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The human brain holds around 86 billion neurons, wired together in a vast web of hundreds of trillions of connections<\/a>. These connections, bridged by structures called synapses, form circuits responsible for everything we feel, perceive and do. And they constantly shift as we grow, learn, make memories and form habits.<\/p>\n Neuroscientists have long sought to hack into these circuits to understand how the brain works. Just 20 years ago they developed a technique called optogenetics<\/a>, which offered some of the first glimpses of these circuits in action\u2014it uses light to turn cells, including brain cells, on and off.<\/p>\n The work won three scientists the 2026 Nobel Prize in Physiology or Medicine<\/a>. If brain pathways were highways, optogenetics would be akin to \u201ccontrolling the volume of traffic on a road network that\u2019s already built,\u201d says Sangkyu Lee, a neurobiologist at the Institute for Basic Science in South Korea.<\/p>\n If you’re enjoying this article, consider supporting our award-winning journalism by subscribing<\/a>. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.<\/p>\n Better yet, however, would be \u201cchanging the structure of the \u2018road\u2019 itself,\u201d Lee says\u2014by actually editing the brain\u2019s connections. More recently, scientists have figured out how to add new connections and delete existing ones, and they have used these techniques to change animals\u2019 behavior and even to implant memories. Ultimately, these tools could yield discoveries about the brain and potentially even treatments for psychiatric conditions such as post-traumatic stress disorder<\/a> (PTSD), schizophrenia<\/a> and obsessive-compulsive disorder<\/a> (OCD).<\/p>\n \u201cThe idea that, by manipulating brain activity, you could, in principle, make someone happy or sad, or thirsty or hungry, is incredible when you think about the ramifications,\u201d says Don Arnold, a neurobiologist at the University of Southern California.<\/p>\n Kafui Dzirasa, a psychiatrist at Duke University, stumbled into \u201csynaptic engineering\u201d by accident. He had been trying to develop treatments for psychiatric conditions using brain-machine interfaces to alter neural activity. Electrodes would pick up activity in one brain region and cause a computer to stimulate another\u2014essentially \u201cwiring\u201d the two regions together. But as a potential treatment for mental illness, it was impractical. So Dzirasa began contemplating other ways to connect two disparate brain regions.<\/p>\n \u201cWe realized that\u2019s what a synapse does, so we thought, \u2018Why don’t we just create a synapse?\u2019\u201d he says.<\/p>\n Neurobiologists had already developed a way to do this in a creature with a very simple brain: the nematode worm Caenorhabditis elegans.<\/i><\/a> It has only around 300 neurons, making it ideal for neuroscientists to study. In 2014<\/a> Ithai Rabinowitch, a neurobiologist at the Hebrew University of Jerusalem, and his colleagues successfully altered the worms\u2019 behavior by rewiring their neural circuits.<\/p>\n The team did this by creating a kind of synapse that passes electrically charged particles between two cells through special protein channels. These proteins are made by genes that are snuck into cells\u2019 DNA using a specially programmed virus. Rabinowitch\u2019s team inserted mouse synapse proteins into the worms, which created artificial connections that didn\u2019t interfere with worms\u2019 existing synapses. The researchers were able to alter a circuit governing the worms\u2019 sense of smell, causing them to avoid an odor they previously found attractive.<\/p>\n This technique has since been used to study neural circuits involved in everything from defecation to learning<\/a>. In one striking example<\/a>, another team of researchers used it to rewire a memory. First, they trained worms to prefer a specific temperature. Then they bypassed the memory with an electrical synapse, causing the worms to move toward warmer temperatures instead. \u201cIt\u2019s like an inception experiment, where you plant a memory by making an artificial connection,\u201d says that study\u2019s senior author Daniel Col\u00f3n-Ramos, a cell biologist at the Yale School of Medicine.<\/p>\n But could this approach work in the more complex brains of mammals? As brains get bigger and more complicated, the potential for unintended connections is harder to prevent\u2014these can wreak havoc, potentially causing death. \u201cYou need to achieve much more control and precision in an animal with billions of neurons,\u201d Col\u00f3n-Ramos says.<\/p>\n In a study<\/a> published in May, Dzirasa, Col\u00f3n-Ramos and their team proved the technique could be done in a mouse. They created synapse proteins that only connected to a specially engineered partner\u2014not to each other or to synapse proteins that were already in the mouse\u2019s brain. They used the tool to connect different cell types in two brain circuits, producing changes in the mice\u2019s behavior<\/a>.<\/p>\n Some of these behavioral changes offer hints at parallels in human brains. In a study posted to the preprint server bioRxiv last March<\/a>, Dzirasa and his colleagues tested the tool in mice with a genetic mutation that caused repetitive grooming behaviors reminiscent of OCD. The researchers introduced synapses to bypass the disrupted circuit, which reduced this pathological behavior. \u201cThat\u2019s a clear demonstration of the potential power of this in thinking about human diseases,\u201d Dzirasa says.<\/p>\n Researchers have developed other<\/a> techniques<\/a> for engineering new connections, too. But some situations may call for the opposite approach: deleting existing connections. For instance, PTSD can cause otherwise innocuous sights or sounds to trigger anxiety. These reactions may stem from connections formed between sensory neurons and \u201cnegative emotion\u201d cells in the amygdala.<\/p>\n \u201cIt\u2019s tantalizing to think, if you could wipe those synapses out, maybe you\u2019d get rid of this,\u201d Arnold says.<\/p>\n So far, synapse-deleting tools are much less precise than synapse-adding ones. For example, Arnold and his colleagues discovered a technique<\/a> that degrades proteins that hold synapses together, deleting them from neurons en masse. Last year they expanded this into a toolkit<\/a> that can delete only inhibitory or only excitatory synapses (which respectively make neurons less or more likely to fire) and that can be activated with light or chemicals.<\/p>\n And in a study<\/a> in April, Lee and his colleagues described a slightly more precise synapse-deleting tool called Synthetic Trogocytosis, or SynTrogo, which works by recruiting astrocytes, a type of brain cell that prunes synapses naturally. Using special \u201clock\u201d and \u201ckey\u201d proteins to trigger pruning, Lee\u2019s team was able to delete less than a third of specific cell types\u2019 synapses in two parts of mice\u2019s hippocampus, a brain region that is crucial for memory. The remaining connections became stronger, and the mice showed better performance than unedited animals in memory tests. This finding hints at potential applications in neurodevelopmental conditions that involve abnormal connectivity, such as schizophrenia, but also those involving memory impairment, such as dementia.<\/p>\n Having techniques that can delete as well as add synapses \u201cgives much more versatility,\u201d Col\u00f3n-Ramos says. \u201cYou have a gas pedal, but now you also have brakes, so you can do much more.\u201d<\/p>\n Looking ahead, Rabinowitch envisages a day when scientists can construct designer connectomes<\/a>\u2014entire brains\u2019 worth of custom connections. \u201cYou sit by your computer and say, \u2018Let\u2019s build this brain,\u2019\u201d he says. \u201cThen it spills out the list of genes you need to introduce into the organism, and you build your synthetic connectome.\u201d Ultimately, this could produce edited animals that perform specific tasks or even artificial life, Rabinowitch says.<\/p>\n We are a long way from these techniques being used in humans. Optogenetics, the 20-year-old, Nobel Prize\u2013winning technology, has only just proven itself safe in trials of human treatments.<\/p>\n To edit human circuits, researchers will have to figure out how to safely deliver DNA across the blood-brain barrier and into neurons. Scientists are working on brain delivery systems<\/a>, but \u201cthat\u2019s a barrier nobody\u2019s really solved yet,\u201d Arnold says. And no one knows how safe these new tools are. \u201cWe\u2019re starting to test if human tissue can tolerate them,\u201d Dzirasa says.<\/p>\n And perhaps more critically, researchers need to understand human brain function better before they can usefully intervene. Synaptic engineering may be just what\u2019s needed to figure this out, however. \u201cIf you don\u2019t know how something works, you cannot fix it,\u201d Col\u00f3n-Ramos says. \u201cThese tools will lead to the knowledge we need for any aspiration of healing.\u201d<\/p>\n<\/div>\nOn supporting science journalism<\/h2>\n
Making Connections<\/b><\/h2>\n
Adding Subtraction<\/b><\/h2>\n