SCIENTISTS PREVENT MEMORY PROBLEMS CAUSED BY SLEEP DEPRIVATION
Sleep is a critical
period for memory consolidation, and most people don't get enough. Research has
shown that even brief periods of sleep deprivation can lead to deficits in
memory formation.
In a new study,
published in the Journal of Neuroscience, a team led by scientists
from the University of Pennsylvania found that a particular set of cells in a
small region of the brain are responsible for memory problems after sleep loss.
By selectively increasing levels of a signaling molecule in these cells, the
researchers prevented mice from having memory deficits.
Robbert Havekes was
the lead author on the study. He is a research associate in the lab of Ted
Abel, the study's senior author and Brush Family Professor of Biology in Penn's
School of Arts & Sciences. Coauthors from the Abel lab included Jennifer C.
Tudor and Sarah L. Ferri. They collaborated with Arnd Baumann of
Forschungszentrum Jülich, Germany, and Vibeke M. Bruinenberg and Peter Meerlo
of the University of Groningen, The Netherlands.
In 2009, a group from
Abel's lab published a study in Nature that identified the
cyclic AMP, or cAMP, signaling pathway as playing a role in
sleep-loss-associated memory problems. Whereas depriving mice of sleep impaired
their spatial memory, restoring levels of cAMP in their brain prevented this
effect.
"The challenge
following this important study," Abel said, "was to determine if the
impact of sleep deprivation was mediated by particular regions of the brain and
particular neural circuits. We suspected that the hippocampus, the brain region
that mediates spatial navigation and contextual memory, was critical."
In the current work,
they set out to answer these questions. They targeted excitatory neurons
because of their importance in transmitting signals in the brain and the fact
that their functioning relies on cAMP signaling. The limitation of previous
studies was that they lacked a way to increase cAMP in just one area of the
brain in a cell-type specific fashion. Havekes, Abel and colleagues devised a
way of doing this that they term a "pharmacogenetic" approach,
blending genetic modification and drug administration.
They engineered a
non-pathogenic virus to harbor the gene encoding the receptor for the protein
octopamine, which triggers cAMP pathway activation in fruit flies but is not
naturally found in the brains of mice. The researchers injected this virus into
the hippocampus of mice so that the excitatory neurons in that region alone
would express the octopamine receptor.
"It sounds weird.
Why would you put a receptor there that is never going to be activated?"
Havekes said. "The trick is, you follow that up by giving mice the ligand
of the receptor, which is octopamine, and that will activate the receptors only
where they are present."
The team confirmed
that only the excitatory hippocampal neurons expressed the receptor and that
they could selectively increase cAMP levels in only these cells by giving the
mice a systemic injection of octopamine.
"This way, we
could manipulate the cAMP pathways that we previously saw being affected by
sleep deprivation but selectively in specific neural circuits in the
brain," Havekes says.
With this
pharmacogenetic tool in hand, Havekes, Abel and colleagues began the sleep
deprivation tests with the mice expressing the octopamine receptor in their
hippocampus. First the researchers trained mice in a spatial memory task. They
put them in a box that had three different objects, each in a distinct
location.
Then, because previous
research had shown that cAMP signaling contributes to hippocampus-dependent
memory consolidation in two time windows -- first directly after training and
again three to four hours after training -- the researchers gave mice in the
experimental groups injections of octopamine in both of these windows to boost
cAMP levels.
Mice receiving the
cAMP boost were divided into two groups: One was left to sleep undisturbed,
while the other was sleep-deprived for five hours by gently tapping their cage
or rearranging their bedding.
One full day after the
initial training, all of the mice were tested again. This time, there was a
twist: one of the objects originally in the box had been moved to a new
location.
"If the mice had
learned and remembered the location of the objects during their training, then
they would realize, okay, this is the object that has moved, and they'll spend
more time exploring that particular object," Havekes explained. "If
they didn't remember well, they would explore all the objects in a random
fashion."
The researchers found
that the sleep-deprived mice that received the octopamine injections spent more
time exploring the object that had moved, just as mice that had not been sleep
deprived did. On the other hand, sleep-deprived mice that didn't express the
receptor explored all the objects at random, a sign that they had failed to
remember the locations of the objects from their initial training as a result
of the brief period of sleep deprivation.
"What we've shown
is this memory loss due to sleep deprivation is really dependent on misregulation
of cAMP signaling in the excitatory neurons of the hippocampus," Havekes
said.
As a next step, the
group would like to explore what cAMP is doing to help consolidate memory. They
would also like to investigate how other cell types in the brain, such as
astrocytes, might be affected. And finally, while this study focused on the
impact of a brief period of sleep deprivation, Havekes is curious to know how
not getting enough sleep on a daily basis, as is more similar to human
experiences, might be affecting memory.
"Thinking about
people who do shift work or doctors who work long hours, if we can tackle the
cognitive problems that result from sleep loss, that would be a great
thing," Havekes said.
"At least in the
mouse using these sophisticated tools, we're able to reverse the negative
impact of sleep deprivation on cognition," Abel said.
The research was
supported by the Netherlands Organization for Scientific Research, the
University Research Foundation and the National Institutes of Health.
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