Q&A: What the noses of mice can tell us about the inheritance of trauma

In the final year of World War II, Nazi troops starved the Netherlands in a brutal event known as the Dutch Hunger Winter. Some 20,000 people died and millions more suffered from this man-made famine. The survivors went on to have children and even grandchildren with increased rates of metabolic issues like diabetes, hypertension, and schizophrenia.

“What does it mean to have a reflection of starvation in a grandparent in an offspring?” said Bianca Jones Marlin, a neuroscientist at the Zuckerman Institute at Columbia University. Marlin investigates how trauma and stress can be inherited from one generation to the next.

Marlin was named a 2017 STAT Wunderkind for her work studying how the hormone oxytocin affects mothers’ behavior. Now she runs her own lab exploring how parents change their brains and their bodies to promote survival in their offspring. One of her projects looks at how mice that were trained to associate an almond smell with an electric shock pass that fear association down to their children, through “epigenetic” changes that regulate the activation of genes.

She sat down with STAT to discuss what her research might tell us about the biology of generational trauma. This interview has been edited for length and clarity.

Tell me about the research you’re doing now with smell and inheritable trauma.

The beauty of being a scientist in general is that we get to answer questions we’re curious about. I started my lab asking a question in the realm of stuff I’m interested in: What does it look like for a parent to give information to an offspring, especially the parents going through a traumatic and stressful event?

I’m studying how smell changes a sensory experience. We pair smell with a stressful experience, in this case it’s a foot shock in mice. What others have shown, and we’ve been able to replicate, is that when you have odor paired with shock, the cells that smell that odor, there are more of them [subsequently formed] in the nose. That’s a big deal, because the brain is not just willy-nilly making more cells left and right and using up all its energy. It’s got a lot of stuff to do to survive, which means that it’s probably important for survival.

My group has gone on to demonstrate that when an odor [in this case almond] is paired with shock, it creates a different milieu in the body that changes the number of neurons that [respond to almond] in the nose. It says: “Oh, you were going to be a mint cell when you grow up, you should now be a cell that is responding to this paired odor. Don’t be a mint cell, don’t be a strawberry cell, be an almond cell.”

The area of the nose I’m talking about is called the main olfactory epithelium. These tissues in the nose have the first neurons that fire when you breathe in a beautiful perfume or something gross on the streets of New York City. A beauty of them is that when they’re born, they develop and then they only express one olfactory — or smell — receptor. This is the work that my postdoc advisor, Richard Axel, got the Nobel Prize for.

Developmentally it’s very committed. It knows what it’s going to be when it grows up and that’s it. It’s pretty inflexible with that. What we’re demonstrating is that there’s a level of flexibility when a stressful event takes place. Those neurons are going to say, “Oh, I was going to be this mint cell, but because of this stressful event, I’m going to switch what I was going to be.”

Not only is it changing the expression of the receptors in the nose, but also we then can take male mice that have been stressed, breed them with a female that’s never smelled the odor, and the offspring are born with the nose of the stressed parent.

What does that mean?

What does that mean to be born with the neuronal makeup of a traumatized or stressed parent? How does a message get from the nose to the testes, to the sperm, to the mother, and then maintained during development into adulthood in the next generation when the neurons in the nose are turning over every 30 days and sperm are turning over about every 30 days? There’s a message living somewhere in the body that says, “this is important enough for me to shift the forever-trajectory of the development of this brain.”

Now what does that mean in the grander scheme beyond the molecular? You have more neurons in your nose that respond to this receptor. It means you could smell this at a lower concentration. So if the smell did become dangerous in the next generation, you could smell it from further away. It could mean that you are more sensitive to it.

These are the questions that we’re answering. If there’s such a big shift — what we’re seeing is a 33% increase — in the structure of an organ in the body, we’re asking, what does this look like for the next generation? And really, what does it mean functionally?

Let’s go back to the lab. What exactly is it you’re doing with mice, smells, and shocks?

We take a mouse. The mouse lives its best life in the cage. We then put it into a separate chamber, and he has five minutes in that chamber. We [add] a smell for 10 seconds. At the end of the 10 seconds we give him a light foot shock and he jumps a little bit. He then has a minute of nothing. He’s like, “Oh, OK, I don’t like this place.” And then we give him 10 seconds of odor again and then a foot shock. By the third time he gets 10 seconds of odor, he’s like, “I’m going to get a foot shock.” So he freezes. He’s learned fear.

We do that for three days. Five times for 10 minutes every three days. Then we put him in a chamber that has the odor that he was shocked with, but no shock. And we see, did he learn that the odor predicts the shock? He usually avoids the odor, meaning he does. He’s like, “I don’t want to hang around this odor, every time I hang around this odor, I get shocked.”

We then take those animals and extract the main olfactory epithelium, that’s the tissue in the nose. … We put it in a huge microscope that images the entire thing. We get a 3D rendering of the nose and we count the cells that have the receptor, so the cells that respond to that odor. We count those in the parents and we count those in the offspring.

And what you’re finding is that the offspring have the same number of receptors or have increased receptors?

The parents that have learned the shock-pairing have more neurons that respond to that odor. So let’s say there are 10 neurons that respond to almond [odor]. The parents that were [shock-]paired, they have 18, not 10. Their kids are born with 18! Why? They’ve never smelled the odor before in their life, but yet they’re born as if they had gone through the stressor.

How do you think this message is getting from the nose of the parent to the next generation?

One of our hunches is that cells, when they fire, can release cellular information, even genetic information. … What we think is happening is that these epigenetic markers are being sent out into the environment of the body, saying “for cells in the future, quiet the mint and amplify the [almond].” We think this is happening in what’s called extracellular vesicles, the little pocketbooks that carry this genetic information. This is what the lab is exploring now: who is the messenger?

When you first saw this in the nose tissue, was it shocking?

We’re not the first to demonstrate the increase in cell number. We’re first to demonstrate why it’s happening: because new cells are being born, and as they’re being born, they’re taking in this information.

It’s as if we’re looking at intergenerational inheritance of a stressful experience on multiple levels, one of them being the nose. We have mature neurons in the nose that we think are sending a message to immature neurons, saying, “Although I may not be here when you’re developing and you’re an adult, here’s important information that I [bequeath] to you.”

In the same way, the parent is saying “I may not be here when you’re born, but I’m going to give you this information. … It’s going to be from my sperm, from my body to the next generation.” One is through distance — in the nose from mature neuron to immature neuron — and one is across time.

What does a finding like that mean to you?

When I think about it like that — that across space and across time, a message can be passed on — it shows that biology wants us to survive. I know that this work can be seen as “Whelp, if you’ve got trauma in your past, there’s no hope for you.” But I don’t see it as such. I think it means biology is smart. It’s quick. It’s fast-acting and it’s adaptive.

What can and can’t be drawn from your research to better our understanding of inheritable trauma in humans?

What we can say is that there is a morphological shift. There’s an increase in the number of cells that can respond to an odor, and that increase is also seen in the next generation. That’s what we can say. That within itself, if we think about how biology works, is astounding.

How does that affect society? It affects society by informing us that an experience in a parent can get to the next generation. But this is an incremental step in understanding what it could mean.

I really look at it that way, the [mice] have an increased cell number [in their nose]. Could this be read as anxiety in the next generation? We’re looking into that now. But really what it means is that biology did its job. So what can we change in the environment so that biology thrives? And how do we take that and mirror that back onto society?