Scientists track unexpected mechanisms of memory
Do
you remember Simone Biles's epic gymnastics floor routine that earned her a
fifth Olympic medal? Our brains hold on to memories like these via physical
changes in synapses, the tiny connections between neurons.
A new study by researchers at Duke University and the Max Planck
Florida Institute for Neuroscience reveals unexpected molecular mechanisms by
which these changes take place. Published in advance online Sept. 28 in the
journal Nature, the findings could also
shed light on how some diseases develop, including certain forms of epilepsy. "We're
beginning to unlock some of the mysteries underlying both the acquisition of a
memory in the normal brain, as well as how a normal brain is transformed into
an epileptic brain," said the study's co-senior investigator James
McNamara, M.D., a professor in the departments of neurobiology and neurology at
Duke University.
As we acquire a new memory, the
connections, or synapses, between certain sets of neurons strengthen. In
particular, the receiving end of a pair of these neurons -- consisting of a
little nub called a spine -- gets a little larger. Researchers have long
suspected that a brain receptor called TrkB was involved with the growth of
spines when we learn, but the new study confirms that the receptor is indeed
crucial and delves further into how it works. The key technologies that enabled
this finding included a molecular sensor that the group developed to track
activity of TrkB, and microscopes that allowed them to visualize a single spine
in the area of living mouse brain tissue, all in real time. The group also was
able to add a tiny amount of signaling chemical, glutamate, at the single spine
in order to mimic what happens during learning. This caused the spines to grow.
"The mouse brain has approximately 70 million neurons, and most of them are
dotted with thousands of spines," McNamara said. "So, to be able to
model and study the events occurring in a single spine in a single neuron is
remarkable."
Without the TrkB receptor, spine
growth did not occur in response to the signaling chemical, the group found. The
team suspected that yet another player, brain-derived neurotrophic growth
factor (BDNF), was involved because it is the molecular key to TrkB's lock. The
scientists created a molecular sensor for BDNF and showed that mimicking the
signal associated with learning caused the release of BDNF from the receiving
end of the synapse. This was surprising because conventional wisdom holds that
BDNF is only released from the sending neuron, not the receiving neuron.
The fact that the receiving neuron
both discharges BDNF into the gap between neurons and also senses it is
"extremely unique, biologically," said co-senior investigator Ryohei
Yasuda, scientific director of the Max Planck Florida Institute for
Neuroscience. "One possibility is that BDNF is regulating several
surrounding cells at once. We're interested in following up to understand the
exact process." Although the experiments were conducted in mice, the
interaction between TrkB and BDNF is likely to be important for learning and
memory in people, McNamara said. What's more, the same mechanisms are likely at
play in one of the most common forms of epilepsy, called temporal lobe epilepsy
(TLE), which targets brain regions responsible for learning and memory. Some
cases of TLE are thought to be caused by a single, prolonged episode of
seizures early in life. During the episode, glutamate, the same neurochemical
involved in memory is released, but at much higher levels and for much longer
times. McNamara's previous work shows that the TrkB receptor is critical for
development of TLE, and last fall his group showed that inhibiting TrkB
signaling briefly following the first seizure episode prevents the development
of TLE in mice.
McNamara's group is carrying out
additional experiments to understand what happens after TrkB is activated in
order for single spines to get bigger. In addition, other mechanisms are likely
contributing to TrkB activation in both memory and epileptic episodes, and
McNamara's group is exploring other potential mechanisms.
By
Rajgopal
III B.Sc.,
Department of Biochemistry
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