New strategy for stimulating neurogenesis may lead to drugs to improve cognition and mood

(Press-News.org) NEW YORK (April 3, 2011) – Researchers at Columbia University Medical Center have developed a new way to stimulate neuron production in the adult mouse brain, demonstrating that neurons acquired in the brain's hippocampus during adulthood improve certain cognitive functions.

In recent years, scientists have been exploring whether stimulating neurogenesis (the formation of new neurons) in the adult brain has a beneficial effect on cognition or mood. Until now, studies have relied on interventions, such as exercise and enriched environments, that affect numerous other processes in the brain in addition to increasing adult hippocampal neurogenesis.

The research, led by René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, appears in the Advance Online Publication of the journal Nature. Amar Sahay, PhD, a postdoctoral fellow, is the lead author on the study.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

"This process is crucial for learning because it enables us to know whether something is familiar or novel," said Dr. Hen. "If it is familiar, you move on to the next bit of information; if it's novel, you want to be able to recognize that it's new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts."

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. "In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what's due to neurogenesis, or what's due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it's very specific to tasks that require pattern separation," said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

"I think a good example of this is someone who has developed PTSD as a result of 9/11. For them, the simple sight of an airplane or high tower may be enough to reawaken the initial traumatic episode and bring back the full aversive memory. Sometimes these generalizations become so pervasive that people basically don't want to leave their home anymore because everything reminds them of the original event," said Dr. Hen.

The normal adaptive response, say the authors of the study, is to separate similar events or experiences. "Even though I may remember 9/11, when I see an airplane over NYC, I am able to recognize that it's a different situation and process it accordingly, while someone in the same situation with PTSD may re-experience the traumatic memory of 9/11 and have a panic attack. So this may be one reason why stimulating neurogenesis to improve pattern separation may contribute to treatment of some of these anxiety disorders," said Dr. Hen.

Enhancing pattern separation, by either the method the Columbia researchers used, or other strategies, may also be useful in treating some of the learning deficits seen in people with normal or pathological aging, such as Alzheimer's disease. In fact, there is already evidence that pattern separation declines during normal aging.

"This paper, as a consequence, may stimulate a whole area of research in humans to try to determine who in the population may have a pattern separation deficit, and whether it is restricted to the emotional domain, or is present even while performing tasks devoid of emotional salience. Once these studies are done in humans, it may be possible to treat these people with specifically targeted drugs or more personalized therapies," said Dr. Hen.

The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

"These drugs are basically doing the same thing that we did with our genetic manipulation–namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive," said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there's also a beneficial effect in humans.

"I think we're getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don't understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox," said Dr. Hen.

### Authors of the Nature study are Amar Sahay, Kimberly N. Scobie, Alexis S. Hill, Colin M. O'Carroll, Mazen A. Kheirbek, Nesha S. Burghardt, André A. Fenton, Alex Dranovsky and René Hen.

This study was supported in part by: the National Institute of Mental Health (NIMH); National Alliance for Research on Schizophrenia and Depression (NARSAD); New York Stem Cell Initiative (NYSTEM); Ruth L. Kirschstein National Research Service Awards (NRSA); and the Sackler Institute of Columbia University.

The authors of this study have reported the following financial interests: Dr. Hen is a consultant to Brain Cells, Inc., and Astra Zeneca.

Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the Nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University's College of Physicians and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States.