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For several years, there have been tantalizing clues of a connection between successful treatments for depression and neurogenesis — the biological process in which new nerve cells are generated. Now, thanks to an ingenious series of experiments conducted by NARSAD Independent Investigator Grigori Enikolopov, Ph.D., and colleagues, the evidence for such a connection seems virtually irrefutable.

It’s an important breakthrough with possible diagnostic and therapeutic implications for many neurological and neuropsychiatric illnesses, from depression to schizophrenia to Parkinson’s, as well as for brain cancer.

Dr. Enikolopov’s findings are a superb example of research made possible by NARSAD grants in an area considered “high-risk” when the grants were first awarded. Indeed, until about a decade ago, it was an accepted “fact” of neuroscience that adulthood marked a period of unremitting nerve-cell loss in adults, and further, that new nerve cells could not be generated in the brains of adults.

From Stem Cells to Mature Neurons

Dr. Enikolopov — a native of Russia who is affectionately called “Grisha” by colleagues and friends — is Associate Professor at Cold Spring Harbor Laboratory (CSHL) in Long Island, New York. His research has focused on the astonishing process by which stem cells in the brain and elsewhere in the body give rise to mature cells. He has concentrated on various kinds of cellular signals that regulate distinct steps in what scientists call the differentiation cascade.

As elsewhere in the body, the rise of new cells in the brain is a process that can be traced to stem cells, which, via mechanisms still not fully understood, give birth to “daughter” progenitor cells that undergo repeated division and maturation into “adult” cells.

Dr. Enikolopov’s lab generated several models to study how brain stem cells give rise to progenitors and, ultimately, to neurons. Interested in the relationship between neurogenesis and mood disorders, they used these models to determine the targets of antidepressant therapies, as well as to identify signaling pathways that control the generation of new neurons in the brain, and search for neuronal and neuroendocrine circuits involved in mood regulation.

In 2006, Dr. Enikolopov and colleagues explained how the antidepressant fluoxetine (Prozac) stimulates the creation of new nerve cells from neural progenitor cells, or NPCs, in the structure of the brain called the hippocampus that is involved in learning and memory. The fact that it is a site of adult neurogenesis has suggested that the generation of new nerve cells is related to those vital functions.

Other observations linking diminished levels of neurogenesis in the hippocampus with chronic stress, and increased levels of neurogenesis with the action of antidepressants, hinted, prior to Dr. Enikolopov’s experiments, that the hippocampus is also important in mood regulation. Such work, particularly that performed by Ronald Duman, Ph.D., of Yale University, and Rene Hen, Ph.D., of Columbia University and the New York State Psychiatric Institute — both of whom are NARSAD Distinguished Investigators and members of NARSAD’s Scientific Council — directly encouraged Dr. Enikolopov to take his own work in a new direction.

“I was switching the focus of my work,” Dr. Enikolopov recalls. “I had worked on stem cells for years, but now, excited by the results Dr. Duman and others were publishing, I became interested in showing a connection between what I knew about stem cells in the adult brain and matters pertinent to psychiatry.”

His experiments were a corroboration and extension of the work of Drs. Duman and Hen, showing a relation between stress, depression, and neurogenesis. Dr. Enikolopov, with a NARSAD grant, would show that a treatment which relieved depression — the administration of Prozac — was correlated with the activation of the very cells — NPCs — that begin the process of generating new hippocampal neurons. He later demonstrated that an even more pronounced effect on stem and progenitor cells in the brain was brought about by other depression treatments — electroconvulsive therapy (ECS) and deep-brain stimulation (DBS).

Tracking Neurogenesis in Living Subjects

If one could track levels of neurogenesis while treatment for depression was underway, it might then be possible to correlate various forms of treatment with their effectiveness in individual people. But would it be possible to develop a method to observe and measure neurogenesis in the brains of living adults?

The experimental challenge was formidable, involving “proof of concept,” first, in cell-cultures derived from animal brains; then in live animals, and only then in living human subjects. “NARSAD support was critical twice in my work, when I was moving into the connection between depression and stem cell science,” Dr. Enikolopov remembers. “I didn’t have much of a track record in this area, yet twice, NARSAD saw value in my approach and, thankfully, awarded me grants.”

In 2007, Dr. Enikolopov, together with Dr. Mirjana Maletic-Savatic of Stony Brook University and CSHL, and a multidisciplinary team from Cold Spring Harbor, Stony Brook and Brookhaven National Laboratory, announced they had identified a marker — a lipid molecule — that consistently signaled when NPCs were actively dividing. “We see this signal only in the hippocampus, not in the cortex, where adult neurogenesis has not been reported,” Dr. Enikolopov notes. The signal is significant because cell division is the hallmark of the differentiation process that takes a “daughter” progenitor all the way to maturity as a functioning neuron.

“Until now, there was no way to identify and track these cells in the live brain, to get a dynamic picture of neurogenesis,” says Dr. Enikolopov. “The technique the team developed makes use of MRI technology that is currently in widespread use. We can now use it to perform non-invasive scans of the living brain that can tell us where the stem-like NPC cells are dividing.”

Discovery of the NPC marker relied heavily upon the development of an ingenious computer algorithm devised by Dr. Petar M. Djuric of SUNY Stony Brook. That formula made the spectroscopic “image” of the NPC marker stand out amid a field filled with visual “noise,” in much the same way as algorithms used in submarine sonar equipment filter out all ambient noise save that of other submarines.

A Broad Range of Potential Applications

“Although we are only just beginning to test applications, this biomarker may have promise in showing us how neurogenesis is related to the course of depression, bipolar disorder (BPD), Parkinson’s, multiple sclerosis (MS), stroke, and post-traumatic stress disorder,” Dr. Enikolopov says.

It is not known why changes in neurogenesis would be seen in stroke, or neurological disorders like MS. But it has been speculated that it’s a sign of a damaged brain trying to repair itself. It might be useful, in Parkinson’s and MS, as in depression, schizophrenia and bipolar disorder, to know whether a given treatment is simulating neurogenesis in a patient.

Before such a course is taken, it will first be necessary, Dr. Enikolopov stresses, to perform studies revealing diminished neurogenesis in the brains of depressed people, and the reverse when the same individuals are placed on antidepressant treatment regimens. In schizophrenia and BPD, the challenge would be to find whether there is a specific correlation between neurogenesis and the onset of psychosis.

Such studies were inconceivable until the discovery of a reliable in vivo marker for neurogenesis. Hence, with their recent discoveries, Dr. Enikolopov and colleagues have opened many new paths for researchers to take in the continuing quest — backed as ever by NARSAD — to find better diagnostics and treatments for debilitating neuropsychiatric illnesses.

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