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To Master Memory, Researchers Pursue Its Roots Novel Approaches Have Reinvigorated the Search for the Elusive Memory Engram—And Energized Attempts to Control It

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To Master Memory, Researchers Pursue Its Roots Novel Approaches Have Reinvigorated the Search for the Elusive Memory Engram—And Energized Attempts to Control It NEWS FEATURE NEWS FEATURE To master memory, researchers pursue its roots Novel approaches have reinvigorated the search for the elusive memory engram—and energized attempts to control it. Helen H. Shen, Science Writer What is a memory? Can it be purposefully erased, had actually occurred (1). This work was a powerful implanted, or altered? Such musings have long cap- demonstration of the access and control that neurosci- tured the public imagination, inspiring cinematic tales entists are gaining over the once-elusive engram, the of memory manipulation, ranging from the political physical embodiment of a memory in the brain. thriller The Manchurian Candidate, to the sci-fi classic Ever since the idea was first formalized in the early Total Recall. In the quirky romance Eternal Sunshine of 1900s, researchers have struggled to capture and the Spotless Mind, memory technicians erase painful elucidate the engram. Neuroscientists theorized that recollections of failed relationships. In Inception, mem- memory would leave behind some physical imprint, a ory mercenaries slip into a businessman’s dreams to structural, electrical, or biochemical change by which surreptitiously plant an idea. networks of neurons might retain information for hours, Memory-tweaking experiments in the laboratory, months, or years. Researchers collected pieces of this although decidedly more prosaic, are nevertheless puzzle over the years, identifying molecules, genes, yielding dramatic results. In 2013, Susumu Tonegawa and cellular processes that are important for learning at the Massachusetts Institute of Technology in Cam- and memory. Since discoveries in the 1960s and 1970s, bridge, and his colleagues stimulated certain neurons many have suggested that memory is supported by in the hippocampus of mice, demonstrating that the long-term potentiation, an effect by which neurons that researchers could plant a fearful memory of being fire together are able to strengthen their connections. shocked on the foot in an environment where no shock But whereas many of the low-level mechanisms of memory attracted thorough examination, it would take a convergence of technological advances over the past decade to enable a more holistic, high-level approach to the engram. Now, for the first time, scientists are beginning to identify, label, and even control the specific networks of neurons that help hold memories. Such work is uncovering new insights into where and how memories are stored, and how they might one day be tweaked in humans to treat disorders such as dementia and addiction. “We’re energizing some very old questions about memory,” says Sheena Josselyn, a neuroscientist at the Hospital for Sick Children in Toronto, who pre- sented a lecture on the engram at last year’s Society for Neuroscience meeting in Chicago. “The purpose of the brain is to allow you to not just breathe, but to inform your future choices by recollecting your past. And this is really getting to the heart of what brains do.” Chasing the Engram Since it was first introduced, the engram concept has taken on a range of connotations from the psycho- logical to the biological. German scientist Richard Semon, who coined the term “engram” in the first decade of the 20th century, theorized that experi- ences and external stimuli created a form of memory imprint in the brain that could later be reawakened to recall the memory. Many modern biologists believe Can memory be purposefully erased, implanted, or altered? Numerous research the engram involves the neuronal circuits that hold a groups are keen to find out. Image courtesy of Dave Cutler (artist). specific memory and that can recall that memory when 11376–11379 | PNAS | October 11, 2016 | vol. 113 | no. 41 www.pnas.org/cgi/doi/10.1073/pnas.1615096113 Downloaded by guest on September 25, 2021 stimulated. In principle, the engram forms when learning activates certain neurons and induces long-lasting changes—altered gene expression or strengthened connections via long-term potentiation, for example— that encode memory information. But tracking down the critical neurons that hold this information has proven exceedingly difficult. In the early 20th century, American neuroscientist Karl Lashley famously spent 30 years trying to prove the engram’s existence. Lashley trained rats on various tasks, such as running a maze, then systematically damaged parts of the cerebral cortex looking for where the memory of the task was stored. He never pinpointed specific brain regions critical for memory, although large injuries appeared to hinder the animals’ performances. By 1950, Lashley gave up his search, concluding that memories were not stored in any cells in particular,butratherdif- fusely throughout the brain. In recent decades, however, researchers have picked up the trail again and succeeded in narrowing the search for the elusive engram. It turns out that memories are indeed distributed across the brain, but specific types or components of memory can be highly localized. (Unfortunately for Lashley, many of these regions lie outside of the cerebral cortex.) The Researchers used a mouse with a head-mounted fluorescent microscope to see hippocampus plays a key role in spatial memory, for the hippocampal cells involved in linking two memories. Image courtesy of Alcino example, and the amygdala mediates fearful memo- Silva and Denise Cai. ries, whereas the cerebellum is essential for certain types of Pavlovian conditioning (2). (a part of the hippocampus) after they fired, leaving Now, researchers have zeroed in on specific net- inactive neurons unaffected. works of neurons that appear to hold memories, or Most of the time, the mice consumed a drug that at least key components of memories. In the case of silenced this labeling mechanism. But the researchers memories involving simple Pavlovian-conditioned fear, withdrew the drug for a brief window while the animals – only about 10 30% of neurons in certain brain areas explored a cage, thus tagging active neurons with are thought to participate in the engram, according to light-sensitive proteins. Next, the scientists restored some estimates in animals (3, 4). But modern molecular the drug, turning off labeling, as they moved the an- genetic techniques have enabled scientists to begin imals to a second cage. There, electrical shocks were finding these neurons. Researchers can now activate paired repeatedly with light stimulation of the neurons engineered genes inside select cells, or in response that had encoded the experience of the first cage. to certain cellular conditions. When linked to genes When the mice were returned to the first (safe) cham- that are induced by neural activity, for example, these ber, the animals automatically froze with fear induced in fluorescent markers and other constructs enable re- the second cage. searchers to identify, control, or alter neurons involved By artificially activating neurons that encoded the in memory. first cage while delivering foot shocks in the second With optogenetics, scientists can use lights to turn cage, Tonegawa’s team had attached a false fearful on and off specific neurons, engineered to express memory to the previously neutral first cage. Plus, light-sensitive proteins, thus artificially stimulating and fear responses to the actual shock-associated cage even distorting memories in mice and other experi- appeared slightly weaker in “incepted” mice than in mental animals. Together, the data from this latest control animals, suggesting neural competition be- wave of engram research are helping scientists dig tween the real and false memories. Control experi- deeper than ever into how memories work, how ments showed that the incepted fear was specific to they fall away, and how they might be amenable to the engram-stimulated cage, and did not extend to alterations. a separate neutral cage. “Those studies were so important because they Touching Memories had a huge ‘wow’ factor,” says Alcino Silva, a neuro- To achieve memory “inception” in their 2013 study, scientist at the University of California, Los Angeles. Tonegawa’s group relied on a technique they had “They captured the imaginations of so many people.” published one year earlier, which allowed them to Others have pushed the boundaries of memory label and control neurons involved in learning (5). The manipulation by leveraging a key memory protein called group developed mice that would express a light- CREB (cyclic adenosine monophosphate response sensitive protein in neurons of the dentate gyrus element-binding protein). Research by Josselyn and Shen PNAS | October 11, 2016 | vol. 113 | no. 41 | 11377 Downloaded by guest on September 25, 2021 Built by Association Silva’s studies, for example, have revealed that memories acquired closely in time tend to share many of the same engram neurons in the hippocampus. This effect could help explain why retrieving one memory (and reactivating engram neurons) often triggers other recollections from around the same time. In a study published in June, Silva’s group found that mice that learned to fear foot shocks in one cage also displayed fear in a cage that they had explored five hours before the fear training (9). At the neural level, imaging revealed that many of the same cells that responded to the first, neutral cage also responded to the second, shock-rigged cage, as if they were already warmed up and still primed to fire. This neural overlap and memory linking disappeared, however, for experiences separated by one week. And the linkage between even closely spaced memories seemed to disappear as animals aged, a finding that could help explain certain memory lapses in aging humans, Silva says. Neural excitability plays a key role in linking memories together in time, Silva and others have found. In middle-aged animals that no longer develop fear of the cage visited five hours before fear training, Silva’s group used a chemical and specially designed virus to boost the excitability of a small number of neurons before the exposure to the first cage. The Neurons in the amygdala (in blue) were activated by recall of two different mem- ability of the mice to link the memories was restored ories (green and red signals).
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