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UNDERSTANDING NEUROGENESIS CAN LEADTO CURES OF NEUROLOGIC DISORDERS

BOSTON, MA — Connectivity. Proliferation. Differentiation. Survival. This is the lexicon of neurogenesis – the birth of new neurons in the brain and central nervous system. This growing research area holds the promise of creating, transplanting and stimulating the growth of new neurons in the human brain to cure neurological diseases and disorders such as Alzheimer disease and epilepsy.

In a symposium here at the American Association for the Advancement of Science's 168th meeting in February, neuroscientists discussed the mechanisms, history, and potential of neurogenesis. Advances in the field have increased at a meteoric rate in the past few years, boosting the potential for new therapies and drawing researchers ever closer to the holy grail of nervous system repair.

MAMMAL STUDIES

Fred Gage, PhD, Professor at the Salk Institute for Biological Studies in La Jolla, CA, began his session with the eye-opening reminder that a mere 10 years ago, it was inconceivable to most researchers that neurons in the central nervous system might actually have the potential to regenerate. Dr. Gage and colleagues studied neurogenesis in mice and rats, but encouraged by finding neurogenesis in mammals, they extended their studies to the human brain.

In a study published in 1998, the researchers labeled cells from the brains of cadavers with the nucleic acid analogue bromodeoxyuridine (BrdU). BrdU only incorporates into the newly synthesized DNA of dividing cells. The researchers found the marker in dividing progenitor cells they had isolated.

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Dr. Fred Gage said the newest research out of the Salk Institutes genetics lab focuses on the phenomenon of neurogenesis regulated by environmental influences and by behavior.

“Now we know cells can divide and give rise to neurons,” Dr. Gage said. “The concept of neurons is really much more of a dynamic concept than we thought of before.”

Even more surprising, Dr. Gage said, was the discovery of the label in both undifferentiated progenitor cells and differentiated neurons and glial cells. Once this was established, “our goal was to take these cells and reintroduce them into areas that we know neurogenesis occurs.”

SPINAL CORD STUDIES

In a study published in 2000, Dr. Gage's team studied the spinal cord of rats to determine if dividing cells migrate or operate in situ. The rats were administered a single BrdU injection and then killed one hour later. The researchers found that the distribution and incidence of BrdU labeling matched those of the four-week post-injection groups, suggesting that proliferating cells divide in situ rather than migrating from another area of the brain.

The data suggested, according to the group, “a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes.”

The newest research out of the Salk Institute's genetics lab focuses on what Dr. Gage describes as “the phenomenon of neurogenesis regulated by environmental influences, and likely, by behavior.”

In a 1999 study, Dr. Gage and his group showed that mice that exercised frequently in large cages with toys produced more brain cells than inactive mice in smaller cages. In a February 2002 study extending those findings, Dr. Gage and his team found that new cells generating in the hippocampus mature over a long period of time and give rise to functional neurons in the adult brain.

“There was neurogenesis going on in the adult brain that is generating cells that are functional and maturing over a long period of time,” he said, adding that it is uncertain if these new cells replace dying brain cells or allow the adult brain to remain adaptable. The exact application of the findings to neurodegenerative disorders such as Alzheimer or Parkinson disease has not yet been established.

Looking forward, however, Dr. Gage said his studies will focus on “endogenous cells and their ability to persist and become functional neurons.” He asked, “Can we harness the capacity to induce endogenous repair? This is one of our goals.”

SEIZURE DISORDERS

Jack Parent, MD, Assistant Professor in the Department of Neurology of University of Michigan in Ann Arbor, spoke about the role of neurogenesis in seizure disorders and other neurologic diseases.

According to Dr. Parent, neural stem cells that are seen in the forebrain subventricular zone and hippocampal dentate gyrus proliferate with various brain insults. Although epilepsy involves deleterious structural changes in the brain, “the persistence of neural stem cells in the adult brain suggests the potential for neural repair,” Dr. Parent said.

“Gliogenesis increases in various parts of the brain after injury,” he said. Cells may even migrate to various parts of the brain after seizure injury. Astrocytes may proliferate after head and brain injuries, and neuroblasts are capable of migrating to the site of injury.

“Although stem-like cells offer a potential source for replacing damaged neurons associated with brain injury or degenerative disorders, their role in normal and pathological states is poorly understood,” Dr. Parent said. He added that neurogenesis associated with brain injury may have beneficial or maladaptive outcomes.

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Dr. Ronald Duman: “Antidepressants may act, in part, by inducing neurotrophic-like effects and thereby reversing the structural changes that have occurred.”

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Dr. Jack Parent said that although epilepsy involves deleterious structural changes in the brain, “the persistence of neural stem cells in the adult brain suggests the potential for neural repair.”

In studies on neurogenesis in the dentate granule cell layer of the adult rat hippocampus, Dr. Parent and colleagues studied the mechanism in epilepsy for the remodeling of neurons, the reorganization of moss fibers, the dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus.

TEMPORAL LOBE EPILEPSY

The researchers used a model of temporal lobe epilepsy and BrdU labeling to study the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats and the role of newly differentiated dentate granule cells to network changes. They found that pilocarpine-induced status epilepticus caused a notable and enduring increase in cell proliferation in the dentate subgranular proliferative zone, which is known to contain neuronal precursor cells.

The BrdU-labeled cells differentiated into neurons in the granule cell layer and newly generated dentate granule cells appeared in ectopic locations in the hilus and inner molecular level of the dentate gyrus. Developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer.

Hippocampal seizure activity induced by perforant path stimulation resulted in an increase in subgranular zone mitotic activity similar to that seen with pilocarpine administration. The findings, according to Dr. Parent, indicate “prolonged seizure discharges stimulate dentate granule cell neurogenesis, and hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.” He concluded therefore that “the mature brain has the potential for self-repair after injury.”

PSYCHIATRIC DISORDERS

In a third presentation, Ronald S. Duman, PhD, Professor of Psychiatry and Pharmacology at Yale University School of Medicine in New Haven, CT, discussed the role of neurogenesis in depression and other psychiatric disorders.

Dr. Duman focused his talk specifically on the relevance of adult neurogenesis and neuronal remodeling to depression. The exact mechanism underlying the etiology of depression is poorly understood, he said, but depression results, in part, from a loss of neurotrophic support, leading to atrophy and loss of neurons in the brain.

“This suggests a role for structural, as well as neurochemical alterations in the etiology and treatment of depression,” Dr. Duman said. “Antidepressants may act, in part, by inducing neurotrophic-like effects and thereby reversing the structural changes that have occurred.”

The role of stress in neuronal atrophy is key in understanding depression, Dr. Duman said, as stress precipitates or exacerbates depression and other mood disorders, decreases neurogenesis of granule cells in the hippocampus, and decreases the expression of brain-derived neurotrophic factor; chronic stress can result in atrophy or death of CA3 neurons in the hippocampus. The volume of the hippocampus and subgenual prefrontal cortex, and the number of neurons and glia in the prefrontal cortex are decreased in depressed patients.

Antidepressant treatment, according to Dr. Duman, increases the number of BrdU-labeled cells in the brain and induces neurogenesis. Although approximately 60 percent of the newborn cells degenerate about two weeks after they are produced, “antidepressant treatment [with various medications] increases the survival of many BrdU-labeled cells and many are viable four weeks after antidepressant treatment,” Dr. Duman said.

“One of the really exciting aspects of the work,” according to Dr. Duman, is that, “as opposed to just observing changes in neurochemical processes in depressed patients, we now know there are morphological and structural changes that are reversible.”