mechanism that we think underlies the formation of memory.” And not only memory; the same mechanism could play a role in all neurological plasticity processes.

As a result, this study could pave the way to understanding, on a molecular level, why humans need sleep, and why they are so affected by the lack of it. It could also conceivably lead to novel therapeutics that could compensate for the lack of sleep, by mimicking the molecular events that occur during sleep.

Finally, the study could lead to a deeper understanding of human memory. Though how and even where humans store long-lasting memories remains a mystery, Frank says, "we do know that changes in cortical connections is at the heart of the mystery. By understanding that in animal models, it will bring us close to understanding how it works in humans."

The research was funded by the National Institutes of Health, the National Sleep Foundation, and L'Oreal USA, and also involved researchers at the Penn’s Center for Sleep and Respiratory Neurobiology, and the School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
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