New neurons are born in your brain every day, which we know because of…nuclear bomb testing?

Long before I started in neuroscience I’d heard that you are born with all the neurons you’ll ever have. I always found this a bit disconcerting, so was pleased when I first heard of studies showing that mammals are able to produce new neurons in adulthood. Surprisingly, the first of these studies was all the way back in 1967 by Joseph Altman, who first showed evidence of new adult neurons born in the hippocampus of guinea pigs (how cliché). The topic wasn’t picked up (or believed, I guess) by the neuroscience mainstream until the 1980s-90s though, maybe because these methods couldn’t be used (for ethical reasons) to show adult neurogenesis in humans. Another reason is that there wasn’t unequivocal proof that these neurons were new and not just being repaired. I’ll save you most of the biochemistry, but the methods involved injecting either radioactive or Brominated thymidine (the T in the A T C G of DNA) into the brain and then measuring how much of these special Ts were later incorporated into neuronal DNA. The problem with these methods is your DNA is always breaking, and instead of throwing away every cell with a DNA mutation, your body has repair mechanisms in place to fix most of these mutations. Meaning the neurons could have just been refurbished (which everyone knows doesn’t sound as good as new) with the injected special Ts.

Now, this is where the eye-catching title—and some really cool science—comes in. From 1945-1998 there have been 2,053 nuclear bomb tests worldwide. Here’s an eerie video made by Japanese artist Isao Hashimoto showing all of them in a time-lapse map (make sure the sound is on). A by-product of nuclear reactions is the breakdown product carbon-14, a carbon atom with 8 neutrons. Even though carbon-14 can occur via cosmic rays acting on nitrogen in the atmosphere, levels spiked sharply during the peak of nuclear bomb tests in the 60s (even though it’s still only 1 part per trillion of the atmosphere’s carbon). See the black line in this graph to visualize how carbon-14 amounts changed over time:

Image(from Cell http://www.cell.com/abstract/S0092-8674%2814%2900137-8)

Now, based on my intro, you might guess where this is going: can we measure how carbon-14 incorporates itself into our DNA? Indeed, since carbon-14 is mixed into all the carbon we ingest throughout our lives, if new neurons were being born, we should be able to compare how much carbon-14 is in our DNA with the carbon-14 in the atmosphere. Jonas Frisén’s lab at the Karolinska Institute in Sweden has pursued this work over the last decade, using mass spectrometry to measure carbon-14 levels in DNA amounts as small as 30 micrograms (about 15 million neurons worth).

The studies go like this: donated, post-mortem human brains are measured for the amount of carbon-14 in the neuronal DNA of different brain regions. The authors can then graph how much carbon-14 they found versus what year that person was born. For example, look at the blue dot in the graph above, which is the carbon-14 from an example person’s hippocampus. This person was born in 1928, and shows MORE carbon-14 in their brain than was in the atmosphere in 1928. If this person was born with all their neurons, they should have the same amount of carbon-14 in their neurons as was in the atmosphere at that time. Instead, this dot shows that this person’s hippocampus has excess carbon-14, which must* have come from the rise in carbon-14 from new neurons that incorporated the increasing levels of carbon-14 throughout their lifetime (again, the black line). Now, look at the pink square representing carbon-14 in a person’s cortex. This person was born in 1968, and their cortex has the same carbon-14 as the atmosphere did. Therefore this brain region DOES have the same number of neurons as they did when they were born (their first 2005 paper showed that adult neurogenesis does NOT happen in the human cortex this way). Just to make sure you get what’s going on, look at the red dot again from hippocampus. In this case, this person born in 1976 has less carbon-14 than was in the atmosphere when they were born. Therefore, some of these hippocampal neurons must have been created after they were born, when carbon-14 levels had dropped below the atmospheric level at the year of their birth.

Now you can understand the main graph of their most recent (2014) paper:

Image

(from Cell http://www.cell.com/abstract/S0092-8674%2814%2900137-8)

Again, each dot is one person. And again, people born before the extensive rise in nuclear testing in the mid-1950s show increased carbon-14, indicative that some of their neurons were new. And again, people born after the peak of nuclear testing in 1965 show less carbon-14 than was present in the atmosphere at their birth, indicative that they had new neurons born after birth.

What’s extra fascinating about this most recent result from 2014 is where they found these new adult neurons: in the human striatum. No one had ever found newly born adult striatal neurons before (in any animal)!! In most mammals (largely rodents), new adult neurons had been found in the hippocampus and olfactory (smell) bulb. Frisén’s lab confirmed human hippocampal adult neurogenesis in 2013, and had surprisingly shown that humans—unlike their mammalian ancestors—had lost the ability to make new olfactory neurons. In fact what seems to have happened is that at some point in our recent evolutionary past, as our primate ancestors lost the smelling capabilities of their predecessor mammals, the neuroblasts (kind of like baby neurons) born in the lateral ventricle migrated into the striatum instead of the olfactory bulb. This means one unique feature of the primate (or maybe even just human) brain is new neurons in this region!

Now what does this mean, exactly? What’s a striatum (pronounced str-eye-ate-um)? Well, it turns out that this is a rather complex region with a lot of functions. Historically the striatum has been associated with motor control, but has more recently been shown to be important for a number of cognitive functions such as motivation, saliency in reward and working memory. In fact, a subregion of the striatum called the nucleus accumbens is considered to be the seat of substance dependency, including all addictive drugs like alcohol and cocaine, as well as a key region in reward for food and sex. What these new neurons do at this point is only speculative, although this paper gives us a few leads. First, as shown in previous work, these new adult striatal neurons were shown to be interneurons (I’ll trust you to read these graphs by now):

Image

(from Cell http://www.cell.com/abstract/S0092-8674%2814%2900137-8)

About 75% of striatal neurons are medium spiny neurons, but it’s the other 25% that show evidence of new adult neurons: the interneurons. Interneurons are typically inhibitory, meaning their job tends to be in more of a regulatory role to temper down excitatory motor/sensory neurons. And in fact, they looked at the brains of a few people that had Huntington’s disease and found a relative decrease in these new (tempering) interneurons in their striatums (striata?). This makes some intuitive sense, as the disease is first characterized by a lack of movement control until it progresses into higher cognitive decline. Therefore these results provide an interesting new avenue for therapies in such neurodegenerative disorders such as this and Parkinson’s, both of which are largely rooted in/near the striatum, wherein rescuing adult neurogenesis has the potential to reverse symptoms (as has actually been shown in mouse models).

One other novel finding from these adult neurogenesis papers you might find interesting is they can model the turnover rate of new neurons at various ages by comparing how many new neurons there are in the brains of people that died at various ages. And, with similar numbers as their previous work in the hippocampus, they show a notable decline in the turnover rate of neurons in the striatum as a person ages:

Image

(from Cell http://www.cell.com/abstract/S0092-8674%2814%2900137-8)

At the extremes, about 10% of a 20 year-old’s striatal neurons are turned over each year, while <1% of an 80 year-old’s striatal neurons are replaced with new ones. As shown in the 3rd graph above, only some types of striatal neurons are replaced by new neurons (the interneurons), and they estimate that overall within this “renewing fraction” 2.7% of neurons are turned over per year. I don’t know about you, but I feel younger already! Thanks, brain.

In the end, these papers that unequivocally prove and expand upon our knowledge of human adult neurogenesis might be the singular good thing to come from nuclear bomb testing (at least until we have to blow up an earth-targeted asteroid). And since adult neurogenesis has become a BIG topic with tons of implications in things such as exercise, antidepressants and new learning/memory, hopefully the future improvements in our lives will provide some solace in the fact we’ve nuked our own world over 2000 times.

 

References:

Humans cortex has no adult neurogenesis (2005): http://www.cell.com/cell/abstract/S0092-8674%2805%2900408-3

Humans don’t produce new adult olfactory neurons (unlike rodents) (2012): http://www.cell.com/neuron/abstract/S0896-6273%2812%2900341-8

Dynamics of hippocampal neurogenesis in humans (2013): http://www.cell.com/cell/abstract/S0092-8674%2813%2900533-3

The first proof of striatal neurogenesis (2014): http://www.cell.com/abstract/S0092-8674%2814%2900137-8

 

*Clever readers might have picked up a problem here: what about those pesky DNA repair mechanisms? Couldn’t the carbon-14 have been integrated into old neurons by those? They rebut this possibility in their method in the most recent paper (4th reference) by saying that:

A.) only some of the neurons have altered levels of carbon-14 (while all neurons should have had some DNA repair).

B.) they’ve looked for carbon-14 in many other brain regions in the past decade and found none, as you would expect if DNA repair mechanisms account for very little carbon-14 integration. This includes in the cortex of neurons after a stroke, when massive DNA damage would have taken place.

C.) they used other biochemical markers to show evidence of neuroblasts (baby neurons) as well as a lack of pigmentation that increases with aged cells (lipofuscin) in these newly born striatal cells.

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