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 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.”
Journal article: https://www.biorxiv.org/content/10.1101/613638v1
Source: https://zuckermaninstitute.columbia.edu/how-does-brain-link-events-form-memory-columbia-study-mice-reveals-unexpected-mental-processes-work
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