FEATURE ARTICLE
Depression and the Birth and Death of Brain Cells
The turnover of neurons in the hippocampus might help to explain the onset of and recovery from clinical depression
Henriette van Praag, Barry Jacobs, Fred Gage
New Brain Cells
All of the cells in the body are derived from stem cells—primitive cells that are formed soon after fertilization and that can divide indefinitely. They can simply copy themselves, or they can make a variety of differentiated cells, including blood, muscle and neuron. They can also make progenitor cells, which can divide a limited number of times and give rise to cell types such as neurons and glia.
Most neurons in the mammalian brain and spinal cord are generated during the pre- and perinatal periods of development. Nevertheless, neurons continue to be born throughout life in the olfactory bulb, which processes scents, and in the dentate gyrus of the hippocampus. (Very recent evidence indicates that some additional brain areas might also produce new brain cells.) These new neurons are derived from progenitor cells that reside in the brain's subventricular zone, which lines open spaces deep in the brain called ventricles, or in a layer of the hippocampus called the subgranular zone. The existing neurons in the adult brain cannot divide. Some progenitor cells, however, remain, and they can go through cell division to produce two daughter neurons, or one glial cell or neuron and one progenitor cell capable of further division. Apparently, in most parts of the adult brain, something inhibits progenitor cells from dividing to produce new neurons. No one knows exactly why neurogenesis continues in some areas and not others. The olfactory bulb and dentate gyrus might require constant renewal in order to process and store new information, whereas other regions might need a stable population of neurons in order to maintain ongoing function. Understanding the mechanisms involved in this process could provide the opportunity for disinhibiting progenitor cells throughout the central nervous system to allow them to produce new neurons. This, of course, could have a major impact on the repair of brain regions where cells have been lost for any of a variety of reasons: disease, trauma, aging and so on.
Investigators follow neurogenesis in the laboratory by treating animals with tritiated-thymidine or bromodeoxyuridine. These compounds get incorporated into the DNA of cells preparing to divide. Once these cells begin the process of cell division, their daughter cells can be identified by examination of post-mortem brain tissue. The compound incorporated into cells can be visualized under the microscope with autoradiographic or immunologic techniques for tritiated-thymidine or bromodeoxyuridine, respectively. Investigators count the labeled cells to quantify the number of proliferating and newly born cells.
These techniques show that progenitor cells in the subgranular zone produce progeny that migrate outward to the granule-cell layer and differentiate into neurons. In this way, these new granule cells join the population of existing neurons. These newly born cells mature in the granule-cell layer and send their dendrites outward, whereas their cell processes go inward and follow paths to other structures within the hippocampus, such as the CA3 cell fields. Consequently, these new neurons get integrated in the basic circuitry of the brain.
The dentate gyrus produces 1,000–3,000 new neurons per day in rats and mice. Although this might seem like a small number, it could represent a substantial proportion of the total population over an animal's lifespan. Furthermore, these recently born neurons might serve a more important role in processing new information than those in the extant population of granule cells. So far, such data have not been collected for primates. Some investigators believe that the magnitude of neurogenesis is lower in higher mammals, but that has not been proved.
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