Tuesday, July 8, 2014

The Discovery of Adult Neurogenesis

If you follow me on Twitter, you probably know I study adult neurogenesis. Prior to working in a research lab I had no idea adult neurogenesis was a thing and now it is my life and I love it. Adult neurogenesis is the birth of new cells in the adult brain. It occurs in songbirds, mice, rats, cats, non-human primates, wild mice, and humans. It probably occurs in all mammals but we can't say for sure because no one has gone out and done a systematic analysis of every mammal's brain looking for new cells. The name, adult neurogenesis, implies the new cells being created are neurons. That's true, most of them are (60-80%), but some of them are actually support cells, called glia. Following is the story about the first time someone observed neurogenesis in the adult brain. 

My favorite part about science is seeing the results of an experiment and knowing that at that moment, you're the only person in the world who knows the answer to the scientific question you asked in your experiment. The ONLY person. Isn't that cool? So I can only imagine how Joseph Altman and Gopal Das felt when they saw the first evidence of adult-generated brain cells. Their experiment upset the dogma that we create brain cells only during development. Sort of. I'll get to that.

The funny thing is that in their seminal 1962 letter in Science, it doesn't even sound like the newborn neurons were the initial focus of the experiment. It was a "simultaneous pilot study" alongside an experiment to examine the kinetics of glial cell proliferation after brain injury in rats. The injury was an electrolytic lesion, which is a fancy way of saying they injected a needle into a specific brain area and applied current to destroy some of the brain tissue. It sounds odd but lesion experiments are very important in neuroscience. In this case, they lesioned the brain and wanted to see how glia responded: would they divide and travel to the lesioned area?

Molecular structure of DNA (Source)
In order to see cells that were dividing, they used a radioactive compound called H3 thymidine or "tritiated" 
thymidine. Thymidine is one of the four molecules, called nucleosides, that make up DNA. The hydrogen atoms in a normal thymidine molecule have one proton, one electron, and no neutrons. Tritiated hydrogen (H3) has one proton and two neutrons, which makes it radioactive. In this study, Altman and Das injected tritiated thymidine at the same site and with the same needle with which they performed the lesions. Then, when cells in that region broke their DNA apart during cell division they used the H3 thymidine hanging around to make the DNA in each new cell.

After the injection and lesion trauma, the rats were sacrificed after 1 day, 1 week, 2 weeks, 1 month, and 2 months. This time course was to help them determine the how glial cells act after injury: they divide and migrate. After removing the brains, they cut them into thin slices called sections and put them on slides. I won't pretend to know exactly how H3 thymidine labeling works. The slides are dipped in a photographic emulsion and then left to develop, in this case, for THIRTEEN WEEKS. For their first experiment where they found adult neurogenesis serendipitously that isn't too big of a deal but the follow-up experiments where they knew what they were waiting for... I can't imagine the suspense!

Anyway, while they were examining the brain sections for glial proliferation due to the lesion injury they noticed... some cells near the ventricles and in the hippocampus were labeled with H3 thymidine. What the what? Neurons can't divide! How freaking excited they must have been! I'll admit just imagining being in their place makes me grin. So cool!

So they published this short letter in the journal Science and... the scientific community was skeptical to say the least. People scoffed and some even tried to discredit Altman and his findings (even after a more detailed study published in 2 papers in 1965). For decades, there was little research on this phenomenon because scientists just couldn't believe it was true. Then in the 1990s the field exploded! Citations for the term "adult neurogenesis" in 1990 equaled exactly 2, according to a Pubmed search. Both of those papers were studying songbirds, which isn't directly applicable to humans because they aren't mammals (but were still very cool!). Now, there are hundreds of papers being published each year regarding adult neurogenesis and two papers have shown that it occurs in humans. It's a fun field to be in and I'm glad I stumbled into it when I chose my grad school lab.

Altman, J (1962). Are new neurons created in the adult mammalian brain? Science 135.

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