FEBRUARY 11, 2009
Penn Study Shows Why Sleep is Needed to Form Memories
First-of-its-kind study shows how brain connections strengthen during sleep
PHILADELPHIA – 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.
Neuron. 2009 Feb 12;61(3):454-66.
Mechanisms of sleep-dependent consolidation of cortical plasticity.
Aton SJ, Seibt J, Dumoulin M, Jha SK, Steinmetz N, Coleman T, Naidoo N, Frank MG.
Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Sleep is thought to consolidate changes in synaptic strength, but the underlying mechanisms are unknown. We investigated the cellular events involved in this process during ocular dominance plasticity (ODP)-a canonical form of in vivo cortical plasticity triggered by monocular deprivation (MD) and consolidated by sleep via undetermined, activity-dependent mechanisms. We find that sleep consolidates ODP primarily by strengthening cortical responses to nondeprived eye stimulation. Consolidation is inhibited by reversible, intracortical antagonism of NMDA receptors (NMDARs) or cAMP-dependent protein kinase (PKA) during post-MD sleep. Consolidation is also associated with sleep-dependent increases in the activity of remodeling neurons and in the phosphorylation of proteins required for potentiation of glutamatergic synapses. These findings demonstrate that synaptic strengthening via NMDAR and PKA activity is a key step in sleep-dependent consolidation of ODP.
Contact information
Marcos G. Frank
Assistant Professor of Neuroscience
Department: Neuroscience
Graduate Group Affiliations
111 Johnson Pavilion
University of Pennsylvania
School of Medicine
Philadelphia, PA 19104-6060
Office: (215) 746-0388
Fax: (215) 573-9050
Email:
mgf@mail.med.upenn.edu
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N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are used in clinical anesthesia and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma.
In addition to the glutamate (NMDA) binding site, there are also multiple binding sites on the NMDA receptor for modulatory compounds. Efficient NMDA receptor activation requires not only NMDA but also a co-agonist, glycine.
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The Big Picture
By manipulating a single gene, scientists have created a geneticallyengineered mouse that outperforms regular mice on learning and memorytests; the results of this study were reported in the September 2, 1999issue of the journal Nature. When they received an extra copy ofthe NMDA receptorgene, the mice were better able to navigate mazes, remember objects, andretain for longer information that they had alreadylearned.
NMD-What?
The NMDAreceptor is an important molecule. It is the receptor for theneurotransmitter glutamate, an excitatorytransmitter in the brain. The receptor is found in many neurons in thebrain where it plays a crucial role in synaptic plasticity(theability for synapses to change) and memory formation, which occurs whenlearning takes place.
