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| Hippocampus Neuron, computer illustration Credit: Kateryna Kon Getty Images |
Specific
patterns of brain activity are thought to underlie specific processes or
computations important for various mental faculties, such as memory. One such
“brain signal” that has received a lot of attention recently is known as a
“sharp wave ripple”—a short, wave-shaped burst of high-frequency oscillations.
Researchers
originally identified ripples in the hippocampus, a region crucially involved
in memory and navigation, as central to diverting recollections to long-term
memory during sleep. Then a 2012 study by
neuroscientists at the University of California, San Francisco, led by Loren
Frank and Shantanu Jadhav, the latter now at Brandeis University, showed that
the ripples also play a role in memory while awake. The researchers used
electrical pulses to disrupt ripples in rodents’ brains and showed that, by
doing so, performance in a memory task was reduced. However, nobody had manipulated
ripples to enhance memory—until now, that
is.
Researchers
at NYU School of Medicine led by neuroscientist György
Buzsáki have now done exactly that. In a June 14 study in Science, the team showed that prolonging sharp
wave ripples in the hippocampus of rats significantly improved their
performance in a maze task that taxes working memory—the brain’s “scratch pad”
for combining and manipulating information on the fly. “This is a very novel
and impactful study,” says Jadhav, who was not involved in the research. “It’s
very hard to do ‘gain-of-function’ studies with physiological processes in such
a precise way.” As well as revealing new details about how ripples contribute
to specific memory processes, the work could ultimately have implications for
efforts to develop interventions for disorders of memory and learning.
The
researchers first examined the properties of ripples recorded in rats
performing tasks from a database acquired over years of experiments. They found
more long-duration ripples occurred when rats had to make their way through
mazes than when they were simply exploring or running along tracks. Negotiating
mazes required rats to exercise their memories.
In
one task, the M-maze, rats were trained to first navigate through the
right-hand arm of a maze shaped as an “M” to receive a sugary reward, then
through the left-hand arm on the next trial. The researchers saw significantly
longer ripples in trials the rats performed correctly, compared to those they
got wrong. “You can record a very simple electrical pattern in the brain and
tell whether the animal's performance will be good or not, or whether the
animal is learning or not,” Buzsáki says. These findings suggest that the hippocampus
generates longer ripples during memory-intensive activities and that these
longer-duration signals improve performance.
To
verify that longer ripples contribute to better performance, the team
artificially prolonged ripples in rats performing the M-maze task. The
researchers used optogenetics, involving the use of light piped through a
fiber-optic cable to activate genetically engineered light-sensitive neurons in
the rats’ hippocampi. They recorded collective neural activity in the
hippocampus during the task, to enable them to detect spontaneously occurring
ripples. Upon detection of a ripple, light pulses were triggered to activate
engineered neurons. This “closed-loop” stimulation roughly doubled the duration
of ripples and significantly improved the rats’ performance, compared to
control conditions with either no light stimulation or stimulation applied
after short, random delays.
The
rats also learned faster, reaching 80 percent correct performance in
remembering which route would lead to a reward earlier than rats in the control
conditions. The researchers also switched off any beneficial effects by
aborting ripples using high-intensity light pulses, confirming that performance was impaired. “It's really nice to see another group do something
slightly different and get the same result,” Frank says. “It makes you feel
confident we're all on to something.”
To
investigate how longer ripples might be enhancing performance, the team
inspected the properties of the neurons involved. A ripple is not simply the repeated activity of the same neurons oscillating over time; instead, its
activity spreads to more neurons as the signal continues.
The team observed that particular neurons tend to “fire” either in the early or in
the later portion of the signal, and they found intriguing differences between
these two groups. “Early” neurons were “chatterboxes” with high baseline
activity, whereas “late” neurons were more sluggish, with lower average
activity. “Neurons that fire fast are like talkative people, they are active in
many situations,” Buzsáki explains. “The majority typically don't fire,
but once they do, they say something important.”
The
hippocampus contains neurons specialized for navigation, called “place” cells,
which fire when an animal is in a specific location. The researchers found that
neurons firing in the late part of long ripples (either spontaneously
occurring, or artificially prolonged), were more highly tuned to location, and
the spots tended to be on the arms of the maze. Previous research suggests one
function of ripples may be to “replay” memories. The new findings support that
idea and suggest that prolonging ripples recruits extra neurons to generate
the signal, whose activity is relevant to the task at hand. “When they extend the
length of ripples, they’re recruiting cells that are reactivating paths the
animals take,” Jadhav explains. “This might be a mechanism for doing a
cognitive search of all the available paths, that other brain areas can read
out and act on.”
The
researchers hope this work eventually may help develop ways to treat the type
of memory problems that occur in age-related cognitive decline or Alzheimer’s
disease. Learning difficulties might also be addressed. The techniques in the
experiments would be tricky to apply to humans because they are invasive and
involve genetic manipulation, but Buzsáki says they are working on noninvasive
methods. A recent study,
published in April and led by neuroscientist Robert Reinhart of Boston
University used weak electrical currents applied to the scalps of elderly
participants to obtain an increase in working memory performance, accompanied
by greater synchrony between oscillations of certain (theta) frequencies in
different cortical regions. “There are intriguing points of connection between
the elegant work by [Buzsáki’s team] and research conducted in my laboratory,”
Reinhart says. “Research in systems and cognitive neuroscience is laying
critical basic science groundwork, which may open up an entirely new avenue of
circuit-based therapeutics for the prevention and treatment of brain
disorders.”
The
problem with existing non-invasive methods, such as transcranial magnetic
stimulation (TMS), or the transcranial electrical stimulation (TES) technique,
used in Reinhart’s study, is their inability to penetrate into the brain,
so manipulating signals in the deeply seated hippocampus is difficult.
Recording from deep in the brain non-invasively is even more tricky. One
possible solution would be to infer when ripples occur in the hippocampus from
activity recorded from the brain’s surface. “There might be a very specific
pattern of, say, prefrontal activity that precedes these events” and produces
ripples in the hippocampus. Frank says. "But we don’t
understand what that looks like yet.”
Also,
modifying cortical activity using these techniques may, as a consequence,
affect activity in the hippocampus. “We know that these sharp wave ripples can
be biased by [specific] neocortical patterns,” Buzsáki says. “In fact, many
companies are trying to affect memory, by changing neocortical patterns.”
Finally, invasive methods, similar to implants used to detect and interfere
with seizures in epilepsy, could be employed, either for detecting, or
manipulating ripples, or both. Invasive and non-invasive methods could even be
combined. “As long as you can measure these events and come up with some way to
manipulate them, you have the possibility of making the system work better,”
Frank says. “There's a world of possibilities there.”
Note: György Buzsáki's affiliation was
corrected from "New York University" to "NYU School of
Medicine."
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