Nestled deep within a brain region that processes memory is a sliver of tissue that continually sprouts brand-new neurons, at least into late adulthood. A study in mice now provides the first glimpse at how these newborn neurons behave in animals as they learn, and hints at the purpose of the new arrivals: to keep closely-related but separate memories distinct.
A number of previous studies have suggested that the birth of new neurons is key to memory formation. In particular, scientists believe the new cell production—known as neurogenesis—plays a role in pattern separation, the ability to discriminate between similar experiences, events, or contexts based on sensory cues such as a certain smell or visual landmark. Pattern separation helps us use cues such as the presence of a particular tree or cars nearby, for example, to distinguish which parking space we chose today, as opposed to yesterday or the day before. This ability appears to be particularly diminished in people with anxiety and mood disorders.
Scientists can produce deficits in pattern separation in animals by blocking neurogenesis, using x-ray radiation to kill targeted populations of cells in the dentate gyrus. Because such studies have not established the precise identity of which cells are being recorded from, however, no one has been able to address the “burning question” in the field: "how young, adult-born neurons and mature dentate granule neurons differ in their activity," says Amar Sahay, a neuroscientist at the Massachusetts General Hospital and Harvard Medical School.
The new study is the first to directly address that problem, says Sahay, who was not involved in the work. Researchers at Columbia University used mice that had been genetically engineered to express florescent molecules in neurons up to 6 weeks old. Then, they blocked the activity of just the young cells using optogenetics—a tool that allows scientists to effectively switch cells on and off with light. When they did so, the mice lost the ability to tell the difference between a chamber where they’d received a mild foot shock, and a subtly different chamber where they had never been zapped: They froze in fear when placed in either chamber, while control animals only froze in the room where they’d been shocked. This confirms earlier work that linked pattern separation to neurogenesis, Sahay says.
A second, more novel experiment was “particularly exciting” to the team, however, says Attila Losonczy, a neuroscientist also at Columbia and co-author to the study. In this set-up, mice ran on a treadmill receiving sips of water as a reward, while different sounds, scents, visual cues, and textures of the treadmill belt simulated two similar but not identical environments. As the mice traveled through the virtual contexts, the researchers peered into their brains, using a special type of microscope that can excite and image fluorescent molecules deep within tissues. Young neurons had been engineered to express a red fluorescent protein to distinguish them from older cells. Meanwhile, both young and mature cells expressed a green fluorescent protein that glowed in response to changes in the concentration of calcium ions, a proxy for neuronal firing. “To actually watch these cells, look at their activity, and compare it with their mature counterparts had not been done before—not even attempted,” Losonczy says.
Some models of neurogenesis in memory predicted that the young neurons would be the main carriers of information about new experiences, events, or environments, Losonczy says. Instead, the team observed a very different pattern: Mature cells’ firing was fine-tuned to a specific location, whereas young neurons fired somewhat indiscriminately, presumably settling into more precise and stereotypical firing patterns as they got older, the team reports today in Neuron. The fact that young cells are more excitable could mean they are better at encoding new stimuli than their more mature peers, Losonczy explains.
The finding that mature cells are more sensitive than young adult-born cells to specific locations “is not that surprising” because it fits well with a different model of neurogenesis’s role in memory, Sahay says. That model holds that the job of the young neurons is not merely to carry new information about the spatial location or environmental context in which experiences occur, but could perhaps also temper the activity of older cells responding to that information. Keeping the firing rate of mature cells low but fine-tuned whenever an animal is placed in a new context would mean that only sparse but specific groups of cells are involved in forming any given memory. By decreasing the amount of overlap between cells encoding similar but separate memories, neurogenesis could help the brain preserve crisp distinctions between different memories, and explain why memories blur when neurogenesis is blocked or slowed due to disease, injury, or old age.
Next, Losonczy and colleagues plan to see what happens to the rest of the network when they switch off the newborn cells. “If you silence the newborn cells, the prediction would be that activity in the rest of population would go up, and the mouse’s ability to discriminate would decrease,” he says.
A growing body of research suggests that deficits in pattern separation—common in people with anxiety, depression, and posttraumatic stress disorder—may underlie difficulty in discriminating between past fearful or sad events and novel experiences. Some evidence suggests that treatments that boost neurogenesis, such as antidepressants and exercise, could help people with these conditions maintain a better separation between past and present.
*Update, 11 March, 10:50 a.m.: A previous version of this story inaccurately paraphrased Amar Sahay and provided the wrong affiliation. Both errors have been corrected.