Study suggests ways to generate new neurons in old brains

Most neurons in the human brain last a lifetime, and for good reason. Complex, long-term information is preserved in the complex structural relationships between their synapses. Losing the neurons would mean losing this critical information, i.e. forgetting.

Interestingly, some new neurons are still produced in the adult brain by a population of cells called neural stem cells. However, as the brain ages, it becomes less and less able to make these new neurons, a trend that can have devastating neurological consequences, not only for memory, but also for degenerative brain diseases such as of Alzheimer’s and Parkinson’s and on recovery from stroke and other illnesses. brain injury.

A new study from Stanford Medicine, published October 2 in Naturesheds hopeful new light on how and why neural stem cells, the cells responsible for generating new neurons in the adult brain, become less active as the brain ages.

The research also suggests exciting new steps to combat the passivity of old neural stem cells – or even stimulate neurogenesis, the production of new neurons, in younger brains in need of repair – by targeting newly identified pathways that could reactivate stem cells.

Anne Brunet, Ph.D., professor of genetics, and her team used CRISPR platforms, molecular tools that allow scientists to precisely modify the genetic code of living cells, to conduct genome-wide research of genes that, when knocked out, increase neural stem cell activation in cultured samples from old, but not young, mice.

“We first found 300 genes with this ability, which is a lot,” emphasized Brunet, Michele and Timothy Barakett Professor. After narrowing the number of candidates down to ten, “one in particular caught our attention,” Brunet said. “It was the gene for the glucose transporter known as the GLUT4 protein, suggesting that high levels of glucose in and around old neural stem cells may be keeping these cells dormant.”

Dynamic brains

There are parts of the brain, such as the hippocampus and olfactory bulb, where many neurons have shorter lifespans, where they expire regularly and can be replaced by new ones, said Tyson Ruetz, Ph.D. , formal postdoctoral researcher. in Brunet’s laboratory and the lead author of the study Nature paper.

“In these more dynamic parts of the brain, at least in young, healthy brains,” he said, “new neurons are constantly being born and the more transient neurons are being replaced by new ones.”

Ruetz, now a scientific advisor and co-founder of ReneuBio, developed a way to test newly identified genetic pathways in vivo, “where the results really matter,” Brunet said.

Ruetz took advantage of the distance between the part of the brain where neural stem cells are activated, the subventricular zone, and where new cells proliferate and migrate, the olfactory bulb, which is several millimeters into the brain of a mouse.

By inactivating the glucose transporter genes in the first, waiting several weeks, then counting the number of new neurons in the olfactory bulb, the team demonstrated that gene inactivation actually had an activating and proliferative effect on the cells. neural stems, leading to a significant increase in the production of new neurons in living mice.

With the best intervention, they observed a twofold increase in the number of newborn neurons in aged mice.

“This allows us to observe three key functions of neural stem cells,” Ruetz said. “First, we can say that they are proliferating. Second, we can see that they are migrating to the olfactory bulb, where they are supposed to be. And third, we can see that they are forming new neurons in that site.”

The same technique could also be applied to brain injury studies, Ruetz said. “Neural stem cells from the subventricular zone also serve to repair damage to brain tissue caused by stroke or head trauma.”

“A discovery full of hope”

The connection with the glucose transporter “is a hopeful discovery,” Brunet said. On the one hand, this suggests not only the possibility of designing pharmaceutical or genetic therapies to activate the growth of new neurons in old or injured brains, but also the possibility of developing simpler behavioral interventions, such as a low-carbohydrate diet which could adjust the amount of glucose. absorbed by old neural stem cells.

The researchers discovered other provocative pathways worthy of follow-up studies. Genes linked to primary cilia, parts of certain brain cells that play a critical role in sensing and processing signals such as growth factors and neurotransmitters, are also associated with neural stem cell activation.

This finding reassured the team that their methodology was effective, in part because previous, unrelated work had already uncovered associations between cilia organization and neural stem cell function. It’s also exciting because the combination with the new leads regarding glucose transmission could pave the way for other treatment avenues that could involve both pathways, Brunet said.

“There could be an interesting interaction between primary cilia – and their ability to influence stem cell quiescence, metabolism and function – and what we discovered in terms of glucose metabolism,” she said. .

“The next step,” Brunet continued, “is to look more closely at what glucose restriction, as opposed to inactivation of genes for glucose transport, does in living animals.”