Turning off intergenerational trauma in mice
November 9, 2019 10:24 AM   Subscribe

A "memory of fear" of a predator's odour can be passed on to baby mice via their father's sperm. However, giving the fathers "'extinction learning,' which is very akin to cognitive behavioural therapy in humans," the transmission of that fear can be prevented. Paper (paywalled).
posted by clawsoon (12 comments total) 21 users marked this as a favorite
Piss On My Head and My Future Children Will Think It's Raining: A Guide to Intergenerational Gaslighting.
posted by srboisvert at 11:33 AM on November 9, 2019 [7 favorites]

So in other words, Lamarkian evolution.
posted by happyroach at 1:59 PM on November 9, 2019 [1 favorite]

Looks interesting! I haven't read it yet, but I know one of the middle authors, very bright guy.
posted by biogeo at 4:23 PM on November 9, 2019

I keep seeing this value-laden assumption that fear and trauma are not useful for humans, supposedly because a harmful event that happened in a person's past is not likely to happen again. But that's a nonsequitur: just because something doesn't repeat, doesn't mean the social conditions that created that event aren't fundamentally dangerous. In other words, fear may be a rational evolutionary response to a scope greater than that of the event itself. So, I would be really interested to know, who came up with this pseudo-theoretical argument in the first place, because it is has been a dominant but unexamined assumption in certain areas of psychology, and to note, strangely taken for granted as fact, just like the title of the article ("Fear and trauma are useful for animals" implying it is rather useless for modern humans).
posted by polymodus at 4:59 PM on November 9, 2019 [4 favorites]

The way the pull quote is highlighted sort of confuses me since the idea of "memory" being passed on in this manner, to me, seems even more notable than it being able to be countered. With the countering seeming more proof of it being like a learned behavior that's being passed on rather than a purely genetic "must" of instinct. This isn't remotely an area of expertise for me though, so maybe that bit was already well known, but to me it seems like something that would have far ranging possible implications if it can be extended to other behaviors, assuming the claim here is true of course.
posted by gusottertrout at 5:01 PM on November 9, 2019 [1 favorite]

Holy shit, a "memory of fear" of a predator's odour can be passed on to baby mice via their father's sperm! That is huge! How long have we known this?
posted by heatherlogan at 6:04 AM on November 10, 2019 [1 favorite]

Looks like the original study finding the inheritance effect was published in 2013/2014.
posted by clawsoon at 9:55 AM on November 10, 2019 [2 favorites]

I think this is all super cool and well done work, but there are a couple of things worth keeping in mind when thinking about it.

First, a little background on epigenetics:

It's been known for a few decades now that certain events in a person (or animal's) life, particularly stress, lead to changes in the way that genes are expressed that can be inherited by their offspring. This is epigenetic inheritance, which is often but slightly misleadingly shortened to "epigenetics." This is a little misleading because epigenetics refers more broadly to any factor other than the genetic sequence in DNA which can be inherited by a daughter cell when a parent cell divides, which has an impact on the functioning of that cell. The major significance of epigenetics is really within an individual organism, being responsible for differentiating cells into different types (e.g., to make a neuron different from a skin cell), and more subtly modulating their functions in response to environmental factors. Epigenetic inheritance at the level of organisms rather than cells provides a mechanism for the life experiences of one generation to impact the physiology of the next generation. This is sometimes compared to Lamarckian evolution, as happyroach noted, but it's not really directly comparable: the effects of epigenetic inheritance are bounded by the underlying genetic mechanisms that are being modulated, and the inherited factors are not in general stable across multiple generations.

Then, a little background on smell:
(Technically I'm talking about "olfaction" rather than "smell"; there's a subtle distinction I don't want to go into but the more common word is close enough.)

This is actually an extremely complex topic, but there are a few major points to know. First, the odor of a substance is produced by the composition of "odorant" molecules that it releases as a gas. Most things have complex odors with lots of odorants, but typically for these studies you just use a single odorant (kind of analogous to studying vision using monochromatic light). In the nose, there are specialized olfactory sensory cells, which are neurons that express olfactory receptors. An olfactory receptor is a molecule that binds with an odorant, with some specificity, causing the olfactory sensory cell to activate; each olfactory sensory cell expresses only one type of olfactory receptor. Humans have a few hundred different types of olfactory receptors; mice have more like a thousand or so. A typical odorant will interact with multiple types of olfactory receptors, and a typical olfactory receptor will interact with multiple odorants, but because of the large number of receptor types, the exact combination of receptors activated by a given odorant is more or less unique. Finally, in some cases researchers have found specific odorant molecules that interact with basically only one type of olfactory receptor, meaning the sensory neurons expressing that receptor can be specifically activated without engaging the others.

Now, the previous work on epigenetic inheritance and olfactory learning:

So a few years ago (apparently 2013; thanks, clawsoon!), Dias and Ressler discovered a new mechanism for epigenetic inheritance in mice that applies to learned associations between certain odors and fear-inducing (or stressful, or unpleasant) experiences. They put male mice through a procedure in which an odor was repeatedly paired with a small electric shock, a fairly standard fear-conditioning paradigm. In general, mice who experience this association quickly learn to expect a shock when they smell the odor, and respond by freezing in place when they smell it (a species-typical response to danger). In this case, though, they looked at the offspring of the mice who had undergone this training, and found that they also froze more upon smelling the same odor their parent had been trained on, but not other odors. In fact, even the grandchildren of the originally trained mice showed an enhanced (though weaker) response to the trained odor.

This is already pretty cool, but Dias and Ressler also looked at the neuroanatomy and epigenetics of the mice in order to better understand what was going on.

It turns out the offspring of the trained mice had a larger portion of their olfactory bulb (the part of the brain that receives input from the olfactory sensory neurons) devoted to the odorant their fathers had been trained on. Furthermore, in the sperm cells of both the trained fathers and their male offspring, there were epigenetic changes on the genes encoding the olfactory receptors that were activated by the odorant they'd been trained on. To me this is perhaps the most remarkable bit. In some sense it's not too surprising to see a change in the epigenetics associated with the olfactory receptor gene in the neurons of the olfactory epithelium or bulb, but that these changes are reflected even in the animal's germ line cells was surprising to me.

So, epigenetic changes associated with learning that an odor predicts a foot shock are heritable up to two generations in mice.

And this study:

This is a pretty straightforward follow-up of the previous study. (Conceptually straightforward, that is; technique-wise there's an awful lot of complexity packed into both of these.) Something that's already been known about these fear-conditioning paradigms is that you can get the animal to "unlearn" the association using what's called "extinction training," where you present the fear-evoking stimulus (in this case, the odor) repeatedly without the negative stimulus (in this case, the shock), and eventually the animal stops responding to it (more on this later). So a somewhat natural question to ask is, in addition to reversing the behavioral change, does this process also reverse the epigenetic change that the original fear conditioning produced? And the answer appears to be yes: animals whose fathers had undergone the extinction training did not show the same behavioral response or neurobiological changes that those whose fathers underwent fear conditioning alone. Additionally, the mice who underwent extinction training did not show the same epigenetic changes in their sperm.

So, behavioral training to reverse the behavioral response to a shock-predicting odor also reverses the epigenetic consequences of that original experience.

But, a caveat about fear conditioning:

This isn't really a criticism of the Dias & Kessler work, because the fear conditioning paradigm is extremely standard in the field. However, it's important to keep in mind exactly what is meant by "fear conditioning." The procedure is to place the mouse in a box with a wire mesh floor, then repeatedly puff in a small amount of odorant, following each puff a few moments later by a small electric shock through the wire mesh. Note that we're not talking about some hugely painful electric current: this is similar to what you get from touching a doorknob after building up static on a dry winter day. It's certainly not nice, but the mice are not experiencing something that should place them in mortal terror, like trying to escape a predator. The word "fear" evokes a complex set of emotions and reactions that the mice probably aren't experiencing, not necessarily because they're not capable of it, but because the stimulus is operationalized in a way that doesn't really map onto the full spectrum of experiences that we label with "fear."

I used to drive a car that, once it became winter, would reliably give me a static shock every time I touched the exterior chassis after driving it, roughly similar to what the mice experience in these kinds of studies. Every winter, I would "re-learn" the association between touching the car while getting out and getting an electric shock over the course of a few days. Then for the rest of winter, every time I got out of the car, I'd have a mental moment of "goddamnit here it comes OUCH stupid car now what should I eat for lunch?" This an almost exact parallel of the "fear conditioning paradigm" (except that it's more operant than Pavlovian, for the pedants), but I wouldn't necessarily say I was afraid of touching my car in winter. Now, maybe this doesn't matter, if the essential biological mechanisms at play are the same, but I don't think that's necessarily always the case. In general I take any rodent study using a well-established behavioral paradigm for studying some psychological construct with a heavy dose of salt, for this reason. Not because the paradigms are wrong, but because they're incomplete but often treated as comprehensive. Most good neuroscientists that do rodent research that I talk with seem to agree with this point, by the way: it's not because people don't understand the limitations of these kinds of behavioral paradigms, it's just because it's really hard to comprehensively study a psychological construct in an animal model, so we compromise and accept the limitations. Unfortunately this nuance sometimes gets lost, both in communicating to the public but also within the scientific community itself.

A caveat about extinction training:

The pull quote is: "'extinction learning,' which is very akin to cognitive behavioural therapy in humans". Well, sort of. More specifically, it's similar to exposure therapy, in which a person with a phobia, anxiety disorder, PTSD, etc., is repeatedly exposed to a trigger without experiencing the expected or feared negative outcomes. However, it's important to understand that fear extinction usually doesn't actually break the stimulus-outcome prediction. In animal studies, it generally takes numerous repetitions of the stimulus-outcome association before the animal learns it for the first time. Extinction training results in the animal no longer behaviorally responding to the stimulus after many exposures without the negative outcome. Generally this takes even more training than the original conditioning, and even once behavioral extinction has occurred, by exposing the animal to even a single negative outcome following the stimulus, you can often return the animal to the full "fear conditioned" state, and it will take just as long to produce extinction as before. This is in fact true of exposure therapy as well, and is one of its limitations: a single bad experience can undo months of therapy. Following extinction training (or naive exposure therapy), the negative stimulus-outcome association is still present, just sort of not "active," but still potentially there to be "reactivated." More comprehensive cognitive behavioral therapy employs strategies beyond only exposure therapy to avoid this problem, although it can still be challenging. Interestingly, there's a modification of the standard extinction training paradigm that doesn't suffer from this problem, with some really interesting theoretical reasoning behind it, but that's an absurd digression on an already ridiculous wall of text so I won't go into it.

And a caveat about the "memory of fear":

As heatherlogan points out, this quote seems like a pretty big deal. But I think it's really misleading, and might be a miscommunication or a bit of overly expressive phrasing from Brian Dias, but more probably is a bit of a literary flourish from the journalist that sounds nice but doesn't really hit the mark in terms of scientific accuracy. The thing is, it's not actually the fear response that's being encoded in the epigentics that Dias, Kessler, and their colleagues identified. In fact, they themselves noted this in their 2014 paper that clawsoon linked above. To understand this requires returning to the neurobiology of smell. As I said above, the only genes they identified that were being influenced via epigenetic inheritance were the two olfactory receptor genes they tested. But the activity patterns of these genes do not themselves have anything directly to do with fear. Furthermore, the area of the brain that they looked at was the main olfactory bulb, which primarily processes smell, not other areas that are known to be involved primarily in processing fear responses such as the amygdala. What they actually found was this:

Genes related to detecting the specific odorants used in the study were upregulated, as was the neuroanatomical volume devoted to processing these odorants, in a way that would improve sensitivity and/or specificity for sensing those odorants. However they did not report, or even really look for, evidence that the fear association with the odorant was inherited. (They did observe a small increase in freezing behavior in the offspring when exposed to the odorants their fathers had been conditioned on, but freezing in response to unfamiliar odors is normal in mice, and they found that this behavior was consistent with an increased sensitivity to the odorant. Hypothetically, the offspring should actually be faster to learn positive stimulus-outcome associations involving the odorant their fathers were trained on, too, simply because they're more attuned to it in general. They didn't do this experiment, but some of the phrasing in their studies suggests they've thought about it.)

Why does it matter that we consider that this is about fear-learning in the context of smell? Well, smell is unusual, and its genetics are unusual, and that might mean that this mechanism for epigenetic inheritance is unusual as well. In particular, being able to upregulate your and your offspring's sensitivity to a particular odor in response to environmental challenges is almost as good as being able to upregulate your and your offspring's fear response to it, particularly if the default response to an unfamiliar smell is a fearful one anyway. And since a given odorant only typically activates a small number of olfactory receptors, and each olfactory receptor is associated with exactly one gene, there's a relatively small number of genes that need to get upregulated. Furthermore, unlike many other genes in the genome, olfactory receptor genes aren't really pleiotropic, meaning they don't have effects on the phenotype other than the sense of smell. (As far as I know anyway, but in biology there are usually exceptions to everything.) So upregulating an olfactory receptor gene in your offspring is unlikely to have any negative "unintended" consequences. In other systems, where the relevant genes are highly pleiotropic, mechanisms for epigenetic inheritance may need to be much more complex to manage it all.

So in summary, I think this is cool, important, and well done research. But as in most cases, we should be cautious in making assumptions about how broadly it applies. It's possible that some features of the mechanism they've discovered are in fact very general and apply to other types of fear learning, other types of stressors, and in other types of situations. It's possible that some features of the mechanism they've discovered are highly specific to olfactory fear learning. Figuring out which it is is going to require a lot more work, but this is a great start.

There you go. Anyone who needs something to bore them to sleep tonight: you're welcome.
posted by biogeo at 2:33 PM on November 10, 2019 [68 favorites]

Thank you ever so much for the long and clear explanation biogeo! It really helps!
posted by gusottertrout at 2:44 PM on November 10, 2019 [2 favorites]

biogeo, awesome exposition, thank you.
posted by en forme de poire at 6:02 PM on November 10, 2019 [1 favorite]

Holy shit, biogeo, that's a great comment. Flagged fantastic!
posted by clawsoon at 6:36 PM on November 10, 2019 [1 favorite]

Nicely done, biogeo!
posted by Dashy at 10:36 PM on December 1, 2019 [1 favorite]

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