Posts Tagged ‘Emily Underwood’

By Emily Underwood

One of the thorniest debates in neuroscience is whether people can make new neurons after their brains stop developing in adolescence—a process known as neurogenesis. Now, a new study finds that even people long past middle age can make fresh brain cells, and that past studies that failed to spot these newcomers may have used flawed methods.

The work “provides clear, definitive evidence that neurogenesis persists throughout life,” says Paul Frankland, a neuroscientist at the Hospital for Sick Children in Toronto, Canada. “For me, this puts the issue to bed.”

Researchers have long hoped that neurogenesis could help treat brain disorders like depression and Alzheimer’s disease. But last year, a study in Nature reported that the process peters out by adolescence, contradicting previous work that had found newborn neurons in older people using a variety of methods. The finding was deflating for neuroscientists like Frankland, who studies adult neurogenesis in the rodent hippocampus, a brain region involved in learning and memory. It “raised questions about the relevance of our work,” he says.

But there may have been problems with some of this earlier research. Last year’s Nature study, for example, looked for new neurons in 59 samples of human brain tissue, some of which came from brain banks where samples are often immersed in the fixative paraformaldehyde for months or even years. Over time, paraformaldehyde forms bonds between the components that make up neurons, turning the cells into a gel, says neuroscientist María Llorens-Martín of the Severo Ochoa Molecular Biology Center in Madrid. This makes it difficult for fluorescent antibodies to bind to the doublecortin (DCX) protein, which many scientists consider the “gold standard” marker of immature neurons, she says.

The number of cells that test positive for DCX in brain tissue declines sharply after just 48 hours in a paraformaldehyde bath, Llorens-Martín and her colleagues report today in Nature Medicine. After 6 months, detecting new neurons “is almost impossible,” she says.

When the researchers used a shorter fixation time—24 hours—to preserve donated brain tissue from 13 deceased adults, ranging in age from 43 to 87, they found tens of thousands of DCX-positive cells in the dentate gyrus, a curled sliver of tissue within the hippocampus that encodes memories of events. Under a microscope, the neurons had hallmarks of youth, Llorens-Martín says: smooth and plump, with simple, undeveloped branches.

In the sample from the youngest donor, who died at 43, the team found roughly 42,000 immature neurons per square millimeter of brain tissue. From the youngest to oldest donors, the number of apparent new neurons decreased by 30%—a trend that fits with previous studies in humans showing that adult neurogenesis declines with age. The team also showed that people with Alzheimer’s disease had 30% fewer immature neurons than healthy donors of the same age, and the more advanced the dementia, the fewer such cells.

Some scientists remain skeptical, including the authors of last year’s Nature paper. “While this study contains valuable data, we did not find the evidence for ongoing production of new neurons in the adult human hippocampus convincing,” says Shawn Sorrells, a neuroscientist at the University of Pittsburgh in Pennsylvania who co-authored the 2018 paper. One critique hinges on the DCX stain, which Sorrells says isn’t an adequate measure of young neurons because the DCX protein is also expressed in mature cells. That suggests the “new” neurons the team found were actually present since childhood, he says. The new study also found no evidence of pools of stem cells that could supply fresh neurons, he notes. What’s more, Sorrells says two of the brain samples he and his colleagues looked at were only fixed for 5 hours, yet they still couldn’t find evidence of young neurons in the hippocampus.

Llorens-Martín says her team used multiple other proteins associated with neuronal development to confirm that the DCX-positive cells were actually young, and were “very strict,” in their criteria for identifying young neurons.

Heather Cameron, a neuroscientist at the National Institute of Mental Health in Bethesda, Maryland, remains persuaded by the new work. Based on the “beauty of the data” in the new study, “I think we can all move forward pretty confidently in the knowledge that what we see in animals will be applicable in humans, she says. “Will this settle the debate? I’m not sure. Should it? Yes.”


By Emily Underwood

Viewed under a microscope, your tongue is an alien landscape, studded by fringed and bumpy buds that sense five basic tastes: salty, sour, sweet, bitter, and umami. But mammalian taste buds may have an additional sixth sense—for water, a new study suggests. The finding could help explain how animals can tell water from other fluids, and it adds new fodder to a centuries-old debate: Does water have a taste of its own, or is it a mere vehicle for other flavors?

Ever since antiquity, philosophers have claimed that water has no flavor. Even Aristotle referred to it as “tasteless” around 330 B.C.E. But insects and amphibians have water-sensing nerve cells, and there is growing evidence of similar cells in mammals, says Patricia Di Lorenzo, a behavioral neuroscientist at the State University of New York in Binghamton. A few recent brain scan studies also suggest that a region of human cortex responds specifically to water, she says. Still, critics argue that any perceived flavor is just the after-effect of whatever we tasted earlier, such as the sweetness of water after we eat salty food.

“Almost nothing is known” about the molecular and cellular mechanism by which water is detected in the mouth and throat, and the neural pathway by which that signal is transmitted to the brain, says Zachary Knight, a neuroscientist at the University of California, San Francisco. In previous studies, Knight and other researchers have found distinct populations of neurons within a region of the brain called the hypothalamus that can trigger thirst and signal when an animal should start and stop drinking. But the brain must receive information about water from the mouth and tongue, because animals stop drinking long before signals from the gut or blood could tell the brain that the body has been replenished, he says.

In an attempt to settle the debate, Yuki Oka, a neuroscientist at the California Institute of Technology in Pasadena, and colleagues searched for water-sensing taste receptor cells (TRCs) in the mouse tongue. They used genetic knockout mice to look for the cells, silencing different types of TRCs, then flushing the rodents’ mouths with water to see which cells responded. “The most surprising part of the project” was that the well-known, acid-sensing, sour TRCs fired vigorously when exposed to water, Oka says. When given the option of drinking either water or a clear, tasteless, synthetic silicone oil, rodents lacking sour TRCs took longer to choose water, suggesting the cells help to distinguish water from other fluids.

Next, the team tested whether artificially activating the cells, using a technique called optogenetics, could drive the mice to drink water. They bred mice to express light-sensitive proteins in their acid-sensing TRCs, which make the cells fire in response to light from a laser. After training the mice to drink water from a spout, the team replaced the water with an optic fiber that shone blue light on their tongues. When the mice “drank” the blue light, they acted as though they were tasting water, Oka says. Some thirsty mice licked the light spout as many as 2000 times every 10 minutes, the team reports this week in Nature Neuroscience.

The rodents never learned that the light was just an illusion, but kept drinking long after mice drinking actual water would. That suggests that although signals from TRCs in the tongue can trigger drinking, they don’t play a role in telling the brain when to stop, Oka says.

More research is needed to precisely determine how the acid-sensing taste buds respond to water, and what the mice experience when they do, Oka says. But he suspects that when water washes out saliva—a salty, acidic mucus—it changes the pH within the cells, making them more likely to fire.

The notion that one of the ways animals detect water is by the removal of saliva “makes a lot of sense,” Knight says. But it is still only one of many likely routes for sensing water, including temperature and pressure, he adds.

The “well-designed, intriguing” study also speaks to a long-standing debate over the nature of taste, Di Lorenzo says. When you find a counterexample to the dominant view that there are only five basic taste groups, she says, “it tells you you need to go back to the drawing board.”