• Researchers control brain circuits from

    From ScienceDaily@1:317/3 to All on Tue Mar 22 22:30:46 2022
    Researchers control brain circuits from a distance using infrared light


    Date:
    March 22, 2022
    Source:
    Stanford University School of Engineering
    Summary:
    Scientists have developed the first non-invasive technique for
    controlling targeted brain circuits in behaving animals from
    a distance.

    The tool has the potential to solve one of the biggest unmet needs
    in neuroscience: a way to flexibly test the functions of particular
    brain cells and circuits deep in the brain during normal behavior.



    FULL STORY ========================================================================== Imagine the brain as a giant switchboard covered with thousands of
    buttons, knobs, dials and levers that control aspects of our thought,
    emotions, behavior, and memory. (You can think of the movie Inside Out,
    if you like).


    ==========================================================================
    For more than a century, neuroscientists have been methodically
    flipping these switches on and off, alone or in combination, to try to understand how the machine works as a whole. But this is easier said
    than done. The cellular circuits that control mind and behavior tangle
    together throughout the opaque, gelatinous mass of our brain tissue and
    don't come with handy on/off switches for easy reverse engineering.

    Now, scientists at the Wu Tsai Neurosciences Institute at Stanford
    University have developed the first non-invasive technique for controlling targeted brain circuits in behaving animals from a distance. The tool has
    the potential to solve one of the biggest unmet needs in neuroscience:
    a way to flexibly test the functions of particular brain cells and
    circuits deep in the brain during normal behavior -- such as mice freely socializing with one another.

    The research was published March 21, 2022 in Nature Biomedical
    Engineering by Guosong Hong and colleagues at Stanford and Singapore's
    Nanyang Technological University. Hong is a Wu Tsai Neurosciences
    Institute Faculty Scholar and assistant professor of materials science
    and engineering in the Stanford School of Engineering who uses his
    background in chemistry and materials science to devise biocompatible
    tools and materials to advance the study of the brain.

    The newly published technique builds on the foundation laid down by optogenetics, a technique first developed at Stanford by Wu Tsai
    Neuro affiliate Karl Deisseroth and collaborators that introduces light-sensitive algal proteins into neurons to let researchers turn them
    on or off in response to different colors of light.

    "Optogenetics has been a transformative tool in neuroscience, but
    there are limitations on what can be done with existing techniques --
    in part due to their reliance on light in the visible spectrum," Hong
    said. "The brain is quite opaque to visible light, so getting the light
    to the cells you want to stimulate typically requires invasive optical
    implants that can cause tissue damage and skull-mounted fiber optic
    tethers that make it hard to study many kinds of natural behavior."
    Thinking as a materials scientist about ways to overcome these challenges,
    Hong recognized that biological tissues -- including the brain and even
    the skull - - are essentially transparent to infrared light, which could
    make it possible to deliver the light much deeper into the brain.



    ========================================================================== Since existing optogenetic tools don't respond to infrared light, Hong's
    team turned to a molecule that evolved to detect infrared's other form:
    heat. By artificially outfitting specific neurons in the mouse brain
    with a heat- sensitive molecule called TRPV1, his team found that it
    was possible to stimulate the modified cells by shining infrared light
    through the skull and scalp from up to a meter away.

    TRPV1 is the molecular heat sensor that allows us to feel heat-related
    pain - - as well as the spicy burn of a chili pepper -- the discovery of
    which led to the 2021 Nobel Prize in Medicine. A similar receptor gives rattlesnakes and other pit vipers the "heat vision" that lets them hunt warm-blooded prey in the dark, and a recent study succeeded in giving
    mice the ability to see in the infrared spectrum by adding TRPV1 to
    their retinal cone cells.

    The new technique also relies on an engineered "transducer" molecule
    that can be injected into targeted brain regions to absorb and amplify
    the infrared light penetrating through the brain tissue. These nano-scale particles, dubbed MINDS (for "macromolecular infrared nanotransducers for deep-brain stimulation"), work a bit like the melanin in our skin that
    absorbs harmful UV rays from the sun, and are crafted from biodegradable polymers used to produce organic solar cells and LEDs.

    "We first tried stimulating cells with TRPV1 channels alone, and it
    didn't work at all," said Hong. "It turns out that rattlesnakes have
    a much more sensitive way of detecting infrared signals than we could
    manage in the mouse brain.

    Fortunately, we had materials science to help us." Hong's team first demonstrated their technique by adding TRPV1 channels to neurons on one
    side of mouse motor cortex -- a region that orchestrates body movements
    -- and injecting MINDS molecules into the same region. At first the mice explored their enclosures at random, but when the researchers flipped on
    an infrared light over the enclosure, the mice immediately started walking
    in circles, driven by the one-sided stimulation of their motor cortex.



    ========================================================================== "That was a great moment when we knew this was going to work," Hong
    said. "Of course it was only the beginning of validating and testing
    what this technology could do, but from that point on I was confident we
    had something." In another key experiment, the researchers showed that
    MINDS could enable infrared stimulation of neurons through the entire
    depth of the mouse brain.

    They inserted TRPV1 channels into the dopamine-expressing neurons of the brain's reward centers, which are located near the base of the brain
    in mice, followed by an injection of MINDS into the same region. They
    then positioned a focused infrared light over one of the three arms
    of a standard radial arm maze and showed that mice became "addicted"
    to the invisible infrared light tickling their dopamine neurons --
    spending nearly all their time in the maze under its beams.

    This experiment demonstrated that the new technique makes it possible
    to stimulate neurons anywhere in the brain through the intact scalp and
    skull - - with hardly any of the light-scattering that would make this impossible with light in the visual spectrum. Remarkably, this worked
    even when the beam of infrared light was positioned as far as a meter
    above animals' heads.

    Hong sees immediate applications of the technique for the growing movement
    in neuroscience to study the brain circuits involved in natural social
    behavior in mice in order to better understand the systems that underlie
    social cognition in humans.

    "Like us, mice are a social species, but studying an animal's natural
    behavior within a social group is challenging with a head-mounted
    fiber-optic tether," Hong said. "This approach makes it possible for
    the first time to modulate specific neurons and circuits in freely
    behaving animals. One could just shine invisible infrared light over an enclosure with cohoused mice to study the contributions of particular
    cells and circuits to an animal's behavior within a social group."
    Hong and collaborators are continuing to refine the technique to make
    it simpler and easier to implement, he said. "In future we'd like to
    combine our current two-stage approach into a single molecular machine -- perhaps by encoding some infrared-absorbing pigment into TRP-expressing
    neurons themselves." The work is one of several approaches Hong is
    involved in to make it possible for researchers -- and perhaps one day clinicians -- to non-invasively modulate neural circuits across the
    brain. For example, Hong and colleagues are also developing nanoscopic
    beads that can convert focused beams of ultrasound into light, and which
    can be injected directly into the bloodstream, making it possible to optogenetically target cells anywhere in the brain and to change this
    targeting at will within a single experiment.

    "Conventional neuromodulation approaches gave us the ability to flip a
    few of the switches at a time in the brain to see what different circuits
    do," Hong said. "Our goal is to take these techniques a step further to
    give us precise control over the entire switchboard at the same time."
    This research was funded by a seed grant from the Wu Tsai Neurosciences Institute at Stanford, Stanford Bio-X, and a Stanford Interdisciplinary Graduate Fellowship; by a Nanyang Technological University startup grant
    and Singapore Ministry of Education Academic Research Fund; and by the US National Science Foundation (NSF), the NIH National Institute on Aging,
    the Rita Allen Foundation, and the Spinal Muscular Atrophy Foundation.


    ========================================================================== Story Source: Materials provided by
    Stanford_University_School_of_Engineering. Original written by Nicholas
    Weiler. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Xiang Wu, Yuyan Jiang, Nicholas J. Rommelfanger, Fan Yang, Qi Zhou,
    Rongkang Yin, Junlang Liu, Sa Cai, Wei Ren, Andrew Shin, Kyrstyn
    S. Ong, Kanyi Pu, Guosong Hong. Tether-free photothermal deep-brain
    stimulation in freely behaving mice via wide-field illumination
    in the near-infrared- II window. Nature Biomedical Engineering,
    2022; DOI: 10.1038/s41551-022- 00862-w ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220322150910.htm

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