New Brain Cells Increase Resilience to Stress

(Originally published by Columbia University Irving Medical Center)

June 28, 2018

New neurons that are formed in the adult brain increase an animal’s resilience against stress, according to a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons and may protect against the development of mental illness.

The study, conducted with mice, shows that the newly formed neurons dampen the increased activity that stress imposes in the hippocampus—an area of the brain that is sensitive to stress—and suggests that treatments targeting the hippocampus could lead to the development of effective new therapies for anxiety and depression.

The paper was published this week in Nature.

More neurons, more resilience against stress

The human brain is largely comprised of cells that are created before birth. But in a few brain regions, new neurons are continually generated throughout adulthood.

Previous studies have shown that these new neurons temper the effects of stress on neuronal activity and reduce the release of stress hormones.

“But we don’t know how these newly formed brain cells work to prevent negative reactions to stress that can lead to anxiety and depression,” says the study’s lead author, Christoph Anacker, PhD, assistant professor of neurobiology in psychiatry, who led the study with senior author René Hen, PhD, professor of pharmacology in psychiatry in the Columbia University Vagelos College of Physicians and Surgeons and a member of the Kavli Institute for Brain Science.

To answer this question, Hen’s team genetically modified mice to produce twice as many new brain cells as normal and compared them to unmodified mice. Over the next several days, both groups were exposed to larger, more aggressive mice—a situation that produces chronic social stress.

The genetically modified mice were less anxious than the normal mice and were more resilient in the face of social stress.

Mini microscopes reveal how new neurons increase resilience to stress

To see how the new neurons worked to increase resilience, Hen’s team used miniature microscopes that allowed them to see inside the hippocampus and record neuronal activity while the mice were experiencing chronic stress. Those recordings show that the hippocampus was less active in mice with more newly formed neurons.

That suggested to the researchers that reduced activity in the hippocampus was responsible for resilience to stress. And to test that idea, they used genetic engineering to directly silence the hippocampus in another group of mice.

“These animals were also more resistant to stress and less anxious—providing us with evidence that new brain cells work by dampening activity in the hippocampus,” Anacker says.

“Chronic stress is a major risk factor for the development of mental illnesses, such as depression and anxiety, and our results indicate that inhibiting the activity of the hippocampus may reduce anxiety and vulnerability to stress.”

Commenting on this work, Jeffery Lieberman, MD, chair of psychiatry at VP&S, says “the technology employed by Dr. Anacker in the Hen lab is so cool and allows researchers to see in real time the biological reactions to stress and how treatments can mitigate or prevent these.”

The researchers are now looking to identify and test drug compounds that stimulate the adult brain to create new neurons or directly reduce the activity of the hippocampus; such compounds could lead to new and potentially more effective antidepressants.

About this study

The study is titled “Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus.”

René Hen also is a professor in the Department of Neuroscience and director of the Division of Integrative Neuroscience in the Department of Psychiatry at Columbia University Vagelos College of Physicians and Surgeons.

Additional authors (all from Columbia University Irving Medical Center) are Victor M. Luna, Gregory Stevens, Amira Millette, Ryan Shores, Jessica C. Jimenez, and Briana Chen.

The study was funded by the National Institutes of Health (K99 MH108719, K01 AG054765, R37 MH068542, R01 MH083862, and R01 NS081203), the Hope for Depression Research Foundation, and the German Research Foundation.