The Brain Wave: The growth of knowledge on adult neurogenesis

For a very long time, the idea that the adult mammalian brain could make new neurons was regarded as a ludicrous idea. The then-pervading dogma in the field posited that we have as many neurons in the brain as we are born with.

Although reports of adult neurogenesis, growth and development of nerve tissue, appeared as early as 1898, these early studies were ignored. Subsequent works in rats and monkeys followed by cell culture studies began to provide compelling evidence for the existence of adult neural stem cells that give rise to new neurons. However, the question then arose: Do humans also have adult neurogenic ability?

The publication of neuroscientist Peter Eriksson’s landmark study in 1998 showed that humans do indeed possess adult neurogenesis. At the time, clinicians were using bromodeoxyuridine (BrdU) to investigate tumor cell proliferation in cancer patients. Widely used in animal research, BrdU is a compound that permanently integrates into the cell’s DNA during mitotic division. By labeling BrdU with antibodies, scientists can see which cells are proliferating and trace the fate of these cells as they differentiate or turn into a more mature state; this method is known generally as lineage tracing. When neural stem cells adopt a mature phenotype, they will express specific genes.

Using post-mortem brain samples of cancer patients injected with BrdU, Eriksson showed that BrdU-incorporated cells also show expression of mature neuronal genes. This means that BrdU was incorporated into proliferating neural stem cells that then later became mature neurons in the hippocampus. Since BrdU is no longer injected into humans due to safety concerns, evidence for human adult neurogenesis relies on this single study. Although Eriksson’s work showed that adult neurogenesis happens, many other skeptical scientists argued that this process does not produce sufficient neurons to significantly influence brain function. Indeed, Eriksson never quantified the occurrence of adult neurogenesis, raising the question of whether or not enough neurogenesis takes place to impart functional significance.

Recently, works from the Jonas Frisén laboratory in Sweden utilized innovative lineage tracing approaches to address lingering questions regarding adult neurogenesis. Instead of relying on BrdU, the Frisén laboratory adopted a carbon dating approach, exploiting elevated levels of a carbon isotope released into the atmosphere from nuclear bomb tests during the Cold War. Like BrdU, this carbon isotope is also able to permanently integrate into a cell’s DNA during proliferation. By studying the incorporation of carbon isotope in the brain of individuals who lived near nuclear bomb test sites, the Frisén lab was able to provide a much-needed confirmation of human adult neurogenesis, estimating that 700 neurons are generated in the hippocampus every day.

Given that adult neurogenesis is a now a widely accepted biological phenomenon, what role does it play in brain function? In order to keep up with environmental demands, animals and humans require the ability to adapt to novel changes, and constant production of new neurons may provide for such plasticity necessary for learning and formation of new memories throughout life. When sensory information travels to the hippocampus, that input has to be separated into individual components, processed and sent back out into the cerebral cortex where that memory is actually stored. The separation of two very similar yet distinct stimuli during memory formation is called pattern separation, in which adult neurogenesis is thought to play a central role.

In addition to learning and memory, adult neurogenesis has also been implicated in mood functions. Prevention of adult neurogenesis in rodent brains has led to increased anxiety-related behavior as well as the suppression of the behavioral effects from antidepressants. These observations have led to the neurogenesis hypothesis in the development of depression, which is that decreased rates of adult neurogenesis set the stage for mood alterations and heightened anxiety.

As a whole, adult neurogenesis research has grown rapidly within the past two decades. While there remains much to be learned about how adult neurons are produced, a better understanding of adult neurogenesis should allow the powerful therapeutic opportunity to develop stem cell-based treatments against brain diseases that impart a significant burden on society and individuals.