From The Quarterly, Fall 2013

Foundation Grantees and members of the Scientific Council of the Brain & Behavior Research Foundation have played a central role in a 25-year effort to prove the adult brain is highly “plastic”―that is, flexible in responding to life’s experiences, both positive and negative.



The revolutionary discovery that the adult brain can add cells and change its circuit patterns has positive implications for the treatment of depression, post-traumatic stress disorder and other anxiety and mood disorders, and potentially all psychiatric disorders. It traces back, in part, to research performed in the 1980s in The Rockefeller University laboratory of Bruce McEwen, Ph.D., now a Foundation Scientific Council member.



Discovering “Neurogenesis” – the Birth of New Neurons in the Brain

Dr. McEwen’s discovery in the late 1960s that stress hormones are active in a part of the brain called the hippocampus, important in learning and memory, led him and others toward the discovery of the adult brain’s plasticity. Among his scientific “progeny” is Elizabeth Gould, Ph.D., who at age 26 started as a postdoctoral researcher in his lab.

Dr. Gould made a breakthrough in the late 1980s. In rodents, she removed the adrenal gland, which produces hormones in response to stress, and observed the impact on the animals’ hippocampi (mammals have one hippocampus on each side of the brain). She saw evidence of cell death, which was expected. Yet when she counted cells in the small structures, the total didn’t change even after the adrenal gland was removed. Later, as she explained, “I realized the brain was making new neurons to compensate for the ones that died.”



In 1994, Dr. Gould used a NARSAD Young Investigator Grant to study the effects of stress hormones on cell birth in the adult hippocampus. She had another breakthrough in 1999, when she demonstrated that new cells in adult monkeys were being born in various cortical areas. Just a few months earlier, Fred H. Gage, Ph.D., a neuroscientist at The Salk Institute in California and a Foundation Scientific Council Member, had shown for the first time in the human brain that newly born neurons were present in the hippocampus throughout the full range of adulthood, from ages 19 to 92. Now known as a pioneer in stem-cell technologies that can generate new brain cells “on demand,” Dr. Gage made history with that 1998 discovery.  



Dr. Gould, meantime, has continued on her path of discovery. Her 2006 NARSAD Distinguished Investigator Grant has led to discoveries about how brain plasticity is affected by parenting. She is examining the impact of sex hormones on the brain in the postpartum period and the continuing impact of hormones on plasticity as parents are called upon to nurture their children. This work promises to improve the chances that children will receive the nurturing they need during the critical early years of life when the brain is more plastic and more vulnerable than at any other time in life.  

 

Promoting the Brain’s Natural Plasticity to Treat Psychiatric Illness

One major question about the plasticity of the brain concerns what the newly born cells of the adult brain actually do. Might they help the brain recover functions lost when stress or other adverse stimuli “damage” the brain?



This question has been addressed by two other NARSAD Grant-funded brain researchers: Ronald S. Duman, Ph.D., of Yale University, and René Hen, Ph.D., of Columbia University. Dr. Duman was curious about the six- to eight-week period that usually elapses before a person taking an antidepressant like Prozac® begins to feel better.  



Dr. Duman realized that stress and depression might not just kill neurons; they might also prevent neurogenesis from taking place. Perhaps Prozac® stimulated neurogenesis and this explained the drug’s therapeutic impact. And the lag? Those new neurons needed time to mature and become integrated into the circuits of the brain affected in depression.  By 2000, Dr. Duman, who had received NARSAD Young Investigator and Independent Investigator Grants to support his research, and Dr. Hen, awarded a NARSAD Independent Investigator Grant in 1998, were separately on paths that would converge on the link between antidepressant treatments and neurogenesis. When effective, Drs. Duman and Hen have found antidepressants do indeed spur neurogenesis in a part of the hippocampus called the dentate gyrus. Dr. Hen, backed in part by NARSAD Distinguished Investigator Grants in 2003 and 2009, has recently published groundbreaking papers clarifying that antidepressants won’t work unless new nerve cells are being generated in the hippocampus. He and colleagues have also shown that antidepressants recruit new neurons to improve the response to stress, an indication of how the new cells enhance brain function. 

A NARSAD Grant-funded scientist who has helped explain these beneficial effects in fine biological detail and tried to find new ways of exploiting them is Francis S. Lee, M.D., Ph.D., of Weill Cornell Medical College. Dr. Lee’s two NARSAD Young Investigator Grants, in 2002 and 2005, followed by an Independent Investigator Grant in 2010, have supported research on a growth factor called BDNF (brain-derived neurotrophic factor), which supports the birth and growth of new brain cells.

Dr. Lee’s work establishes that a common human genetic variant (called Val66Met) in the gene encoding BDNF produces a biological malfunction in the brain by generating genetically modified rodents with the human mutation. These mice tend to behave anxiously, and they resist antidepressant therapy. In recent years, Dr. Lee has figured out that the mutation impairs a form of plasticity controlled by signal transmission at NMDA-type receptors on brain cells. These receptors are critical in modulating messages sent among neurons.



Dr. Lee’s recent work on plasticity may explain changes in developmental and gender-based susceptibility to stress. BDNF and other nerve cell growth factors play very specific roles during early development, and later on, in response to sex hormone activity. Disturbances in their function may help explain differences in individual responses to stress. In 2012, he led a team that showed how the brain’s plasticity is reduced during adolescence in parts of the prefrontal cortex that act to extinguish “fear” memories. This helps explain the risk-taking so common in young people. But Dr. Lee’s new understanding of the underlying mechanisms of fear extinction also promises to help doctors improve the timing of therapies designed to help people who abnormally retain fear memories and suffer severe anxiety––for instance, those who suffer from post-traumatic stress disorder (PTSD).