• Long-suspected turbocharger for memory f

    From ScienceDaily@1:317/3 to All on Thu Mar 17 22:30:46 2022
    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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