If youngsters told their elders to be quiet, stress levels would surely rise. But, when it comes to brain cells, it seems the opposite is true—silencing of old neurons by young ones appears to make an animal more stress resilient. A report today (June 27) in Nature shows that mice whose production of new hippocampal neurons was ramped up suffered less anxiety in a stressful social situation than their control counterparts, and this was thanks to an increased inhibition of mature hippocampal cells.
“It’s a very elegant paper showing how adult neurogenesis protects against chronic stress,” says neuroscientist Sandrine Thuret of King’s College London in the U.K. who was not involved in the research. It was known that the birth of new neurons in the hippocampus could prevent stress, “but we didn’t really know how,” she explains. “[The authors] show that the new neurons modulate the activity of mature neurons and that this has a behavioral effect.”
With more adult born neurons . . . the mice are resilient to the effects of stress.—Christoph Anacker, Columbia University
In the adult brains of most mammals, neurogenesis occurs in two regions: the dentate gyrus of the hippocampus—an area implicated in memory formation, exploration, stress, and depression—and the striatum—implicated in, among other things, reward and reinforcement. While humans appear to have little if any striatal neurogenesis, evidence suggests they continue to produce new neurons in the dentate gyrus throughout life, though there has been some recent debate regarding this.
In rodents, both antidepressants and exercise (which alleviates stress) increase neurogenesis, while, in turn, the production of new neurons itself can diminish anxiety-like behavior. “But what we didn’t know is how these adult-born neurons actually affect the function of the hippocampus to mediate these effects on behavior,” says behavioral neuroscientist Christoph Anacker of Columbia University in New York who led the research.
Anacker’s team performed genetic manipulations to create mice that either had decreased activity of adult-born neurons in the dentate gyrus or increased numbers (and thus activity) of these cells. The team then exposed each mouse to a stressful situation—repeatedly caging it with an aggressive mouse for short periods—and observed its behavior in a subsequent social interaction with a nonaggressive mouse. The animals with reduced neurogenesis avoided their new cage partners, while the mice with increased neurogenesis had social interactions with the new mouse akin to those displayed by unstressed control animals.
“So, if we silence activity of adult-born neurons, the mice become anxious more quickly,” says Anacker, but “with more adult born neurons . . . the mice are resilient to the effects of stress.”
Using a combination of immunohistochemistry, electrophysiological recordings from brain slices, and calcium imaging in live mice, the team then examined the activity of mature neurons in the animals’ dentate gyri. The investigators found evidence of greater neuronal activity in the mice with fewer new neurons, and reduced neuronal activity in the mice with more new neurons, thus indicating that the young cells were somehow suppressing the activity of established neurons.
Lastly, the group genetically engineered mice to enable either direct chemical stimulation or inhibition of the mature neurons without altering neurogenesis. These experiments confirmed that increased activity of mature dentate gyrus cells produced mice prone to social anxiety, while reduced activity created stress-resilient animals.
Altogether, the work by Anacker and colleagues was “technically, a tour de force,” says Thuret.
In humans, stress and anxiety disorders are extremely common, with an estimated 5 to 30 percent of people being affected at some point in their lives. Antidepressants are the standard treatment, but, “50 percent of patients do not respond,” says depression specialist and neuroscientist Catherine Belzung of the University of Tours in France who was not involved in the research. In short, “we need to find other targets,” she says.
By figuring out the mechanism of neurogenesis-induced stress resilience, Anacker’s papers may help identify such targets, she adds. “Now we know that the effect of the newborn neuron is to act on the mature neurons in the same network, then we can [find drugs that] act directly on the mature neuron . . . for therapeutic action.”
C. Anacker et al., “Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus,” Nature, doi:10.1038/s41586-018-0262-4, 2018.