Source:
The Zuckerman Institute at
Columbia University
Summary:
The brain has a powerful ability
to remember and connect events separated in time. And now, in a new study in
mice, scientists have shed light on how the brain can form such enduring links.
A
woman walking down the street hears a bang. Several moments later she discovers
her boyfriend, who had been walking ahead of her, has been shot. A month later,
the woman checks into the emergency room. The noises made by garbage trucks,
she says, are causing panic attacks. Her brain had formed a deep, lasting
connection between loud sounds and the devastating sight she witnessed.
This
story, relayed by clinical psychiatrist and co-author of a new study Mohsin
Ahmed, MD, PhD, is a powerful example of the brain's powerful ability to
remember and connect events separated in time. And now, in that new study in
mice published today in Neuron, scientists at Columbia's Zuckerman
Institute have shed light on how the brain can form such enduring links.
The scientists
uncovered a surprising mechanism by which the hippocampus, a brain region
critical for memory, builds bridges across time: by firing off bursts of
activity that seem random, but in fact make up a complex pattern that, over
time, help the brain learn associations. By revealing the underlying circuitry
behind associative learning, the findings lay the foundation for a better
understanding of anxiety and trauma- and stressor-related disorders, such as
panic and post-traumatic stress disorders, in which a seemingly neutral event
can elicit a negative response.
"We
know that the hippocampus is important in forms of learning that involve
linking two events that happen even up to 10 to 30 seconds apart," said
Attila Losonczy, MD, PhD, a principal investigator at Columbia's Mortimer B.
Zuckerman Mind Brain Behavior Institute and the paper's co-senior author.
"This ability is a key to survival, but the mechanisms behind it have
proven elusive. With today's study in mice, we have mapped the complex calculations
the brain undertakes in order to link distinct events that are separated in
time."
The
hippocampus -- a small, seahorse-shaped region buried deep in the brain -- is
an important headquarters for learning and memory. Previous experiments in mice
showed that disruption to the hippocampus leaves the animals with trouble
learning to associate two events separated by tens of seconds.
"The
prevailing view has been that cells in the hippocampus keep up a level of
persistent activity to associate such events," said Dr. Ahmed, an
assistant professor of clinical psychiatry at Columbia's Vagelos College of
Physicians and Surgeons, and co-first author of today's study. "Turning
these cells off would thus disrupt learning."
To
test this traditional view, the researchers imaged parts of the hippocampus of
mice as the animals were exposed to two different stimuli: a neutral sound
followed by a small but unpleasant puff of air. A fifteen-second delay
separated the two events. The scientists repeated this experiment across
several trials. Over time, the mice learned to associate the tone with the
soon-to-follow puff of air. Using advanced two-photon microscopy and functional
calcium imaging, they recorded the activity of thousands of neurons, a type of
brain cell, in the animals' hippocampus simultaneously over the course of each
trial for many days.
"With
this approach, we could mimic, albeit in a simpler way, the process our own
brains undergo when we learn to connect two events," said Dr. Losonczy,
who is also a professor of neuroscience at Columbia's Vagelos College of
Physicians and Surgeons.
To
make sense of the information they collected, the researchers teamed up with
computational neuroscientists who develop powerful mathematical tools to
analyze vast amounts of experimental data.
"We
expected to see repetitive, continuous neural activity that persisted during
the fifteen-second gap, an indication of the hippocampus at work linking the
auditory tone and the air puff," said computational neuroscientist Stefano
Fusi, PhD, a principal investigator at Columbia's Zuckerman Institute and the
paper's co-senior author. "But when we began to analyze the data, we saw
no such activity."
Instead,
the neural activity recorded during the fifteen-second time gap was sparse.
Only a small number of neurons fired, and they did so seemingly at random. This
sporadic activity looked distinctly different from the continuous activity that
the brain displays during other learning and memory tasks, like memorizing a
phone number.
"The
activity appears to come in fits and bursts at intermittent and random time
periods throughout the task," said James Priestley, a doctoral candidate
co-mentored by Drs. Losonczy and Fusi at Columbia's Zuckerman Institute and the
paper's co-first author. "To understand activity, we had to shift the way
we analyzed data and use tools designed to make sense of random
processes."
Ultimately,
the researchers discovered a pattern in the randomness: a style of mental
computing that seems to be a remarkably efficient way that neurons store
information. Instead of communicating with each other constantly, the neurons
save energy -- perhaps by encoding information in the connections between
cells, called synapses, rather than through the electrical activity of the
cells.
"We
were happy to see that the brain doesn't maintain ongoing activity over all
these seconds because, metabolically, that's not the most efficient way to
store information," said Dr. Fusi, who is also a professor of neuroscience
at Columbia's Vagelos College of Physicians and Surgeons. "The brain seems
to have a more efficient way to build this bridge, which we suspect may involve
changing the strength of the synapses."
In
addition to helping to map the circuitry involved in associative learning,
these findings also provide a starting point to more deeply explore disorders
involving dysfunctions in associative memory, such as panic and pos-ttraumatic
stress disorder.
"While our study does not explicitly model the
clinical syndromes of either of these disorders, it can be immensely
informative," said Dr. Ahmed, who is also a member of the Losonczy lab at
Columbia's Zuckerman Institute. "For example, it can help us to model some
aspects of what may be happening in the brain when patients experience a fearful
association between two events that would, to someone else, not elicit fright
or panic."
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