Long-suspected turbocharger for memory found in brain cells of mice
Floods of calcium inside neurons can influence learning

Date:
March 17, 2022
Source:
Columbia University
Summary:
Scientists have long known that learning requires the flow of
calcium into and out of brain cells. But researchers have now
discovered that floods of calcium originating from within neurons
can also boost learning. The finding emerged from studies of how
mice remember new places they explore.



FULL STORY ========================================================================== Scientists have long known that learning requires the flow of calcium
into and out of brain cells. But researchers at Columbia's Zuckerman
Institute have now discovered that floods of calcium originating from
within neurons can also boost learning. The finding emerged from studies
of how mice remember new places they explore.


========================================================================== Published today in Science, the new research doesn't suggest that you
should drink more calcium-rich milk to pass that math class. It provides a better understanding of the mechanisms that underlie learning and memory: knowledge that could help shed light on disorders such as Alzheimer's
disease.

"The cells we studied in this new work are in the hippocampus,
the first area of the brain affected by Alzheimer's disease," said
Franck Polleux, PhD, a principal investigator at Columbia's Zuckerman Institute. "Understanding the basic principles of what allows these brain
cells to encode memory will provide tremendous insights into what goes
wrong in this disease." The brain's ability to learn and remember -- everything from our first words and steps to where we parked our car or
left our keys -- depends on the gaps where neurons connect to each other, called synapses. Synapses, through which cells exchange information,
can be modified over time. This malleability to experience, known as plasticity, relies on how calcium ions flow within the brain.

Nearly all research into the part that calcium plays in plasticity has
focused on how it can rush into and out of a synapse through channels
on the surfaces of neurons. For more than two decades, scientists have suspected that stockpiles of calcium within neurons might also play a
major role in shaping plasticity. But until now, scientists had no way
to investigate the effects that calcium discharged from these internal reservoirs had within the mammalian brain.

"For a long time, there were no good tools out there to really probe
this intracellular calcium release in a living animal as it learned,"
said postdoctoral researcher and first author Justin O'Hare, PhD, in
the Polleux lab and the lab of Attila Losonczy, MD, PhD, at Columbia's Zuckerman Institute.



==========================================================================
In the new study of mice, the Polleux lab and the Losonczy lab focused on
the hippocampus, a seahorse-shaped region of the brain central to memory.

Specifically, the scientists analyzed pyramid-shaped neurons that can
encode memories of locations, called place cells, in the hippocampal
region known as CA1.

"Place cells are one of the key tools with which we not only create
maps of the world but also associate a place with something, such as
a reward, a color, a smell, anything," said Dr. Polleux, who is also a professor of neuroscience at Columbia's Vagelos College of Physicians
and Surgeons. "The big question is, 'How are these cells doing this?'"
To answer this question, the researchers had mice run on treadmills with
belts made of three different kinds of fabric and decorated with sequins,
furry pompoms and other ornaments. These decorations provided visual and tactile sensory cues about specific places on the belts. Place cells in
the brains of those mice had been genetically modified to switch on in
response to laser light, a technique known as optogenetics. This allowed
the researchers to tune those place cells to specific spots on the belts.

Inside place cells, the researchers focused on a gene called Pdzd8. It
encodes a protein that normally helps limit the amount of calcium released
from the endoplasmic reticulum (ER), an elaborate network of tubes within
the cells.

"The ER stores a huge amount of calcium," Dr. Polleux said. "It's like
a calcium bomb inside all cells." The researchers deleted Pdzd8. This
deletion removed the brakes on calcium release from the ER. The scientists
next looked for changes in the activity of the place cells in both the
cells' central bodies and their dendrites, the treelike branches with
which cells receive signals from other cells.



==========================================================================
"Any one of the technologies we used to perform these experiments
is difficult on its own. Combining them is just nuts," Dr. Polleux
said. "This is probably one of the most challenging sets of experiments
that has come out of my lab, and it would have never happened without a
deep collaboration with the Losonczy lab and the incredible experimental
and analytical talents of Dr Justin O'Hare." The scientists found
that increasing the amount of calcium released within a place cell significantly widened the area to which it was attuned, increasing the
size of the location it helped a mouse remember. Boosting intracellular
calcium release also dramatically increased the duration that a place
cell was attuned to a specific location.

"Intracellular calcium release can act like a turbocharger for
plasticity," Dr.

Polleux said. "We found that it also makes place cells perhaps even too
stable if left uncontrolled." The scientists also found the dendrites
at the apex of each pyramid-shaped neuron in CA1 are normally all tuned
to different places. Increasing the amount of calcium released within
these neurons helped attune many of the dendrites at their apexes to a
single place during learning but had less of an effect on dendrites at
the base of the neurons. Discovering the ways in which all the components
of these extraordinarily complex neurons change during learning could
help researchers decipher how these cells work.

"Dendrites have long been suspected to function as 'cells-within-cells'
that can work independently or, when needed, together to enhance the computational power of single neurons," Dr. Losonczy said. "Our study
not only shows that this is indeed the case, but it also provides a
molecular mechanism for how this dendritic cooperation is regulated in
the behaving brain." "Each potential place cell probably receives tens
of thousands of inputs carrying information about a space," Dr. O'Hare
said. "If you think about all this complexity, you can appreciate that
even a single neuron in the brain is basically like a supercomputer."
Future research can explore what effects deleting Pdzd8 has on behavior
in general. "Recently a paper came out that for the first time identified mutations in Pdzd8 in humans," Dr. Polleux said. "The individuals that
carry those mutations have severe learning and memory deficits, showing
how important it is for the brain." Dr. O'Hare and his colleagues are now investigating what happens to CA1 in a mouse model of Alzheimer's disease.

"What's happening to place cells as this disease progresses? It's still
not known," Dr. O'Hare said. "Understanding the basic principles endowing
place cells with the ability to encode memories in the hippocampus could
have enormous consequences for our understanding of what goes wrong in
this disease.

Then we can think about how that might translate into new therapies."
The work was supported by National Institutes of Health grants
R01MH100631, R01NS094668, U19NS104590, R01NS067557, R01NS094668,
F32MH118716, K00NS105187, F31MH117892, K99NS115984 and T32NS064928, JST
PRESTO grant JPMJPR16F7, the Zegar Family Foundation and the Foundation
Roger De Spoelberch. The authors declare no competing interests.


========================================================================== Story Source: Materials provided by Columbia_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Justin K. O'Hare, Kevin C. Gonzalez, Stephanie A. Herrlinger, Yusuke
Hirabayashi, Victoria L. Hewitt, Heike Blockus, Miklos Szoboszlay,
Sebi V. Rolotti, Tristan C. Geiller, Adrian Negrean, Vikas
Chelur, Franck Polleux, Attila Losonczy. Compartment-specific
tuning of dendritic feature selectivity by intracellular Ca 2
release. Science, 2022; 375 (6586) DOI: 10.1126/science.abm1670 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220317143228.htm

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