From The Quarterly, May 2016

Every day, new neurons are born in our brains—often in the hundreds per day, and in some people, over a thousand. This process, called neurogenesis, has long been known to be active at a much more intensive level in utero, when the brain is growing very rapidly, and was thought to cease in the first years of life.

Beginning in the 1960s, however, researchers began to explore what was then a radical idea that has since been confirmed: new neurons continue to grow in the already developed brains of adults, almost to the very end of life.

Which then raises a new set of questions. What do these new brain cells do? Is there an impact on our mental state if we don’t make enough new cells? And ultimately, what would happen in someone with a brain disorder like depression if we could increase the rate at which these new cells are born?

One pioneer in this field is René Hen, Ph.D., a Professor of Psychiatry, Neuroscience and Pharmacology at Columbia University and Director of Integrative Neuroscience at the New York State Psychiatric Institute. A member of the Foundation’s Scientific Council and three-time recipient of NARSAD Grants, Dr. Hen has been at the forefront of the effort to find out what newly born neurons do in the adult brain. In recent work, he and colleagues have sought to parlay the knowledge they have gained over the past 15 years to identify new treatments for anxiety and depression.

In a 2014 article titled “Add Neurons, Subtract Anxiety,” which appeared in Scientific American, Dr. Hen and his Columbia colleague Mazen Kheirbek, Ph.D. explained that new neurons arise in adults only in two regions of the brain, one affecting our ability to distinguish odors, and one area called the hippocampus, involved in learning, memory andemotion. It’s that latter area, the hippocampus, and specifically a thin wedge of it called the dentate gyrus (DG), where most neuroscientists have focused their attention, for that is where new hippocampal brain cells are born.

After Fred Gage, Ph.D. of the Salk Institute, (Foundation Scientific Council member), proved in 1998 that adult neurogenesis did in fact occur, Ronald Duman, Ph.D. of Yale University, (another Scientific Council member and a multiple NARSAD Grantee) two years later showed that SSRI-class antidepressants like Prozac act indirectly to increase the rate at which new neurons are born in adult brains. Did this account for Prozac’s ability to relieve depression and anxiety? What was the relation between adult neurogenesis and mood disorders? The answers are still being explored and debated.

In the early 2000s, Dr. Hen’s team looked at what happened to anxious mice treated with Prozac when adult neurogenesis was artificially blocked. In 2003, they published their findings and reported that the drug no longer worked to counteract anxiety in these mice.

While these findings were indeed intriguing, Dr. Hen points out that conditions like clinical anxiety and depression are complex; they affect multiple parts of the brain. Hence, his team’s 2003 finding did not by itself prove that when one “added” neurons, one could be assured of “subtracting” anxiety (or vice-versa). It did suggest a relationship, however.

Figuring out the exact nature of the relation between adult hippocampal neurogenesis and mood disorders has continued to be one of the chief goals of Dr. Hen’s lab over the past 12 years. In 2015, adding to a long list of research findings they have made on the subject, he and his colleagues achieved their long-sought goal of specifying (in rodents) if the survival of new neurons in the hippocampus was alone sufficient to diminish anxiety or depression symptoms.

The idea was to give adult mice a drug that boosted neurogenesis and then observe how they fared in a battery of behavioral tests, designed to induce anxiety- and depression- like behaviors. While SSRI-class antidepressants like Prozac boost neurogenesis, these drugs affect many parts of the brain and body, which makes their effects are very hard to isolate. Dr. Hen’s premise was: what if we had a method that only boosted the rate at which new brain cells in the adult hippocampus survive? Would it act like an antidepressant or anti-anxiety drug?

Mice in the experiment were genetically modified to prevent a normal process in which some newly born nerve cells wither and die before connecting to other brain cells. These mice would have especially robust neurogenesis in the hippocampus. After waiting several weeks for the new cells to “wire up” to the existing neural network, the scientists treated some of the mice with cortisol, a stress hormone.

Results of these experiments were encouraging. Dr. Hen’s team did find that increasing the number of new nerve cells in the hippocampus of adult mice was indeed sufficient to reduce anxiety- and depression-related behaviors. The most important qualification: this was true only in mice that were exposed to the stress hormone. The addition of new neurons did not change what the scientists call “baseline” anxiety or depression behavior in the animals.

In other words, while boosting neurogenesis had no impact on baseline behavior, it did protect against the negative impact of subsequent stress. Might a drug that boosts new nerve cell survival in the hippocampus therefore act as a kind of prophylactic against stress? Perhaps, but Dr. Hen reminds us that his team tested only one model of stress. Stress takes other forms which are not modeled by injecting cortisol, and more research needs to be done.

Dr. Hen and another Columbia colleague Bradley Miller, M.D., Ph.D. recently discussed a different candidate drug called P7C3 that they both believe is “exciting,” in a paper published in Current Opinion in Neurobiology. The drug acts like an antidepressant in rodents, and these effects vanish when adult hippocampal neurogenesis is blocked. If this or a similar drug is proven in future trials to be safe in people, it might serve to do what the experiments just described did: boost new nerve cell survival in the hippocampus.

Drs. Hen and Miller suggest that if such a drug makes it to human trials, it might first be tested on adults in whom neurogenesis is impaired. With this in mind they and others seek to discover a biomarker or to develop an imaging method that can readily measure levels of hippocampal neurogenesis in the living human brain—to help identify people who may benefit from therapies targeted to boost neurogenesis.