Memories are made by breaking DNA – and fixing it | Hacker News Reader

Memories are made by breaking DNA – and fixing it

nature.com

210 pointsbirriel78 comments

Interestingly, although the hippocampus plays a massive role in memory consolidation, memories are ultimately distributed throughout the cortex.

I'm curious whether this mechanism generalizes to all neurons or is specific to how the hippocampus can learn quickly, especially since the hippocampus is the one place where neurogenesis has been found in adults.

What evidence is there for this distribution over the whole cortex hypothesis?

The classic study of patient H.M., who had his hippocampus removed, showed that the hippocampus isn't where memories are stored long-term https://www.ncbi.nlm.nih.gov/pmc/articles/PMC497229/ (this was one of the first studies to discover the role of the hippocampus in memory). H.M. was still able to recall memories from before the surgery, and numerous animal and human studies have demonstrated this too.

The hippocampus connects to most of the cortex, and there is an entire research area looking into hippocampal replay and how it facilitates consolidation, but there definitely isn't a singular place where memories are stored in the brain long-term.

As Michael Levin's work shows, one doesn't even need a brain or a nervous system for memory

https://www.scientificamerican.com/article/brains-are-not-re...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526749/#:~:tex....

Interesting that this involves a response similar to an immune response to a pathogen. I've read a couple articles about alternate theories of Alzheimer's linking it to an increased immune response in the brain.

> similar to an immune response to a pathogen

Maybe that is the origin? Cells learning to counter different threats and communicating that information to other cells could be a plausible first step towards intelligence.

there’s no learning involved in the immune response in the brain. the brain is limited to the innate immune system, of which TLRs and their binding to conserved domains are basically the major component. there’s no adaptive immune system that does “learning” here (and by learning in the adaptive immune system we mean recombination of antibodies, presentation of contents of each cell on the surface of the cells for antibodies to try and bind to, and the preservation of cells that carry antibodies that bound to something successfully as memory cells to enable long term immunity)

This does not seem right. From what I recall, there is some sort of memory for the immune system.

you should reread what I wrote

How does that work in visual memory, does it break and fix it too and that quickly? I have strong visual memory that I remember back in school I used to remember the page and it’s page number just by looking at it for few seconds, and if I saw a face for a second even randomly anywhere, I can recall when and where for a long period after.. I find it hard to imagine or rather scary all that is breaking/fixing the dna..

My guess would be that it’s not all happening at once as you have short and long term memory.

The simplest analogy is that your short term memory is a buffer that doesn’t use DNA, but a limited electro chemical storage of new present-moment information.

Then it is transcribed through several steps of ever longer term storage methods in the brain. Some of which require sleep.

The article doesn't seem to claim that this is the only mechanism, even if the title seems to suggest so.

There is a lot of activity with DNA for long term potentiation even without this breaking/fixing stuff. Learning requires epigenetic modifications to DNA in the neuron. DNA near the synapse (not necessarily in the Soma) is altered to produce the proteins that sustain the synapse at new level.

Fascinating that the apparatus for memory between generations may also be used for memory within a generation. "Breaking" and "fixing" DNA could also be taken as a description of meiosis or mitosis. Perhaps there is some code re-use there.

Antihistamines that cross the blood brain barrier make people feel stoned or tired because histamine does something entirely different in the brain from what it does in the rest of the body.

Seems like there's a lot of code reuse in the brain. It operates almost like a different sort of biology encapsulated within an animal body.

Neuron's DNA is not passed down, it would be quite logical for evolution to use neuronal DNA for weight storage.

Many nervous system behaviours do appear to be passed through genetics - for example, the ability to breathe, the reflex to avoid pain, etc.

I suspect in the future we might find mechanisms beyond simple natural selection that allowed those mechanisms to get encoded in genetics.

I think you're talking to the wrong point. These memories aren't being encoded in germ cells, they are after the fact changes to DNA in mature neurons which have completely differentiated. I would think it's very possible at that stage of development for them to add or remove segments of DNA in order to encode new information not related to the development of the cell as long as it didn't interfere too much with parts that are actively used for the ongoing upkeep of cell activity. It would need to alter how the cell functions a little bit for the changes to modify the neuron's ability to process signals though.

I should note that studies have demonstrated that bacteria who have been modified not to be able to consume lactose will develop mutations that allow them to consume lactose again much more quickly than would be expected given the number of bacteria, the rate of random mutations and the size of the genome. It has been hypothesized that there is a cellular mechanism to control which portions of DNA are easily mutable, possibly through a combination of chromatin structure, epigenetic modification and changes to the local chemical environment via metabolism.

This mechanism might exist in a scaled up form in humans.

Isn't that what happens in antibody germinal centers?

https://en.wikipedia.org/wiki/Somatic_hypermutation

bacterial plasmids are a common form of horizontal gene flow between individuals

Could they be transferred while in the womb?

>> it would be quite logical for evolution to use neuronal DNA for weight storage.

To pass that down you'd have to replicate the connectivity of the network for the weights to be relevant right?

Related: The article doesn't say which DNA areas are broken and repaired. Nor does it say if they are modified. It seems like encoding weights in DNA would make them more robust but harder to change. If so, there should be a particular region where this is happening. Maybe there's a mapping between certain DNA areas and each synapse. That'd be really interesting.

Independent of this breaking/fixing, it's already known that DNA near the synapse (not necessarily in the neurons Soma) is modified via epigenetics to sustain the synapse at the new level.

So yes, DNA epigenetic changes near the synapse are a key part of maintaining the "weight" or strength of that particular connection. ("key part" phrase because there is a lot of complexity and they haven't nailed it all down, there could be other "key parts").

>> DNA epigenetic changes near the synapse are a key part of maintaining the "weight" or strength of that particular connection.

What do you mean by "near the synapse"? Is there DNA outside the nucleus or something? Is there DNA that maps (corresponds to) the synaptic pattern of the neuron?

Yes there is DNA outside the nucleus. The DNA near each synapse gets modified (epigenetic) based on activity in that physical area so it can produce the proper proteins to preserve the state of that synapse over the long term.

Edit: the DNA is in Synaptic Vesicles

Neurons are not on the germ line, whatever happens to their DNA is not passed down to your children.

There was another article in the recent years about neurons using RNA or DNA for storing information related to their activation patterns.

The baby is connected to the mother's placenta for months, maybe information could be transmitted then. I've never heard anything to support that idea, though!

This always seemed like one of those little biological details, like the well known example of that nerve which loops all the way down a giraffe's neck and back again in order to connect two regions only a few inches apart, that shows that nature doesn't refactor.

Because it seems like such a waste of the opportunity afforded by extended physical secueity and direct connection between mother and developing child, that some means of transferring a portion of the mother's learned knowledge, or at least some coarse grained abstraction of it, to the fetus, has never developed.

The lazy dismissal of this question is just to say, if nature needed it, it would have evolved it, but this doesn't seem to hold in every case [0]. It seems rather that there was no way for such a capability to be built out of extending existing mechanisms, with the major barrier being the absence of nerve tissue in the umbilical cord, where higher level CNS connectivity might have evolved from as a foothold

[0] and certainly doesn't account for what may happen in the future unless nature is completely done developing everything that could be developed. Nor does it incorporate the idea that human manipulation of our own biology is not itself also part of nature.

Wellcome. Sometimes it may happen that familiar stem cells cross maternal-fetal barrier in placenta, persist somehow and start to function regardless, where stem cells are needed - usually in younger sibling coming from the older, in place of original cells, even in the brain - forming part of it as of another person (more or less) - interconnected but not the same..

The Most Mysterious Cells in Our Bodies Don't Belong to Us https://www.theatlantic.com/science/archive/2024/01/fetal-ma... ( https://news.ycombinator.com/item?id=38861497 )

In addition, most parts of the first cell of what will become a baby, come from the mother. This includes all DNA in mitochondria and another organelle that I don't remember the name.

epigenetic inheritance is real

I wonder if that means that each neuron could act as a mini turning machine

Check out Michael Levin's work, who's done some experiments with skin cell and has shown that they learn to do stuff.

stop wondering and look deeper, youve bumped into the begining of an incredible journey. even individual protiens, exhibit rule paring.

My equivocation was to avoid downvote brigades that hit me last time I posited this same idea on HN.

so, my body is refactoring all the time? Cool 8)

so, my body is refactoring all the time?

Although I have nothing substantial to contribute to the topic, I can't help but notice the beautiful mess of the neural field shown in the image; a reminder of the complexity of the real world and the challenges that still remain. Very far from our organized models arranged in layers of 'objects' and the didactic diagrams containing two neurons, or even convolutional network diagrams. Which brings to mind the good Professor “it must be made as simple as possible, but not simpler”.

Interesting. I think TLR-9 stands for toll-like receptor 9. And these toll proteins were originally studied in fruit fly dorsal ventral patterning and also play a role in the innate immune system which we share with insects.

If this study is right (who knows if it will end up being reproducible), then this would be a great example of how evolution recycles existing proteins to "invent" new stuff.

Toll proteins were probably originally involved in body pattern formation, were recycled into a role in innate immunity, and finally in mammals may also play a role in triggering an immune response based DNA damage repair event that plays a role in memory formation.

Or a innate signal recognition of anything that is worth remembering (sensory stimuli, internal stimuli, etc)

https://www.nature.com/articles/s41586-024-07220-7

I found one of the most interesting aspects of memory to be its non-locality. There were a lot of experiments in the 20th century (lesions etc.) showing that memory is fundamentally non-local. You could remove large parts of brains and the memories were still there. This is difficult to explain with "local" / neural-network-like theories of memory. If you lesion specific parts of GPT4, the "memory trace" will be gone.

I find this incredibly interesting. Is this still the primary view?

The hippocampus is involved in formation of new memories. Without it this process is not working at all.

You can build that into a neural net by training with dropout, but I don't know if it's still fashionable.

Every neuron in the brain has unique DNA and ancestorship - ongoing record of neuronal life history.

https://www.science.org/doi/10.1126/science.aab1785 (2015) : Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.

https://www.scientificamerican.com/article/scientists-surpri...

Dumb question from a very last biology person. I thought memories were stored in the brain and The brain retrieved them. How does the brain get the data from the DNA for long term memories?

The article seeks like a simple explanation, but it still doesn’t make sense to me.

Like most cells, brain cells have DNA. I don't think this is saying that the memory is directly encoded in the DNA, but that when a memory is formed (in this case a fear response), that can lead to breaks in neuronal DNA, and loose DNA in cells triggers the immune system, which then tries to repair the damage.

And the repairing of this broken DNA by the immune system somehow strengthens the encoding of the memory? But the DNA itself doesn’t actually capture any of the memory. Is that accurate?

> And the repairing of this broken DNA by the immune system somehow strengthens the encoding of the memory?

"In other words, during damage-and-repair cycles, neurons might encode information about the memory-formation event that triggered the DNA breaks, she says."

I'd say the researchers speculate something like what you said. The inflammatory response and the activities involved in DNA repair seem correlated with long term memory formation.

so far its a correlate, not yet determined to be a direct mechanistic causation

interesting. Brings to mind this study:

https://sheldrake.org/files/pdfs/papers/An-experimental-test...

Memory and DNA are both weird. As an appreciator of weirdness it's fun to see that there's some kind of connection between the two. Anyone know if there a theory of weirdness where it would compound?

Huh, I wonder if this is why RCCX genes associated with autoimmune conditions / inflammation is also associated with higher IQs.

The OP observation is that memory formation includes damaging DNA and repairing it , either as a side effect or as a mechanisms of memory formation, but it's unclear which.

Generalized autoimmune disorders probably wouldn't increase memory formation as a mechanism -- that effect would be "memorizing" "white noise", not a specific meaningful memory (neuron path).

But perhaps high IQ individuals, associated with hyperactivity/high metabolism of some kind, have more/faster neuronal activity, cause more of this DNA damage then the average person experiences, to the point where it has detrimental inflammatory effects?

I have multiple TNXB SNPs, tested very high IQ, and have debilitating levels of inflammation with ME/CFS. Wasn’t so bad when I was younger but got really bad in my 20s and 30s. I have it under control now with quite an exotic mix of medications.

My memory is pretty insanely good as is my ability to learn new things. I had previously thought it was due to interest and acumen but have come to accept that I am fortunate in ways that others are not - the difference being that I no longer blame others inability to learn as much or as quickly on an apparent laziness or lack of interest.

ME/CFS is very debilitating though so most people with this will probably just fade away in their 20s and 30s. There are ways to treat it that I wish more people knew about.

Edit; I should mention that too much inflammation is associated with brain fog which inhibits working memory and memory formation. Brain fog is one of the many core symptoms of ME/CFE.

It would make sense if the body is optimizing childhood learning over long term health.

What approaches are there for treating ME/CFS?

It depends on the cause but for the TNXB subset which is probably a big chunk of them there is hGH peptides, Testosterone replacement therapy (TRT), low dose modafinil, amitriptyline, IGF-agonists (semaglutide/ozempic), low dose naltrexone (LDN), TUDCA, eliminate sugar (including fruit) from diet, melatonin, UV-A light therapy in eyes during the day, blue light blocking glasses at night, sleep hygiene, lower stress lifestyle, supplemental T3 hormone, caffeine, and resistance exercise. Cardio above a fast walk should probably be eliminated due to post exertional malaise (PEM). The cause of PEM is a tough one that I’m still working on.

For PEM specifically have you had any experience with pyridostigmine or cumin (the kitchen spice)?

I’ve tried Enalapril which seems similar to Pyridostigmine, I ended up with pretty strong blood pressure swings. I’ll check it out though. The problem with testing PEM for me is the extreme downside if the test fails, it could be many months before I’m good again. Instead of trying these things myself I’m more apt to crowd source from people who I know that also have PEM and more open to testing it.

That's something we can use to interpret what is mentioned in "The Talent Code" book: https://www.amazon.com/Talent-Code-Greatness-Born-Grown/dp/0...

Prior research by the same lab in 2015:

https://www.eurekalert.org/news-releases/610899

What might this news imply about NSAIDS and their impact on forming memories?

> Participants using aspirin at baseline but not 5 years prior were more likely to develop cognitive impairment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670291/

Many related articles

Uh oh.. my doctors never told me this. That explains the last 10 years x.x

I immediately thought of that too. But also other influences on these reactions might be interesting to look at. From stress levels to metabolic issues including unbalanced supply with nutrients, infections, injuries. How do you remember your last exhausting argument or traumatic experience...

Not sure about the actual mechanisms, but the idea of these kind of influences on individual memory formation is intriguing.

After all, it's hacker news :)

If it's not already known it opens an intriguing avenue for research.

Shit, what does this mean for alcohol, and its ability to interfere with forming memories? We think we know why (alcohol affects glutamate which affects memory), but with this new information, does that change things?

I was thinking recently about this thing I've encountered as a recovering alcoholic. I'm pretty sure I have a "drunk memories" brain and a "sober memories" brain - and I don't know I can access some of each while I'm in the other, that is to say sober memories when I'm drunk and drunk memories when I'm sober. I'd like to test this more, but I'm not willing to break my sobriety, so who knows if it's imagined or real.

> Research shows that individuals are less likely to remember information learned while intoxicated when they are once again sober. However, information learned or memories created while intoxicated are most effectively retrieved when the individual is in a similar state of intoxication.

https://en.wikipedia.org/wiki/State-dependent_memory

>> I'm pretty sure I have a "drunk memories" brain and a "sober memories" brain

A pet hypothesis of mine is that maybe some of the brain chemicals act like an extra input to the neural network, and can be associated with various behaviors or memories. Lets say there are 5 of them which would create a 5 dimensional "chemical space" you're operating in. Certain things can be remembered and associated with regions in this space. Being anxious, depressed, afraid, or whatever could be temporarily "cured" by shifting you out of the current region in this space. Which chemicals work would depend on your specific programming. This might explain people who have a fear response to positive emotional situations (they were traumatized by someone that otherwise gave them positive emotions that release certain chemicals). Just a weird hypothesis - I bet it's been researched but I haven't looked.

Edit: One of the other responses to the parent post provided this:

https://en.wikipedia.org/wiki/State-dependent_memory

damn assassin's creed got it right?

I am surprised no one has referenced the Animus here.

While I see the association, there's no reason to think that DNA from a billions of nerve cells in your brain is somehow being synced to specific single cells. (Haploid cells that are missing half the usual load of DNA, to boot.)

Terrence McKenna called it.

Please elaborate.

There was at least one talk where he clearly speculated that, spirituality aside, he thinks DNA plays a role in long term memory formation just because that's physiologically the only place memories could persist. Unfortunately the only record of this I knew about has been deleted from youtube.

Terrence talked a lot about everything as code, and DNA being that code, or part of that code anyway. He's talked about it a lot in different ways, so I'm not sure what talk OP is specifically referring to. He gave a couple of talks that are related to I Ching, it might be in detail in one of those.

https://www.youtube.com/watch?v=Zk8GsaRA6aY

Does this mean education is carcinogenic?

Reply on news.ycombinator.com