An ancient cellular program to protect cells when oxygen is low seems crucial for the production of new brain cells.

Celeste Simon has shown that some cells need low oxygen to function well. In the brain, that finding offers clues on depression.

For more than two billion years on this planet, O₂ has been the go-to gas for generating efficient cellular energy. But life on Earth never takes oxygen for granted. “When it runs low, cells swiftly adapt,” says cell biologist Celeste Simon.

This ancient adaptive reaction, known as the low-oxygen, or hypoxia, response, typically involves a cascade of protective changes in cells: protein synthesis drops and cells switch to a less efficient process of energy production that doesn’t require oxygen. But organisms have evolved uses for the hypoxia response that are not merely protective.

Simon, an HHMI investigator at the University of Pennsylvania, recently found evidence that the response is crucial for maintaining the health of stem cells in the hippocampus, a key memory region of the brain. The discovery could alter our understanding of a host of stem cell-related brain conditions.

“It’s a seemingly puzzling finding, but the normal functioning of neural stem cells in the hippocampus does appear to require low oxygen levels and consequent hypoxia responses,” says Simon.

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The neural stem cells in question are meant to keep the population of hippocampal neurons replenished. A certain level of this replenishment, or “neurogenesis,” is increasingly thought to be important for a healthy mood and memory. Interruption of neurogenesis causes depression-like behavior in mice, while in humans antidepressant medications appear to work largely by boosting neurogenesis. Alzheimer’s disease, as well as ordinary aging, features a decline in this replenishment process.

In an October 2010 Nature Cell Biology paper, Simon and her colleagues reported that neurogenesis markedly declined in mice when their brain cells were genetically altered to knock out their ability to produce the hypoxia response. “We saw fewer stem cells, fewer of the immature daughter cells that stem cells produce, and fewer connections coming from these daughter cells,” says Simon.

Why would the hypoxia response even matter to brain cells, which are known for their voracious intake of oxygen? Simon and her team found that the usual habitat for stem cells in the mouse hippocampus is riddled with low-oxygen zones, where the signs of stem cell activity are particularly evident. “It seems that these lower-oxygen zones are essential for maintaining neural stem cells’ healthy activity,” she says. “In fact, these stem cells appear to be spread out, in and near these zones, with different activities depending on the oxygen level, suggesting that the stem cells’ activities are being regulated by the local oxygen levels.” The hypoxia response may be acting as a growth signal for the stem cells.

Photo: Nick Antony

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